Genetics and

Genomics
in Nursing and Health Care
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 Genetics and
Genomics
in Nursing and Health Care
Second Edition

Theresa A. Beery Dr.M. Unda Workman Julia A. Eggert

PhD, RN, ACNP PhD, RN, FAAN PhD,AGN-BC,AOCN, FAAN

Professor Emerita. University Author and Consultant Formerly the Mary Cox
of Cincinnati College Cincinnati, Ohio Professor and Coordinator
of Nursing of the Healthcare Genetics
Cincinnati. Ohio Doctoral Program
Clemson University School
of Nursing

ERRNVPHGLFRVRUJ
Clemson, South Carolina

• F.A. Dam Company. Philadelphia

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Library of Congress Cataloging-in-Publ.icacion Data

Names: Beery,Theresa A., author. I Workman, M. Linda, author. I Eggert, Julia, author.
Tide: Genetics and genomics in nursing and health care 1 Theresa A. Beery, M. Linda Workman, Julia A. Eggert.
Description: Second edition. I Philadelphia, PA: EA. Davis Company, [2018J I Includes bibliographical references and index.
Identifiers: LCCN 20170531131 ISBN 9780803660830 (pbk.)
Subjects: I MESH: Genetic Phenomena I Genomics I Genetic Diseases, Inborn I Genetic Techniques I Nurses' Instruction
Classification: LCC QH447 I NLM QU 500 I DOC 576.5-<1c23
LC record available at htrps:IIlccn.loc.gov/20 17053113

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Transactional Reporting Service is: 978-0-8036-6083-0/17 + S.25.
 To our genetics mentors, those scientific giants upon whose shoulders we stand to reach greater
heights. Their vision, patience, and dedicated service to others were instrumental in shaping our
genetics worldview as well as the format and content of this textbook.
Dr. D. Woodrow Benson
Dr. Mary M. Haag
Dr. Lyn Larcom
Ms. Cynthia Prows
Dr. Shirley Soukup
Dr. JosefWarkany

To our families and loved ones who made the difficult times better and the good times
great, especial":
Dennis C. Beery
John B. Workman
Douglas j. Eggert
Theresa (Terry) A. Beery received her BSN from Miami University, her MS in Nursing from Wright State
University, and her PhD in Nursing Science from the University of Cincinnati. She completed a post-master's
certificate as an acute care nurse practitioner (ACNP-BC). Her genetics training included the Summer Genetics
Institute at the National Institute for Nursing Research. In 2002 she received a career award from the National
Institutes of Health, which supported her development in molecular genetics. This enabled her to spend
3 years working in the cardiovascular genetics laboratory at Cincinnati Children's Hospital Medical Center
under the mentorship of Dr. D. Woodrow Benson. Terry is a Professor Emerita at the University of Cincinnati
(UC) College of Nursing, where she taught undergraduate and graduate genetics. She is the recipient of the
College of Nursing's Excellence in Teaching Award and is a member of the UC Academy of Fellows for Teach-
ing and Learning. Terry was the director of the Center for Educational Research, Scholarship, and Innovation
at the UC College of Nursing. She continues to reach online classes for UC from her home in New Mexico.

Dr. M. Linda Workman received her BSN from the University of Cincinnati (UC) College of Nursing.
She later earned her MSN and a PhD in Developmental Biology from the Uc. The developmental biology
education provided Linda with extensive formal education in genetics. In addition, she worked for more than
5 years in a cytogenetics laboratory, where she conducted basic genetic research on human tumors. Linda has
taught genetics to undergraduate and graduate nursing students, practicing nurses, advanced-practice nurses,
and physicians. She has been recognized nationally for her ability to present genetics/genomics and other
complex physiologic concepts in a manner that promotes student retention of the information. In addition,
she received Excellence in Teaching awards from Raymond Walters College, the University ofCincinnaci, and
Case Western Reserve University. Over the past 35 years, she has presented numerous seminars and authored
many journal articles and book chapters on the topic of genetics.

Julia A. Eggert received her BSN from the University of Kansas Department of Nursing and later her MN
from Wichita State University. Later she completed a PhD in Microbiology from Clemson University. As part
of the doctoral degree, Julie received extensive education in cancer and aging. Julia co-led the development
of a breast health center and implemented the local site for the international Breast Cancer Prevention Trial
in South Carolina. This national trial influenced the identification of the BRCA genes in women at high risk
of developing breast cancer. In 2002, Julia was invited to attend the Summer Generics Institute through the
National Institute of Nursing Research (NINR) and Georgetown University. As a result of this experience,
she worked with a team of faculty at Clemson University to develop and implement the interdisciplinary
Healthcare Genetics doctoral program in the School of Nursing. Julia has taught genetics to oncology and
genetics nurses via classroom courses, podium presentations, webinars, and online modules, including social
media, nationally and internationally. She is widely published in this area. In addition to her former academic
appointment as the Mary Cox Professor in Nursing, she manages an inherited cancer genetics clinic one day
a week as an advanced generics nurse (AGN-BC). She was recognized by a national nurse practitioner group
for being the first advanced-practice genetics nurse to develop an inherited genetics clinic in South Carolina.

vi
Genetics and Genomics in Nursing and Health Care is geared toward nurses and other health-care professionals
who are not basic science majors. This text was derived from our desire, as both nurses and educators, to create
a book that would help students identify the most important content areas for incorporating genetic informa-
tion into their practices and interactions with patients, families, and the general public. Part of making this
information accessible is the use of a second-person writing ("you") format rather than the more "scholarly"
third-person style. In addition, the authors ask questions of the reader within the presentation of content to
stimulate application and critical thinking. With the goal of clarity and understanding in mind, we developed
a unique format based on six focus areas:
1. Basic conceptsfrom molecular genetics
2. Gene expression
These first two focus areas present foundational information on the biological basis of genetic inheritance as
well as how environmental factors influence the actual risk or resistance for a developing disorder. Although
genetic terminology is used throughout this section, it is tempered with "everyday" language to help students
learn, retain, and use this conceptual information. Complex concepts are reduced to basic components and
presented in a style that makes them logical to the learner. Essential to this process is the use of clear, concise
explanations that are free from jargon and academic pretension. Information critical for individual and family
assessment of genetic risk and variation from normal is presented in a manner that enables it to be incorporated
into general assessment techniques and data management. Analogies are used to enhance learner mastery of the
content and to provide a starting point for learners to be able to share genetic information with the lay public.
Two new chapters have been added to the gene expression section: Epigenetic Influences on Gene Expression
(Chapter 5) and Sex Chromosome and Mitochondrial Inheritance and Disorders (Chapter 7). The addition
of Chapter 5 reflects the increased importance of epigenetics in the expression of genetic disorders and its
possible role in modifying genetic disease expression in the future. The authors believe that the separation
of sex chromosome disorders, which are the most common inherited aberrations, from autosomal disorders
is more than justified by the degree of societal misconception of the contributions of affected individuals.
3. Genomic health problems acrossthe Lifespan
The three chapters in this focus area explain genetic factors influencing common health problems rather than
rare syndromes. In addition to generic disorders that are idenrified in childhood, this section also discusses
those genetic disorders that may not manifest until adulthood and older adulthood. Clinical examples abound,
and case studies help personalize the information. It presents what every nurse or other health-care profes-
sional needs to know about applying generic information when caring for patients and families. These chapters
include the most recent information regarding the diagnosis and long-term management of many disorders.
4. Genomic influences on selectedcomplex health problems
The issues presented in the three chapters of this focus area include disorders that have both a strong genetic
influence coupled with strong environmental influences on disease expression. This focus area brings common
disorders to the forefront that are the result of the input of more than one gene and that may respond to
personal changes to alter the severity of the problem. In a society in which these complex disorders repre-
sent a disproportionate health-care burden, it is critical for health-care professionals to understand how the
environmental issues can be modified to have a positive effect on genetic potential. Again, clinical examples
abound, and case studies help personalize the information.

vii
viii Preface

5. Genomics and diseasemanagement

The three chapters in this focus area include thought-provoking issues regarding the benefits and risks of genetic
testing and the roles of various professionals in the genetic counseling process. Additionally, personalized health
care and "precision medicine," especially the variation in responses to drug therapy, are explored and explained.
6. Global genomic issues
The two chapters in this focus area concern the questions "How did we get here?" and "Where are we going?"
They explain the reasons why the predisposition and expression of some genetic disorders are greater for some
ethnic groups than for others. They also present issues and potential problems people are likely to face as they
rush into the genomic era of health care.
The style of presentation for the content of this textbook is direct, active, and clear. Health-care terms and
related physiological mechanisms are explained in common, everyday language to promote better student
understanding and continuous application of the content. Illustrations and tables were selected and devel-
oped to enhance student understanding of cellular activities, inheritance patterns, and genetic risks. The use
of color and new illustrations is expected to help achieve the goal of student understanding.
We have included key features in each chapter. Each chapter opens with a list of learning outcomes fol-
lowed by a list of key terms. Each key term is also presented in the chapter text and highlighted in boldface
when first used. A full alphabetical listing of key terms with definitions can be found in the glossary at the
end of the text. At the end of each chapter, there is a list of Gene Gems highlighting essential key points
for the student co take away from the reading. Students will also find self-assessment questions keyed to
the learning outcomes of the chapter. The answers for these can be found at the end of each chapter. Finally,
critical thinking case studies are located at the end of every clinical chapter. These realistic cases present issues
and problems that require clinical decision making about individual patients and families that are at increased
genetic risk for health problems.
Additional materials and study cools can be found on DavisPlus, including activities for critical thinking
and learning key terms, links to online genetics resources, and extensive teaching resources for instructors.
Janet Adams, MSN, RT (ARRT), RN Elizabeth Louise Pestka, MS, RN,
Instructor PMHCNS-BC, APNG
Southeast Missouri State University Assistant Professor of Nursing & Clinical Nurse
Cape Girardeau, Missouri Specialist
Mayo Clinic
Julie Baldwin, RN, MSN Rochester, Minnesota
Assistant Professor of Nursing
Missouri Western State University Michael A. Rackover, PA-C, MS
St. Joseph, Missouri PA Program Director & Associate Professor
Philadelphia University
Laurie Brooks, MSN, MBA, RN Philadelphia, Pennsylvania
Assistant Professor
Saint Luke's College of Health Sciences Catherine Read, PhD, RN
Kansas City, Missouri Associate Dean/Associate Professor
Connell School of Nursing, Boston College
Deborah Ellis, RN, MSN, NP-C Chestnut Hill, Massachusetts
Assistant Professor
Missouri Western State University Jackie Shrock, RN, BSN, MEd
St. Joseph, Missouri Nursing Program Coordinator/Teacher
Wayne County Schools Career Center
Kathleen T. Hickey, EdD, FNP-BC, ANP-BC Orrville, Ohio
Assistant Professor of Nursing
Columbia University Yona D. Victor, MD
New York, New York Full-Time Faculty
The School of Nursing at Platt College
Anita H. King, DNp, MA, FNP-BC, CDE, FAADE Aurora, Colorado
Clinical Associate Professor, College of Nursing
University of South Alabama Lottchen Wider, RN, PhD
Fairhope, Alabama Associate Professor
Maryville University
Judith A. Lewis, PhD, RN, WNP-BC, FAAN S(. Louis, Missouri
Professor Emerita
Virginia Commonwealth University
Richmond, Virginia

Carrie J. Merkle, PhD, RN, FAAN

Associate Professor
University of Arizona College of Nursing
Tucson, Arizona

ix
Many talented people are needed to make any textbook a success. The authors wish to acknowledge the fol-
lowing individuals for their guidance, dedication, hard work, constructive criticism, and creative input that
were so important to this project: Kelly Horvath, Amy Romano, and Susan Rhymer.

x
 abla.ot.C
UNIT I Basic Concepts From Chapter 5 Epigenetic Influences
Molecular Genetics 1 on Gene Expression 96
Introduction 96
Chapter 1 DNA Structure and Function 2
Microbiome 100
Introduction 3
Epigenetics and Cancer 101
Genetic Biology 3
Nature and Nurture Working
DNA 5
Together 103
Chapter 2 Protein Synthesis 23 The Future of Epigenetics:
Introduction 24 Are There Clinical
Transcription 26 Applications? 105
Translation 30 Chapter 6 Autosomal Inheritance
Mutations 35 and Disorders 109
Summary 40 Introduction 109
Chromosomal Inheritance 110
Chapter 3 Genetic Influences on Cell
Division, Cell Differentiation, Common Chromosomal
and Gametogenesis 43 Disorders 115
Introduction 44
Summary 127
Normal Cell Biology 44 Chapter 7 Sex Chromosome
Early Embryonic Cell Biology 52 and Mitochondrial
Commitment and Inheritance
Differentiation 54 and Disorders 130
Gametogenesis 56 Introduction 131
Summary 65 Extra X Chromosomes 131
Extra Y Chromosomes 132
UNIT II Gene Expression 69 Monosomy 133
Chapter 4 Patterns of Inheritance 70 Genotype-Phenotype Gender
Introduction 70 Mismatch 135
Mendelian Inheritance 71 Fragile X Syndrome 138
Punnett Square Analysis Mitochondrial Gene
and Probability 84 Inheritance 140
Chromosomal Inheritance 85 Summary 147
Complex (Multifactorial) Chapter 8 Family History and Pedigree
Disease 85 Construction 152
Genomic Variation Influencing Introduction 152
Susceptibilityand Resistance
to Health Problems 89 Family History 153
Summary 92 Pedigree Construction 155

xi

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xii Table of Contents

Punnett Squares 158 UNIT IV Genomic Influences

Pedigree Analysis 159 on Selected Complex
Summary 161 Health Problems 263
Chapter 9 Congenital Anomalies, Chapter 13 Cardiovascular Disorders 264
Basic Dysmorphology, Introduction 265
and Genetic Assessment 167 Atherosclerosis and Coronary
Introduction 168 Artery Disease 265
Major and Minor Anomalies 169 Stroke 268
Classification of Congenital Hypertension 271
Anomalies 170 Arrhythmias 272
Syndrome or Sequence 172 Cardiomyopathy 274
Dysmorphology Assessment 173 Summary 278
Assessment Through
Chapter 14 The Genetics of Cancer 283
a Genetic Lens 175
Summary 185 Introduction 283
Benign Tumor Cells 284
UNIT III Genomic Health Problems Cancer Cells 286
Across the Life Span 189
Cancer Development 287
Chapter 10 Enzyme and Collagen Summary 299
Disorders 190
Chapter 15 Genetic Contributions
Introduction 191
to Psychiatric
Enzyme Disorders 191 and Behavioral
Collagen Disorders 200 Disorders 303
Summary 207 Introduction 303
Chapter 11 Common Childhood-Onset Genetics Applications
Genetic Disorders 211 for the Psychiatric
Patient 304
Introduction 212
Autism 306
Monogenic Disorders 212
Attention-Deficit
Complex Disorders 226
Hyperactivity Disorder 308
Summary 234
Schizophrenia 309
Chapter 12 Common Adult-Onset AffectiveDisorders 311
Genetic Disorders 239 Substance Use Disorders 312
Introduction 239 Personality Disorders 314
Monogenic Disorders 240 Sununary 316
Complex Disorders 245
Diseases Affecting Older
Adults 253
Summary 257

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 Table of Contents xiii

UNITV Genomics and Disease UNITVI Global Genomic

Management 321 Issues 373
Chapter 16 Genetic and Genomic Chapter 19 Financial, Ethical, Legal,
Testing 322 and Social Considerations 374
Introduction 322 Introduction 374
Genetic Testing Samples 323 Ethical Goals of Clinical
Types of Genetic Tests 326 Genetics 375
Oversight of Genetic Testing 331 Genetic Discrimination 375
Laboratory Methods Used Duty to Warn Versus
for Genetic Testing 332 the Right to Privacy 378
Direct-to-Consumer Genetic Intellectual Property Rights
Testing 334 and Gene Patents 381
Risks and Benefits of Genetic Gene Therapy 381
Testing 334 Summary 383
Summary 337 Chapter 20 Genetic and Genomic
Chapter 17 Assessing Genomic Variation 387
Variation in Drug Response 341 Introduction 387
Introduction 341 Population Genetics 388
Pharmacodynamics 344 Race,Ethnicity, and Human
Pharmacokinetics 346 Genetic Variation 394
Genetic/Genomic Variations 350 Summary 395
Clinical Applications Appendices
of Pharmacogenomics 354
Appendix A Genetics Organizations
Genetic Testing for Drug
Response 356 and Support Groups 399
Summary 357 Appendix B Selected Educational
Websites 400
Chapter 18 Health Professionals
and Genomic Care 360 Glossary 402
Introduction 360 Index 423
Genetics Professionals 361
Role of General Nurses
in Genomic Care 364
Interdisciplinary Health -Care
Professionals 366
Summary 370

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ERRNVPHGLFRVRUJ
Basic Concepts From
Molecular Genetics

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 DNA Structure and Function

Learning Outcomes
1. Compare the components, structures, and forms of DNA.
2. Describe the events and processes involved in DNA replication.
3. Explain the formation and purpose of chromosomes.
4. Assess a karyotype for gender and ploidy.
5. Distinguish genotype from phenotype.
6. Explain how dominant gene alleles and recessive gene alleles determine expression of single-gene traits.

Key Terms
Allele Dominant trait Nucleoside
Aneuploid Euploid Nucleotide
Autosomes Gene p arm
Base pairs Gene locus Phenotype
Bases Genetics Ploidy
Centromere Genome Polyploidy
Chromatid Genomics Proteome
Chromosome Genotype Proteomics
Codominant trait Haploid chromosome number Recessive trait
Complementary pairs Heterozygous q arm
Deoxyribonucleic acid (DNA) Histones Sex chromosomes
Diploid chromosome number Homozygous Single-gene trait
DNA replication Karyotype
DNA synthesis Mitosis

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 Chapter 1 DNA Structure and Function 3

INTRODUCTION
Genetics and genomics are common issues that have an impact on the health and well-being of everyone.
All health-care professionals are expected to be familiar with basic terminology and patterns of inheritance to
recognize when a patient or family has a possible genecic risk for a health problem. The use of genetics and
genomics can assist in developing health-problem prevention strategies and precision therapies that take into
account each person's genetic differences. This chapter presents informacion about basic genetics to help your
understanding of how this information can have an impact on caring for patients and families.
The terms genetics and genomics are often used interchangeably, although there are some differences.
Genetics is the study of the general mechanisms of heredity and the variation of inherited traits. Genomics
is the study of the function of all the nucleotide sequences present within the entire genome of a species,
including genes in deoxyribonucleic acid (DNA) coding regions and in the DNA noncoding regions. (Coding
regions and noncoding regions are discussed in Chapter 2.) These definitions indicate that genomics includes
genetics but has a broader scope.

GENETIC BIOLOGY
All living cells, even bacteria and other lower organisms, have genes. A gene is a specific set of instructions cells
use to produce a specific protein. Consider all the hormones, enzymes, and other proteins your body makes,
both those that exist as individual, identifiable substances and those that are parts of larger components. Some
genes tell each ceU what protein to make and how to make it, whereas other genes control a cell's protein-
making activity by determining when to make a specific protein and how much to make. Thus, a gene acts
as a specific "recipe" for making a protein.
Most genes are part of the DNA in the nucleus of body cells. Figure I-I shows a cell nucleus with DNA
in the form of chromosomes. Figure 1-2 depicts an enlarged chromosome to show that a chromosome is
composed of DNA and contains segments that are genes.

Figure 1-1 Human cell and its nucleus with

metaphase chromosomes.

Metaphasechromosomes
withinthe nucleus

• Maternal-originchromosome
• Paternal-originchromosome

ERRNVPHGLFRVRUJ
4 Unit I Basic Concepts From Molecular Genetics

All human cells with a nucleus contain rwo sets of every gene that humans possess. This complete set of
genes for our species is called the human genome and contains between 20,000 and 25,000 individual genes.
(Mature germ cells-sperm and ova-contain only one set of every human gene.) The fact that all nucleated
cells contain all the human genes can be a confusing concept because no single cell type produces all the
proteins coded for by these genes. For example, only the thyroid gland normally produces thyroid hormones,
even though all cells have the genes for thyroid hormones. Although genes for thyroid hormones are present
in all cells, they are selectively activated and expressed exclusively in the thyroid gland, resulting in the pro-
duction of thyroid hormones. The activation of a gene allowing its product to be made by the cell is called
gene expression. In all other cell types, regulator genes prevent the structural genes for thyroid hormones from
being expressed.
The complete set of all proteins that a person makes at a given time under certain conditions is called the
proteome. This term combines the word protein and suffix -ome to indicate the totality of all proteins found
in a person, organ, tissue, or cell. The study of how proteins found in the proteome interact with each other
is known as proteomics. Proreornes can be examined for one cell type or for an entire organism. The protein
estrogen is part of the proteome for ovarian cells but is not part of the cardiac muscle cell (myocardial cell)
proteome. When considering the entire human proteome, we are looking at the proteins produced by all the
individual cellular proteomes. Proreornes are discussed in more detail in Chapter 2.
Although DNA appears different from a gene and from a chromosome, they are all the same substance.
DNA is the basic genetic chemical structure, containing gene-coding regions and noncoding regions, which
can be compressed into a chromosome form (see Fig. 1-2). A chromosome is a temporary but consistent
state of condensed DNA structure formed for the purpose of cell division. Chromosomes are discussed later
in this chapter. Just remember that genes and chromosomes are both composed of DNA. Consider a sweater
as a chromosome and each separate part of the sweater (right sleeve, left sleeve, pocket, collar, front, and back)
as a gene. Now consider that the entire sweater (chromosome) and its parts (genes) are composed of yarn

-- One small segment

01 DNA containing
Nucleated cell a single gene

~e_.A
Nucleus containing
Gene 2-

the entire genome

C-G
Centromere -A
C-G
One chromatid,-- A-
the longitudinal -A
half of a chromosome G-C

Chromosome composed of a large I Six base pairs

segment of DNA containing as many Double helix composed 01 12
as 1,000 individual genes 01 DNA individual nucleotides

Figure 1-2 Different forms of cellular (nuclear) DNA.

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 Chapter 1 DNA Structure and Function 5

_Telomere
(telomericDNA)

parm

Insulin gene region (11q13){ h:~- ....

13.4
....,j

13.5
14.1
14.2
14.3
21
21.1 qarm
22.2
22.3
23.1
23.2
23.3
24- __ Figure 1-3 Banded chromosome 11 showing
25 -,---, locus of insulin gene (11q13) and the telomeres
Telomere (telomericDNA)____..
that "cap" the ends of the chromosome.

(DNA). A sweater is not a person's entire wardrobe, however, just like one chromosome and all the genes it
contains are not the entire genome. Think of the genome as being the entire wardrobe (all the person's shoes,
socks, underpants, undershirrs, pants, shirts, sweaters, coats, hats, gloves, and scarves). Each chromosome has
many genes within it. Larger chromosomes contain thousands of genes, and smaller chromosomes may have
fewer than 100 genes.
Another analogy for understanding how DNA, chromosomes, and genes are connected is to consider the
DNA of the genome to be a large recipe book with all the instructions (recipes) needed to make every protein
your body can produce. Each chromosome is a separate chapter, and the genes are the individual recipes. Each
gene has a specific chromosome location, called a gene locus; think of this as the "page" of the chapter where
the recipe is located. For example, the insulin gene's locus is llq 13, which means that the gene is located on
the long arm of chromosome 11 in region 13 (Fig. 1-3). When it is time to make more insulin, this is the
"page" where the recipe can be found, Although all ceLIshave the "recipe" for insulin on chromosome 11, it is
only opened and read by the beta cells of the pancreas. Other cells normally cannot "read" the insulin recipe
and do not make insulin. Protein synthesis, which is the process of manufacturing proteins, is discussed in
Chapter 2.

DNA
More than 99% of the human body's DNA is in the nucleus. This DNA is termed nuclearDNA. Cell
mitochondria also contain a small amount of DNA called mitochondrialDNA (mtDNA). This is discussed
in Chapter 3.

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6 Unit I Basic Concepts From Molecular Genetics

DNA Structure
The basic structure of DNA is a set of four nucleic acids. These nucleic acids are nitrogen-containing compounds
made in part from the individual amino acids derived from the proteins we eat. Because these elements are the
basic structure of DNA, they are called bases. These four bases are adenine (A), cytosine (C), guanine (G),
and thymine (T) (Fig. 1-4). Thymine and cytosine are single-ring strucrures known as pyrimidines. (Memory
hint: The words thymine and cytosine contain a Y, as does the word pyrimidine.) Adenine and guanine are
both double-ringed structures known as purines. (Memory hint: The words adenine, guanine, and purine do
not contain a Y) These four bases are present in the DNA of humans and other mammals, plants, bacteria,
and viruses.
Each base becomes a nucleoside when a five-sided sugar (known as a deoxyribosesugar) is attached to it (see
Fig. 1-4). Each nucleoside becomes a complete nucleotide when a phosphate group is attached The nucleotide
is the final form of a base that is placed into the DNA strand. The nudeorides within each strand are held in
position by the linked phosphate groups, which act like the string holding beads together to form a necklace.
Base pairs are the complementary bases in the twO strands of DNA. These DNA strands must remain
perfectly parallel to each other, and the pairings of the nucleotides make this happen. For double-stranded
DNA (dsDNA) to remain parallel, the twO strands must Stay the same distance apart down the total length of
DNA. A pyrimidine with a single-ring Structure always pairs up with a purine that has a double-ring structure
to maintain this proper distance (see Fig. 1-4). Not only must a purine always pair with a pyrimidine, but
the bases are also always specific, forming complementary pairs.
Normally, adenine and thymine always pair together, and cytosine and guanine always pair together
(Fig. 1-5). The reason for these specific and complementary pairings of bases is related to the forces that hold
the twO DNA strands together. The twO strands are held together loosely most of the time by weak hydrogen

T-A complementary base pair

I

One nucleoside -------;

(a base with its
deoxyribose
sugar attached)

One nucleotide ----

(a base with its
CoG complementary
deoxyribose
base pair
sugar and
phosphorus
attached)

Figure 1-4 Four bases arranged as nucleotides in complementary base pairs. A == adenine,
C == cytosine, G == guanine, T == thymine, DR == deoxyribose, P == phosphorus.

ERRNVPHGLFRVRUJ
 Chapter 1 DNA Structure and Function 7

Linear and straight complementarystrands

Figure 1-5 Double-stranded (ds) DNA arranged as

complementary strands in a linear structure and a
loose double helix. T = thymine, A = adenine, C =
Same strands arrangedin a loose doublehelix cytosine, G = guanine.

bonds. Importantly, these weak bonds allow the (WO strands to separate easily during cell division when the
DNA is to replicate. This separation does not require a 10[of energy and can occur quickly. Within a base
pair, the hydrogen bonds form between the rwo nucleorides. Adenine and thymine each have a site for (WO
hydrogen bonds to form, whereas cytosine and guanine each have three sites for hydrogen bonds to form (see
Fig. 1-4). Although purines must always pair with pyrimidines. they can pair only with the base that can form
the same number of hydrogen bonds. Thus, under normal conditions, adenine can pair only with thymine,
and cytosine can pair only with guanine.
As mentioned, DNA in humans and other mammals is a linear, double-stranded structure with the nucleo-
tides of each strand connected by the phosphate groups as the backbone of the strand (see Fig. 1-4). These
two individual strands are held together loosely by hydrogen bonds. In this way, dsDNA is arranged like a
long set of railroad tracks. The long steel rails of the track are the phosphate backbones, and the bases of the
nucleotides are each half of the individual railroad ties (Fig. 1-6).
Complementary base pairs in DNA are specific because adenine normally pairs with thymine, and cytosine
normally pairs with guanine. This means that if the base sequence of one strand of DNA is known, the opposite
strand's sequence can be predicted accurately. For example, the left-hand strand of DNA in Figure 1-6 has
the sequence T-G-G-C-A-T-T-G from tOp to bottom. and the corresponding (complementary) right-hand
section has the sequence A-C-C-G-T-A-A-C. Except during cell division. the two parallel strands of DNA are
twisted into a loose helical shape (see Figs. 1-2 and 1-5). The DNA supercoils rightly into the chromosome
shape (which is visible with standard microscopes) only when a cell undergoes mitosis.
Billions of bases are found in the DNA of just one cell. In its most common shape, DNA can be seen
only by using an electron microscope; however. if the DNA of one cell could be pur together and stretched
OUt, it would be about 6 feet long. If this same piece of DNA from one cell could be made about a half-inch
wide, it would stretch out more than 1,000 feet! Each nucleus contains much more DNA than is needed
for the 20,000 to 25,000 genes. The gene part of the DNA is only about 5% of all the total DNA in each
cell's nucleus, with the remaining DNA (called noncoding DNA) playing various roles in regulating gene
expressIOn.

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8 Unit I Basic Concepts From Molecular Genetics

Complementarybase pairs
(railroadties)
3' 5'
~

Figure 1-6 An 8-base-pair segment of double-stranded (ds) DNA

similar to a section of railroad track. Phosphatelinkages(rails)

DNA Replication
Cell Division
Every time a cell divides, DNA replication occurs, which is duplication or reproduccion of itself, resulting in
two identical sets of DNA. This is needed because every cime a cell undergoes mitosis, a duplicacion division
results in two new cells that are idencical both to each other and to the original cell (parent cell) that began
the mitosis, and each cell must have a complete genome. For the two new cells created from mitosis to be
identical to the parent cell, the DNA of the parent cell must replicate exacrly. Mitosis occurs in a regulated
pattern known as the cell cycle. Figure 1-7 shows the phases of the cell cycle, which starts with one cell and
ends with two new cells. When mitosis is normal and the parent cell divides correcrly, each new cell has the
identical (and correct) amount of DNA and genes.
Cells not actively dividing are in a reproduccive rescing state known as Go- In this state, the cell is accively
performing its specific funccions but is not reproducing. For example, skin cells in the Go state produce keratin
and other skin products but do not reproduce. Normal cells are in the state of Go most of the time and leave
it only to reproduce when generacion of more cells is needed. To undergo mitosis, a cell first must be a cell
type capable of cell division. Some cells do nor divide once organ maturation is complete. Examples of these
nondividing cells include skeletal muscle cells, cardiac muscle cells, and neurons. If a cell has retained the
ability to divide when needed (e.g.. skin celis, bone marrow cells, liver cells, and epithelial cells that line most
organs), it will respond to signals to leave Go and enter the cell cycle. The cell cycle involves four phases.
Movement through these phases for successful generation of two new cells requires selective gene input. The
actions of these promitosis genes are discussed in Chapter 3. The acciviciesoccurring at each stage of the cell
cycle are outlined in Table 1-1.

ERRNVPHGLFRVRUJ
 Chapter 1 DNA Structure and Function 9

DNA Synthesis
Generating twO new cells from one parent cell requires twice the DNA present in the parent cell. Notice in
Figure 1-7 that the nucleus during S phase is twice as large as it was during G. because it now has twice as
much DNA. This replication of the DNA ensures that the two new cells resulting from mitosis will each have
the same amount of DNA as the parent cell. The parent cell doubles its DNA content by DNA replication
in S phase. (Memory hint: S phase stands for synthesis of DNA.) To distinguish between the related concepts
of DNA replication and DNA synthesis, recall that DNA synthesis is the process of manufacturing DNA,
whereas DNA replication is synthesis resulting in two identical strands-an original and a replica, or copy.
One point to remember about human cellular DNA is that the complete genome within anyone cell is
not present as one very long double strand of DNA. Instead, there are 46 separate sets of dsDNA correspond-
ing to the 46 chromosomes (see Fig. I-I).These 46 metaphase chromosomes represent the 46 loosely coiled
double helices mat are not visible with a standard microscope.

G1 Phase

S Phase

G2 Phase

M Phase

Figure 1-7 Phases of the cell cycle for a cell undergoing mitosis.

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10 Unit I Basic Concepts From Molecular Genetics

.'!.1:J.::aIl!!lii!
Activities of the Cell Cycle
Cell Cycle Phase Activities/Purpose
G, Cell prepares for division by taking on extra nutrients, making more
energy, and growing extra membrane
Amount of cell fluid (cytoplasm) also increases
S DNA replication and synthesis
G2 Production of proteins important to cell division and to normal physiologic
function after mitosis is complete
M Mitosis in which the DNA in the nucleus pulls apart and creates two nuclei
(nucleokinesisl. followed by the cell separating into two cells, each with
one nucleus (cytokinesis)

DNA replication begins when the individual sets of dsDNA separate by breaking the hydrogen bonds
holding the two strands in the double-helix form (Fig. 1-8). Once they separate, enzymes at each end of the
strands read the sequence of the original strands and build two new strands that are complementary to the
original strands. DNA must be "read" in one direction to correctly place the new nucleotides during DNA
synthesis, JUStas written languages must be read in only one direction to make sense. These strands are read
from the 5' (' stands for "prime") end of the DNA to the 3' end (these numbers refer to the specific carbon
on the sugar molecule that connects with the phosphorous molecule). Because new bases can only be added
at the 3' end, building or reading from 5' to 3' is termed downstream, and reading from 3' to 5' is termed
upstream. At the end of DNA replication, rwo new sets of dsDNA representing each of the 46 chromosomes
are present in the cell. Each new set of dsDNA contains one strand of the original dsDNA and one newly
synthesized strand (Fig. 1-9). Because each of the two new sets of dsDNA contains one of the original strand,
this type of DNA synthesis is known as the semiconseruatiue model of DNA replication.
Thus, new complementary strands are synthesized along the old strands, using the old strands as a model
or template to place each new complementary base in the proper order. We tend to think that the new
strand is built in a continuous fashion, starting at one end and proceeding to the other. Such a process would
be very slow, taking weeks, which is not compatible with Lifeas we know it. Imagine building a 300-mile
(SOO-kilometer) road with construction beginning only at one end and proceeding at the rate of 2 miles
(1.2 kilometers) per year, taking about 150 years to complete. Instead, road construction starts at many places
at the same time so that only a few years are needed to complete it. In the same way, to make the process of
replication efficient and rapid (seconds to minutes), DNA synthesis begins at multiple SPOtSsimultaneously
within each set of separated DNA strands. This allows many thousands of DNA areas to be replicated at the
same time. When replication is complete, the individual newly synthesized pieces are then linked together as
a continuous strand.
Many enzymes are involved in DNA synthesis, and these enzymes have different activities important to
correct DNA replication. Some of these enzyme functions include the following:
• Relaxing and unwinding the DNA helix
• Breaking the hydrogen bonds of dsDNA and separating it into two single strands (ss) of DNA (ssDNA)
• Keeping the ssDNA separate
• "Reading" the original DNA strands and determining the base order for the new strands
• Placing the nucleorides in the order specified by the template strand

ERRNVPHGLFRVRUJ
 Chapter 1 DNA Structure and Function 11

Breaking of hydrogen bonds and separation

of a section of original ds-DNA at the
beginning of DNA replication

Strand separation is --_ .........

followed by enzymes
reading the original strands
and starting to build
complementary strands

A section of double-stranded
DNA just before DNA replication
Figure 1-8 A section of double-stranded (ds) DNA during breaking of hydrogen bonds and separation
of the dsDNA at the beginning of DNA replication and the building of new complementary strands.

• Linking the separate pieces of newly synthesized DNA into a conrinuous strand
• "Spell-checking" the new strands of DNA to ensure that each base in the new strand is complementary
to its base pair on the original strand
Table 1-2 lim some of me differem enzymes and their roles in the DNA replication process.

Chromosomes
After the DNA has completely replicated, 46 chromosome structures develop as rightly packed forms of DNA
during the metaphase (M phase) of mitosis in the cell cycle. During M phase, one complete set of DNA moves
into one of the rwo new cells made during mitosis, and the second complete set moves into the oilier new
cell. Thus, the rwo new cells each have the right amount of DNA with all the genes. The correct movement
of the DNA into the twO new cells requires that the 46 separate chunks of DNA twist very tightly, forming

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12 Unit [ Basic Concepts From Molecular Genetics

Two original
complementary
ds-DNA strands
before DNA
replication

New sets of ds-DNA, each retaining one

single strand from the original ds-DNA
Figure 1-9 The semiconservative model of DNA replication in which the two new sets of double-stranded (ds)
DNA each retain one of the original strands.

ERRNVPHGLFRVRUJ
 Chapter 1 DNA Structure and Function 13

.'!':jllll~·,
Enzymes Participating in DNA Replication
Enzyme Action/Purpose

DNA helicase Unwinds the double helix and initially separates the dsDNA
DNA ligase Connects the individual pieces of newly synthesized DNA during
replication, forming a single strand within a chromosome.
DNA polymerase (subtypes DNA chain elongation; adds one nucleotide at time to the new strand
with different activities) while it is being synthesized
Editing/proofreading newly synthesized strand, comparing it to the original
template strand
Exonuclease action, recognizing a misplaced nucleotide, clipping it out.
and replacing it with the correct one
DNA topoisomerases Creates a "nick" in the supercoils of dsDNA, allowing them to loosen so
that eventually, the two strands can separate
Also repairs the nick (closes it) so that the DNA can resume its
supercoiled helical shape
Primase Responsible for initiating DNA synthesis in multiple sites down the single
strand being copied
Single-stranded DNA-binding Helps keep the two single strands separated long enough for initiation of
proteins (SSB proteins) DNA replication

dsDNA • double-strandedDNA
'---

dense chromosomes, which, when stained, can be seen (unlike their loosely coiled form) using a standard
microscope. Condensed chromosomes are temporary structures that have me important job of making me
delivery of DNA to me tWOnew cells precise so mat one new cell does not get more or less than the correct
amount of DNA and the correct distribution of the genes. This precision is critical for the new cells to be
able to function and eventually reproduce normally.

Chromosome Formation
Figure 1-10 shows me formation of one chromosome from its helical DNA after DNA replication has occurred.
This means mat the visible chromosome now contains twice me DNA and will split in half during mitosis,
allowing one new cell to receive the left half of me chromosome and me other new cell [Q receive the right
half. Wim each chromosome splitting in half during mitosis, each of me two new cells receives one complete
set of me entire human genome ar the completion of cell division.
Chromosome formation begins with me chunk of DNA (after replication) corresponding to me chromo-
some supercoiling on itself and becoming a shorter, much denser structure. This is similar to an old-fashioned
spiraled telephone cord mat is 12 feet long. Over rime, me long cord twists around itself until it is much
shorrer (perhaps only a foot long) and thicker, DNA supercoiling happens in multiple organized steps ramer
than just as a random tangle. As shown in part A of Figure 1-10, me dsDNA first starts [Q coil up more
tightly. Then, me tighter structure begins to wind around a set of globular protein balls known as histones,
forming a "bead" on me DNA strand (pan B of Fig. 1-10). This process allows the DNA to compact itself
without creating tangles or damaging its basic structure (base pairs are not broken or lost during this process).

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14 Unit [ Basic Concepts From Molecular Genetics

Tightly supercoiled
DNA condensed
and packed into a
chromosome structure

Simple
double
helix,
loosely
coiled

Supercoiling with
tight compression
C
Figure 1-10 One drunk of loosely coiled double-stranded (ds) DNA supercoiling into a chromosome.

Individual DNA-wrapped histones continue to wind, which clusters them, forming larger "bead" groups (known
as a nucleosome) that are packed closely together (between part B and C of Fig. 1-10). These thicker beaded
groups continue to coil nearly into a solenoid (parr C of Fig. 1-10), which is a dense, compressed supercoil
and loop, forming the basic structure of the chromosome. In this way, millions of base pairs now occupy a
much smaller space in the cell. The densiry allows chromosomes to take up the stain.
As shown in Figure 1-10, a chromosome is a specific large chunk of dsDNA that has already under-
gone DNA replication and contains millions of bases and hundreds (sometimes thousands) of genes. During
M phase (metaphase of mitosis), each chromosome forms and moves to the center of the cell that is about to
divide. Just before the cell splits into two cells {cytokinesis}, each chromosome is pulled apart (nucleokinesis) so
that half of each duplicated chromosome goes into one new cell, and the other half goes into the other new
cell. This action is illustrated in Figure 1-11, showing JUSt2 chromosomes rather than 46.

ERRNVPHGLFRVRUJ
 Chapter 1 DNA Structure and Function 15

Interphase Prophase
Centrioles Early mitotic Aster
(wHh centriole pairs) spindle

Plasma Nucleolus Nuclear Chromosome. Centromere

membrane envelope consisting 01 two
sister chromatids

Fragments
of nuclear
envelope
Completion of
the cell cycle Kinetochore JKinetOChore
microtubule

Metaphase

Telophase and Cytokinesis

Anaphase

Metaphase
plate Centrosome at
one spindle pole

Nuclear envelope
forming

Figure 1-11 Chromosome formation and nucleokinesis during the M phase of the cell cycle.

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16 Unit I Basic Concepts From Molecular Genetics

Chromosome Structure
Ploidy is the actual number of chromosomes present in a single-cell nucleus at mitosis. Humans have
46 chromosomes divided into 23 pairs. A complete set of one of each chromosome is the haploid chromo-
some number (1N) representing 23 individual chromosomes. When the nucleus contains both pairs of all
chromosomes, the number present is the diploid chromosome number (2N). When additional whole sets
of extra chromosomes are present, the condition is termed polyploidy (such as 69 chromosomes [triploidy
or 3N] and 92 chromosomes [terraploidy, 4N]). Normal human somatic cells (any body cells that are not
reproductive cells) with a nucleus have the diploid number (2N) of chromosomes, 23 pairs (46 chromosomes).
Mature human germline cells (reproductive cells, ova [eggs] and spermatocytes [sperrnj) each have the haploid
number of chromosomes (1 N), 23, half of each pair. Germline cells have the haploid number so that fertiliza-
tion (union of an ovum and spermatocyte) results only in the normal diploid number. When a cell's nucleus
contains the normal diploid number of chromosomes for the species, the cell is termed euploid. When a cell
contains more or fewer chromosomes than the normal diploid number for the species, it is termed aneuploid.
Figure 1-2 shows a chromosome after DNA replication right before cell division, and Figure 1-3 shows a
Giemsa-banded chromosome after the chromosome has been pulled apart. At the tips of this chromosome are
the telomeres (relomeric DNA), which act as chromosome caps that hold the DNA strands together similar to
the way a small plastic tube keeps the ends of a shoestring from unraveling. (The Structure and function of
relorneres is discussed in Chapter 3). As shown in Figures 1-2 and 1-3, the pinched-in area of the chromosome
connecting the twO sides is the centromere. The centromere also connects the chromosome segments above it
and below it. Each longitudinal left and right half of the chromosome is a chromatid. The two chromatids of
a chromosome are termed sister chromatids. The segmentS of chromosome extending above the centromere are
known as the short arms, or the p arms (p is for "petite"). The segments of chromosome below the centromere
are the long arms, or the q arms (because q is the next letter of the alphabet after pl. The locus of a gene on
a chromosome is pinpointed using these names (see Fig. 1-3). A discussion of terms used to identify a gene
locus is presented in Chapter 4.

Chromosomal Analysis
Limited genetic information can be determined by examining a person's chromosomes, a process known as
chromosomal analysis. This information is limited because each chromosome is composed of a large chunk of
DNA. Thus, only large changes with tens of thousands of base pairs of DNA can be seen at the chromosome
level as rearrangements, deletions, or additions. As shown in the nucleus in Figure 1-1, individual chromosomes
are scattered just before cell division. Photographs of these metaphase chromosomes can be taken through the
microscope to examine and analyze them closely.
The first step in chromosomal analysis is to count the chromosomes in one cell that is in M phase to
determine how many chromosomes are presenr (the normal cell should have 46 chromosomes consisting of
23 pairs). After the chromosome number per cell has been established, further analysis requires grouping the
chromosomes into a karyotype, which is an organized arrangemenr of all the chromosomes within one cell
during metaphase of mitosis. Although some of this analysis is commonly performed by a computer and then
interpreted by a geneticist, the following explanation demonstrates the actual steps of the process.
A technician first organizes the chromosomes into pairs and then arranges them by number according to
size and centromere position (Fig. 1-12). The largest chromosome pair is number 1, and this pair has the
centromere nearly in the middle of the chromosomes so that the p arms and q arms are close to the same
length. When the centromere is close to the center of the chromosome, it is termed a metacentric chromosome.
The next largest chromosome pair is the number 2 chromosomes. Their cenrromeres are not in the center, so
the p arms are clearly shorter than the q arms. This rype of centromere location is termed suhmetacentric. The

ERRNVPHGLFRVRUJ
 Chapter 1 DNA Structure and Function 17

2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18

.. til

19 20 21 22

Sex chromosomes,/
Figure 1-12 A karyotype of G-banded (Giemsa-banded) metaphase chromosomes.

chromosome pairs continue to be arranged by size, from the number 1s to the number 22s. When chromo-
some pairs are nearly the same size, the one with the more metacentric centromere has a lower number than
rhe pair (or pairs) of the same size with a submeracenrric centromere, Some chromosomes have rhe centromere
ar the top of rhe q arms, and rhere is little or no p-arm material. These chromosomes are termed acrocentric.
In Figure 1-12, pairs 13, 14, and 15 and pairs 21 and 22 are acrocenrric chromosomes. Figure 1-13 shows
rhe general proportions of rneracentric, submetacenrric, and acrocentric chromosomes.
The sex chromosomes are positioned lasr in a karyotype even though the X is a medium-sized chromosome.
Of the 23 pairs of chromosomes, autosomes are the 22 pairs of human chromosomes (numbered 1 through
22) that do nor code for the sexual differemiacion of a person. These chromosomes contain the genes for most
of rhe srrucrures and regularory proreins needed for normal somaric function. The sex chromosomes (circled
on rhe karyorype in Fig. 1-12) are the pair that contains the genes for sexual differentiation along with some
additional genes that are needed for somatic funccions. Most commonly, males have an X and a Y as the sex
chromosomes, and females have cwo X chromosomes.

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18 Unit [ Basic Concepts From Molecular Genetics

Short Satellite Stalk

arm p

Long
arm q

Telomere
Figure 1-13 Structures of metacentric, submetacen-
tric, and acrocentric chromosomes. Metacentrlc Submetacentrlc Acrocentric

The chromosomes in Figure 1-12 have been processed to enhance the accuracy of identifying each chro-
mosome. One way to increase the accuracy of chromosomal analysis is by treating the chromosomes with
special enzymes and stains so that each pair of chromosomes has a unique and consistent striped pattern. The
most common way to enhance chromosome appearance
is through the G-banding (Giemsa-banding) process. So, What Can Be Learned About the Person
Notice how different the banding patterns are for pairs From Whom the Karyotype in Figure 1-12 Was
4 and 5, which are the same size and shape, and for the Made?
acrocentric, same-sized pairs of 13, 14, and 15. With The person is human, male, and euploid (diploid,
this G-banding-enhanced karyotype, it is possible for 2N), having chromosomes that are normal in number
a genetics technician to accurately distinguish a pair of and appear normal in structure. lMlat this karyotype
does not indicate is whether any genes are mutated
number 13 chromosomes from a pair of number 14
or nonfunctional.
chromosomes.

Single-Gene Traits
As described earlier, a gene is a specific segmenr of DNA that contains the code (recipe) to direct the synthesis
of a particular protein. Thus, a gene is the smallest functional unit of the DNA Although genes vary in size,
even a large individual gene containing a million bases is only a very small segment of DNA.
Most of what is known currently about specific genes is related to those genes in which one gene controls
the expression of a specific structure, protein, or function. These conditions are known as single-gene traits
(monogenic traits). For example, a single gene determines whether a person can synthesize normal beta chains
of hemoglobin or has some degree of sickle cell disease. Another single gene determines whether a person
has a "widow's peak" or a straight hairline. Expression of blood type also is a single-gene trait. Table 1-3 lisrs
some single-gene traits and common health problems related to changes in single genes.
The blood type gene is located on chromosome 9 (locus 9q34). An individual has two copies of this single
gene, with one copy on the number 9 chromosome inherited from the father and the other copy on the
number 9 chromosome inherited from the mother. These two copies of the single gene for blood eype are
known as gene alleles. An allele is an alternative form or variation of a gene at a specific location. For each
single gene at a specific chromosome location, tWO alleles together control how that gene is expressed. Humans
have three possible gene alleles for blood type: A, B, and O. However, each person has only two of the three

ERRNVPHGLFRVRUJ
 Chapter 1 DNA Structure and Function 19

.r!1:1.=UClC1

Examples of Common Single-Gene Traits

and Disorders
Normal Traits Disorders

A. B, 0 blood groups Achondroplasia

Blood clotting factors Cystic fibrosis
(individual) Hemophilia (classic)
Color vision (red/green) Hereditary hemochromatosis
Dimples (facial) Huntington disease
Earlobe position Hurler syndrome
Hair texture Marian syndrome
Male pattern baldness Muscular dystrophy
Rh blood groups Phenylketonuria
Taste discrimination Sickle cell disease
Tongue rolling Sickle cell trait
Widow's peak Syndactyly
Tay-Sachs disease

specific gene alleles for blood cype (unless me person has trisomy 9 with three number 9 chromosomes, an
abnormal condition). Some single-gene traits have even more man three possible alleles; however, regardless
of how many possible different alleles are present in the entire human population, each person has only two
because he or she has only two chromosomes per pair, with one allele on each chromosome. A person's blood
type is determined by which blood type gene alleles were inherited from his or her parents.

Dominant and Recessive Single-Gene Traits

When a person inherits a blood cype A allele from one parent and a cype B allele from me other parent, he or
she has me A and B alleles and expresses blood cype AB. Anomer factor that determines which blood cype is
expressed with different alleles is whether me allele is dominant or recessive. The A and B blood type alleles
are dominant. A dominant gene allele is always expressed when it is present, which is why an individual who
has an A blood cype gene allele and a B blood type gene allele expresses both alleles as cype AB blood. A
person who has two blood type A gene alleles has type A blood, and a person who has two blood type B gene
alleles has cype B blood. A dominant trait is expressed even when the tWOgene alleles for that trait are dif-
ferent. When two alleles are different and each is dominant, they are both expressed equally as a codominant
trait. The alleles for type 0 blood are recessive and are expressed only when both 0 alleles are present. For
a person who has one blood cype B gene allele and one blood cype 0 gene allele, the expressed blood cype is
B, not OB. A recessive trait is a single-gene trait that is expressed only when both gene alleles are the same.
When a recessive gene allele is paired with a dominant allele, the recessive allele is silent (not expressed), and
only the dominant allele is expressed.

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20 Unit [ Basic Concepts From Molecular Genetics

Genotype and Phenotype

The exact gene allele composition a person has for a specific single-gene trait is the person's genotype for that
trait. The phenotype of a trait is the person's observed expression of any given single-gene trait. Thus, a person
with the genotype of AO for blood type and a person with the genotype of AA for blood type both express
the phenotype of type A blood, even though their genotypes are different. When a person has twO identical
gene alleles for a single-gene trait, the alleles are termed homoz.ygous. When homozygous gene alleles are
present for a single-gene trait, the genotype and phenotype for that trait are the same. When a person has
two different gene alleles for a single-gene trait, the alleles are termed heterozygous. For heterozygous alleles,
the actual genotype may be different from the phenotype.
Normally, recessive single-gene traits are expressed only when the person is homozygous for the two gene
alleles. Thus, for recessive traits, phenotype and genotype are always the same. Dominant single-gene traits
are expressed whether the person is homozygous or heterozygous for the gene alleles. For dominant traits,
phenotype and genotype can be the same but do not have to be. Information about dominant, recessive,
and codominant expression of single-gene traits and problems is presented in the discussion of patterns of
inheritance in Chapter 4.

GENE GEMS

• Genetics and genomics are similar concepts, but genomics has a broader scope.
• All human nucleated somatic cells contain two sets of the human genome.
• Germ cells are the cells for sexual reproduction (sperrnarocyres and ova) and contain only one set of
the human genome.
• Larger chromosomes contain thousands of genes, and smaller chromosomes may have fewer than
100 genes.
• More than 99% of human DNA is in the nucleus, and a small amount is in the mitochondria.
• Thymine and cytosine are pyrimidines; adenine and guanine are purines.
• Adenine and thymine are complementary to each other and always pair together; cyrosine and guanine
are complementary and always pair together.
• When the base sequence of one strand of dsDNA is known, the opposite (complementary) strand's
sequence can be predicted accurately.
• When mitosis is normal and the parent cell divides correctly, each of the two new cells has the correct
amount of DNA and genes, identical to each other and to the parent cell.
• The complete genome within anyone cell is present as 46 separate sets of dsDNA, not as one very
long double strand of DNA.
• The semiconservacive model of DNA replication results in twO complete sets of dsDNA, with each set
containing one DNA strand from the parent cell and one newly synthesized strand.
• The initiation of DNA synthesis begins at multiple spotS simultaneously on the parem strands of dsDNA
to make the process rapid and efficiem.
• Bases can only be added to the 3' end of DNA strands.
Continued

ERRNVPHGLFRVRUJ
 Chapter 1 DNA Structure and Function 21

• The most important feature of mitosis is the delivery of the correct amount of DNA to each of the
twO newly created cells.
• Chromosomes can be seen only with a standard light microscope during metaphase of mitosis.
• In a karyotype, one cell's metaphase chromosome pairs are organized by size from largest to smallest
and by the position of the centromere.
• Chromosomal analysis is enhanced by techniques that "band" chromosome pairs with a unique striped
pattern.
• For each single gene at a specific chromosome location, two alleles together control how that gene is
expressed.
• Some single-gene traits have even more than three possible alleles; however, regardless of how many
possible different alleles are present in the entire human population, each person only has twO because
he or she has only two chromosomes per pair, with one allele on each chromosome.
• When homozygous gene alleles are present for a single-gene trait, the genotype and phenotype for that
trait are the same.
• For recessive traits, the genotype and the phenotype are the same.
• For dominant traits, the genotype and the phenotype can be the same but do not have to be.

Self-Assessment Questions. ~
..
1. Which statement regarding DNA structure is true?
a. The same four bases compose the DNA of all living things.
b. All DNA contains genes, but not all genes contain DNA.
c. Noncoding regions of DNA make up a relatively small portion of total cellular DNA.
d. In addition to the nucleus, the only other cell organelle that contains DNA is the microtubule.
2. How does the enzyme DNA Ligasecontribute to DNA replication?
a. It unwinds the double helix and separates the double-stranded DNA.
b. It creates a "nick" in the DNA supercoils, allowing them to straighten before replication.
c. It initiates DNA synthesis in multiple sites down the strand, making the process more efficient.
d. It connects the individual pieces of newly synthesized DNA [Q form a single strand.
3. What activity occurs during S phase of the cell cycle?
a. The cell undergoes cytokinesis.
b. Activity StopS, and the cell "sleeps."
c. All DNA is completely replicated.
d. Chromosomes separate, causing nucleokinesis.
4. Which substance is responsible for holding nucleorides in place in single-stranded DNA?
a. Hydrogen bonds
b. Phosphate groups
c. Purines and pyrimidines
d. Deoxyribose sugars
Continued

ERRNVPHGLFRVRUJ
22 Unit I Basic Concepts From Molecular Genetics

5. Why does thymine normally only pair with adenine rather than with guanine?
a. Guanine has three hydrogen bond formation sites, whereas adenine only has twO hydrogen bond
formation sites.
b. Adenine can only attach to a phosphate group at the 3' posicion, whereas guanine only attaches
at the 5' position.
c. Guanine coils to the right when forming a helix, whereas thymine can only coil to the left.
d. Thymine, a pyrimidine, can only pair with a purine.
6. What is the correct interpretation of the statement "the HD gene locus is 4p l6.3"?
a. The HD gene is located in a coding region of DNA.
b. The HD gene is located in a noncoding region of DNA.
c. The HD gene alleles are located on the "long arms" of chromosome number 4.
d. The HD gene alleles are located on the "short arms" of chromosome number 4.
7. What are the expected blood types of children from a mother with AB blood type and a father with
00 blood type?
a. All children will have type 0 blood.
b. All children will have type B blood.
c. The children will not have the same blood type: 75% will have type AS blood; 25% will have
type 0 blood.
d. The children will not have the same blood type: 50% will have type A blood; 50% will have
type B blood.
8. Under which condition is a genotype different from a phenotype?
a. When a single gene trait's locus is on an autosome
b. When a male inherits a trait from his mother
c. When the gene alleles are heterozygous
d. When a person ages

References
Buckingham, L. (2012). Molecular diagnostics: Fundamentals, 1JIl'IIJods,and clinical applicllriom. Philadelphia, PA: EA. Davis.
National Cancer Institute. (n.d.). Dictionary of cancer terms. Retrieved from htrps:llwww.cancer.gov/dictionary?cdrid=446543
National Human Genome Research Institute. (2015). A briif guide 10 gl'l1omics. Retrieved from https:llwww.genome.gov/
18016863
National Human Genome Research Institute. (n.d.). Educators. Retrieved from htrps://www.genome.gov/Educatorsl

Self-Assessment Answers
1. a 2. d 3. c 4. b 5. a 6. d 7. d 8. c

ERRNVPHGLFRVRUJ
 Chapter 2__
Protein Synthesis
Learning Outcomes
1. Compare the locations, processes, and purposes of transcription, translation, and posrtranslarional modi-
fication of proteins.
2. Explain the differences, functions, and interactions of DNA triplets, RNA codons, and tRNA anticodons.
3. Analyze the factors determining when and how gene transcription occurs.
4. Compare the structure and function of inrrons and exons.
5. Compare the implications of different types of mutations on protein synthesis and protein function.
6. Explain how and why not every mutational event has a deleterious result.

Key Terms
Anticodon Germline mutation Ribonucleic acid (RNA)
Codon Introns Ribosome
DNA antisense strand MicroRNA (miRNA) Single-nucleotide
DNA coding region Mutagen polymorphism (SNP)

DNA noncoding region Mutation Somatic mutation

DNA sense strand Point mutation Transcription

DNA triplet Posttranscriptional modification Transfer RNA (tRNA)

Exons Posttranslational modification Translation

Frameshift mutations Protein Uracil

Gene expression Protein synthesis

23

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24 Unit [ Basic Concepts From Molecular Genetics

INTRODUCTION
A protein is a molecule composed of one or more long chains of amino acids occurring in a specific sequence
or order. This very specific sequence is coded for by the sequence of DNA within the gene for mat protein.
Thus, the purpose of a gene is to provide me directions for assembling (synthesizing) a very specific protein
when it is needed. All hormones, enzymes, growth facrors, and other protein-based chemicals needed for
normal human physiologic function are protein gene products mat are produced when me correct genes are
activated and expressed. A few examples of common gene producrs include insulin, hemoglobin, erythropoi-
etin, angiotensinogen, thyroid hormones, antibodies, collagen, fibrinogen, and various intracellular proteins.
Protein synthesis is me selective activation of a gene, eventually resulting in me production of me appro-
priate protein. For this reason, proteins are called gene products. Each gene provides me code for making one
specific protein. For example, as discussed in Chapter 1, the hormone insulin is a protein produced by the
beta cells of the pancreas mat works to maintain blood glucose levels within the normal range. When the
blood glucose level rises above normal, me pancreatic beta cells rapidly synthesize insulin, which then binds to
insulin receptors on cell membranes, making the cells permeable to glucose. This action allows glucose in me
blood and other extracellular fluids to move across cell membranes into cells, thereby reducing blood glucose
levels. When blood glucose levels begin to rise, individuals who do not have diabetes are able to synthesize
enough insulin to return glucose levels back to me normal range.
When a gene product (protein) is synthesized, me gene is turned on, or expressed Gene expression is the
activation of a gene, leading to its transcription and translation and, ultimately to the synthesis of a specific
protein. Figure 2-1 shows me sequential processes involved in protein synthesis.
The basic structure of a protein is its amino acid sequence. The 20 different amino acids are commonly
called the building blocks of life. Every active protein has a specific amount of me amino acids and a unique
sequence in which they are connected. The exact sequence is critical for protein function. Although two separate
proteins can have the same total number of amino acids (and perhaps even me same numbers of individual
amino acids), the sequencing order of me amino acids is what makes one protein different in structure and
function from anomer protein. If one amino acid is out of order or completely deleted from the sequence, me
protein will be affected and may not perform its function well. For example, me beta chain of hemoglobin
(also known as beta globin) is a protein that is part of me group of four proteins that form each hemoglobin
molecule. Beta globin contains 146 amino acids connected in a specific order. A change in the sixth amino

Figure 2-1 The sequential processes involved

in protein synthesis. Cell nucleus Cellcytoplasm

Posttranslatlonal
Transcription Translation modification

C3L R~A 1,01." 1 proton "00' proteln

ERRNVPHGLFRVRUJ
 Chapter 2 Protein Synthesis 25

acid in the sequence (glutamate, or glutamic acid) reduces how well hemoglobin retains its shape and carries
oxygen. This change is responsible for sickle cell disease. Sickle cell hemoglobin bends improperly, causing red
blood cells (RBCs) to assume a sickle shape. RBCs with this type of hemoglobin have a life span of only about
20 days instead of the 120 days of an RBC that contains normal hemoglobin. Thus, the order of the amino
acids is critical for the final function of any protein, and even one amino acid change can alter the protein's
function. Figure 2-2 shows an example of a short protein made up of only eight amino acids.
JUSt how a gene directs the correct placement of amino acids [Q result in a normal and active protein
relies on DNA. Each amino acid has at least one specific code within the DNA (Table 2-1). These codes are

PRIMARY PROTEIN STRUCTURE Figure 2-2 The sequence of amino acids in a

very short protein.

·'~':II_r.
The DNA Triplets and RNA Codons for the 20 Amino Acids
f--
Amino Acid Abbreviations DNA Template Triplets RNA Codons

Alanine ala (A) CGA, CGG, CGT. CGC GCU, GCC,GCA,GCG

Arginine arg (R) TCT.TCC, GCA, GCG, GCT. GCC AGA,AGG,CGU,CGC, CGA,CGG
Asparagine asn (N) TIA,TIG AAU, AAC
Aspartic acid asp (D) CTA, CTG GAU, GAC
Cysteine cys (C) ACA,ACG UGU,UGC
Glutamic acid glu (E) crt CTC GAA, GAG
Glutamine gin (0) crt GTC CAA, CAG
Glycine gly (G) CCA, CCG, CCT. CCC GGU,GGC,GGA,GGG
Histidine his (H) GTA, GTG CUA, CAC
Isoleucine ile (I) TAA, TAG, TAT AUU, AUC, AUA
Leucine leu (L) GAA, GAG, GAT. GAC, AAT. AAC CUU,CUC,CUA,CUG, UUA, UUG
Lysine Iys (L) mTIC AM, AAG
Methionine met (M) TAC AUG
Phenylalanine phe (F) AM, AAG UUU, UUC
Proline pro (P) GGA, GGG, GGT, GGC CCU, CCC,CCA,CCG
Serine ser (S) AGA, AGG, AGT. AGC, TCA, TCG UCU, UCC, UCA, UCG,AGU,AGC
Threonine thr (T) TGA, TGG, TGT.TGC ACU, ACC, ACA,ACG
Tryptophan trp (W) ACC UGG
Tyrosine tyr (Y) ATA, ATG UAU, UAC
Valine val (V) CAA, CAG, CAT, CAC GUU, GUC, GUA, GUG
Start AUG
Stop UAA, UAG, UGA

ERRNVPHGLFRVRUJ
26 Unit [ Basic Concepts From Molecular Genetics

each three nucleotide bases long and are called DNA triplets. As described in Chapter I, a gene is a specific
segment of DNA that contains the directions (recipe) for making a specific protein (see Figs. 1-2 and 1-10).
It contains all the DNA triplets of amino acid codes in exactly the right order for that protein. For example,
the final active form of beta globin has 146 amino acids. Thus, the minimum number of bases needed in the
gene for beta globin is 438 (3 bases per amino acid multiplied by 146 amino acids).
The gene for beta globin (the HBB gene) is located on the short arm (p arm) of chromosome II. The
synthesis of beta globin occurs only in immature RBCs, although the HBB gene is present in the nucleus of
every cell. This means that the HBB gene is part of every cell's genome, and beta globin is part of the cellular
proteome for RBCs. Synthesis of beta globin, JUStlike for any protein, involves the processes of transcription,
translation, and protein modification.

TRANSCRIPTION
Overview
Transcription is the process of making a strand of ribonucleic acid (RNA) that contains the same amino
acid codes as the DNA sequence of the gene for the protein needed. This phase of protein synthesis takes
place completely within the nucleus. Examining DNA reveals DNA coding regions separated by noncoding
regions. DNA coding regions contain many genes, and the sequences of these genes are largely the same from
one person to another. For example, the gene for insulin has the same DNA sequence in all healthy humans.
DNA noncoding regions are sections of DNA that contain multiple repeat sequences that are not genes or
parts of genes and that do not code for specific proteins. These noncoding regions, sometimes called redundant
DNA or desert DNA, make up about 95% of nuclear DNA. These regions vary from one person to another
and are used to identify the DNA from a specific individual. The noncoding regions of DNA influence how
genes are expressed, but nor all of their functions are yet understood.
Some of the steps used in protein synthesis involve similar enzymes and processes as those used in DNA
synthesis during DNA replication, with some differences. One of the biggest differences is the extent of the
process. During DNA replication, both double strands of nil the DNA within one cell are entirely copied,
resulting in the total synthesis of tWOnew complete strands of each chunk of nuclear DNA. During protein
synthesis, only the segment of DNA that contains the actual gene for the protein needed is involved in the
process, not the entire genome. This means that only a segment of one DNA strand is read and transcribed
into RNA.

Process
Using the cookbook analogy with the cookbook containing all the genes for the entire genome, consider each
chromosome to be a separate chapter of recipes in a very large book located in a library. To make chocolate
chip cookies, the cook must open the chapter that contains cookie recipes, rather than vegetable recipes. The
cook then determines on which page (gene locus on me chromosome) the chocolate cookie recipe is located.
After finding the correct recipe, the cook then writes it down (transcribes) and rakes it to the kitchen, where
the ingredients and processes for translating the recipe into actual cookies are located.
In protein synthesis, only the area of DNA that contains the actual "recipe" for the protein is read (tran-
scribed), and a complementary strand of RNA is synthesized. RNA is a single strand of niuogenous bases
constructed during transcription from a segment of DNA containing the template for a specific protein. Several
types of RNA exist, and the ultimate purpose of all types is to ensure that the information held in the genes
reaches cell areas where formation of the actual proteins needed for normal human funcrion can occur. In this
sense, RNA is a molecular interpreter of the DNA information stored in the genes.

ERRNVPHGLFRVRUJ
 Chapter 2 Protein Synthesis 27

Newly transcribed RNA functions as the initial pattern for protein synthesis. RNA is very similar to DNA,
with a few differences. First, functional RNA is single stranded (ss) rather than double stranded (ds). The sugar
component of RNA is ribose rather than deoxyribose, which JUStmeans that it contains one more oxygen
molecule than does the sugar in DNA. Another difference is that RNA does not contain the pyrimidine base
thymine. The base uracil is used in place of thymine. It is a pyrimidine base almost identical to thymine
except that uracil does not contain the methyl group (CHj) that thymine has (Fig. 2-3). However, this dif-
ference is important because molecules in the nucleus that contain a methyl group remain trapped inside the
nucleus. Because the remaining phases of protein synthesis occur outside the nucleus, the newly transcribed
RNA must be able to exit the nucleus.

Sense Versus Antisense

To synthesize beta globin, chromosome II is the correct "chapter." In one gene-coding region of chromosome
11, many genes are located, including HBB. When more beta globin is needed, the gene-coding region on
chromosome II containing the beta globin gene area loosens (Fig. 2-4). Some of the same enzymes involved
in DNA synthesis assist in the loosening and unwinding of the DNA coding region that contains the beta
globin gene. Once this DNA is loosened and unwound, the twO strands are slightly separated into a sense
strand and an antisense strand (Fig. 2-5). The DNA sense strand, also known as sense DNA, contains the actual
gene-coding sequence for the protein to be synthesized, in this case, beta globin. The DNA antisense strand,
also known as antisense DNA, contains the complementary base sequence to this gene, not the gene itself.
After the strands are slightly separated, an enzyme known as RNA polymerase 1/ reads and then transcribes the

Methyl Figure 2-3 Comparison of thymine and uracil structure.

H group H
0/ I 0/

N~ N~

H-OAN) H-OAN)
thymIne Uracil

Figure 2-4 Gsne-codinq region with the genes

for beta globin, insulin, and secretin.

Beta globin Insulin Secretin

ERRNVPHGLFRVRUJ
28 Unit [ Basic Concepts From Molecular Genetics

gene sequence on the antisense strand of DNA (template

So, Why Is the DNASense Strand Not Used
as the Template? strand), resulting in the formation of a complementary
strand of RNA that will have exactly the same amino
If the sense strand were used as the template for
acid codes as the gene in the sense strand. Thus, the
RNA synthesis, the order of amino acids in the
resulting protein would not be the order specified
antisense strand is the "template" used to direct RNA
by the gene. Instead, it would be totally different. synthesis. The DNA information is transcribed using
Think about this issue as a "mirror image" of a the bases adenine, guanine, cytosine, and uracil into a
photograph of a person who has a mole under his single RNA strand that amino acid codes identical to
or her right eye. In the mirror image, the mole looks the gene (see Fig. 2-5). Because this RNA is used as a
like it is under the left eye, not the same as the recipe to direct the building of the actual protein coded
photograph. However. a mirror image of the mirror for by the gene, it is known as messengerRNA, or mRNA.
image shows the mole to be under the right eye. The instructions in the gene have now been converted
So, the DNA antisense strand is a mirror image of into RNA codons by the process of transcription of the
the sense strand. The mRNA made complementary
template (antisense) strand (Fig. 2-6).
to the antisense strand is the mirror image of the
mirror image, which is identical to the DNA sense
strand's sequences.
Starting and Stopping
So, how does the enzyme know where to begin synthe-
sizing RNA from the gene? Within the DNA around the gene for beta globin (and all other genes) are codes
that direct the starting and stopping of RNA synthesis. The Start signal is located in front of or upstream from
the gene triplets that code for the specific amino acids in the protein. Start signals can be more than 100 base
pairs upstream from the actual gene. For RNA synthesis, these start-signaling regions are known as promoter
regions. (Note that in cancer development, the term promoter has a different meaning; see Chapter 14.) One
of the most common of the known promoter sequences contains many thymine and adenine bases and is
known as a TATA box. In the DNA after the gene (downstream) are transcription "stop" signals. These result
in the inhibition of further transcription of DNA triplets into RNA codons and in the addition of a poly-A
tail to the newly transcribed RNA. Development of a poly-A tail is known as polyadenylation. This segment
of RNA contains mostly adenine and is nor translated inro part of the protein.
A codon is a specific RNA base sequence containing the complementary code to each amino acid's DNA
triplet. For example, the DNA triplet for the amino acid methionine is TAC-thymine, adenine, and cytosine
(see Table 2-1). Remember that RNA contains uracil instead of thymine. Thus, everywhere an adenine is

DNA complement01template
(DNA sense strand)

Figure 2-5 Transcription of the gene from the DNA sense strand into RNA.

ERRNVPHGLFRVRUJ
 Chapter 2 Protein Synthesis 29

RNA codons Figure 2--6 A demonstration of the codons

Codon 1 Codon2 Codon 3 Codon 4 Codon5 Codon6 present in a specific segment of RNA.
~~~~~~
C G

RNA

G C

positioned in the gene's DNA, a uracil is positioned in the complementary strand of RNA. This makes the
RNA codon for methionine AUG-adenine. uracil. and guanine.
In addition to serving as a template. the DNA antisense strand of a specific gene is often the sense strand of
a different gene. Thus, for one gene in the gene-coding region of dsDNA, the gene for protein A is on strand
1 and therefore is the DNA sense strand for protein A. The DNA antisense strand (strand 2) for protein A is
the DNA sense strand for protein B. So, the DNA sense strands are not all located on one "side" of dsDNA
and neither are the antisense strands. Each of the rwo dsDNA strands is the DNA sense strand for some
proteins and the DNA antisense strand for other proteins. It all depends on the gene.

Results
Interestingly, the sequence for a single gene in the DNA is not continuous. Instead, the sequence for one
gene is separated by parts of sequences for other genes. So, our genes are in pieces, and the pieces of coding
and noncoding regions are integrated together. Thus, when a gene is first transcribed into RNA, the initially
produced RNA strands (known as the transcript) contain extra sequences. In a sense, this is like having the
recipe for chocolate chip cookies conraining all the usual ingredients for chocolate chip cookies (flour, sugar,
eggs, butter, salt, baking soda, vanilla, chocolate chips) and also containing the ingredienrs for peanut butter
cookies and molasses cookies. The sectional parts of the gene that actually belong in the gene are known as
exons (for expressedsequences). The additional sequences that do nor code for part of that protein are introns
(for interoening sequences). For example, the beta globin gene area contains three exons and multiple inrrons.
When the initial mRNA is transcribed from the ancisense template, it contains both the needed exons and
the extra inrrons, If the introns remain and are translated, the resulcing protein would not be functional.

Posttranscriptional Modification
Once the gene has been inicially transcribed into mRNA, the RNA must be further processed to its mature
form through posttranscriptional modification. This is a process that eliminates the inrrons before the mRNA
can be translated and used to direct the precise synthesis of the protein coded for by the gene (Fig. 2-7).
Removing the inrrons and conneccing the exons is known as RNA spLicing. After the initial mRNA transcript

ERRNVPHGLFRVRUJ
30 Unit [ Basic Concepts From Molecular Genetics

Templateof a Exon 2 Exon3 Exon 4

-t- t -
gene-coding
region
1 1 1
t
Intron 1 Intron2 Intron 3

Transcription
Inilial mRNAtranscript
l
M/v---==-=-==-f-<WI! -- -
Figure 2-7 Processing of messenger RNA
(mRNA) to create a mature transcript ready Mature mRNA ready for translationaner removalof
for translation. introns and splicing togetherof exons

has been processed and the introns eliminated, the mature mRNA is moved our from the cell nucleus into
the cytoplasm, where actual translation into a protein occurs.

TRANSLATION
Overview
Translation is the process of using a mature mRNA molecule as the directions for placing amino acids in
the correct sequence to synthesize a protein. This energy-requiring activity involves the interaction of amino
acids and mRNA along with two other rypes of RNA: transferRNA (tRNA) and ribosomalRNA (rRNA).
Translation occurs in the cytoplasm. If chromosomes are (he recipes in a cookbook, consider the cytoplasm
to be the "kitchen," where all the ingredients and the appliances for cooking are available for translating the
transcribed recipe into an actual product (such as chocolate chip cookies).
Transfer RNA molecules are specialized carrier molecules that can move an amino acid into position to
be incorporated correccly into a growing peptide chain during protein synthesis. For each of the 61 codons
specifying individual amino acids, a separate tRNA molecule binds to each individual codon. (Keep in mind
that the remaining codons code for a Stop signal and not an amino acid.) Each type of tRNA can carry and
transfer only one specific amino acid. For example, alanine rRNAs attach to and transfer only the amino acid
alanine, whereas valine tRNAs attach to and transfer only the amino acid valine. The tRNAs have an upside-
down, three-leaf-clover appearance, with two important areas for protein synthesis: the amino acid attachment
site and the anticodon (Fig. 2-8).
The amino acid attachment site is where a specific amino acid can attach to and be carried by anyone rRNA.
Which amino acid attaches depends on the tRNA's anticodon. An anticodon is the tRNA complementary
code for an amino acid codon. For example, the amino acid methionine has the RNA codon of AUG. The
corresponding anricodon on the rRNA that can attach and carry methionine is UAC Because the anticodon
is complementary to the methionine RNA codon, this tRNA can bind with and carry only methionine. It
does not recognize or attach to any other amino acid. This means that every amino acid has irs own specific
tRNAs. (Remember, some amino acids have more than one codon and anticodon.)

ERRNVPHGLFRVRUJ
 Chapter 2 Protein Synthesis 31

Acceptorarm

o loop

Figure 2-8 Basic structure of a transfer RNA (tRNA)molecule.

A ribosome is a cycoplasmic adapter molecule containing a complex of proteins and some RNA that essen-
tially decodes the mRNA and ensures me placement of [he proper individual amino acid into the growing
peptide chain during protein synthesis. Ribosomes have twO subunits, both containing small amounts of RNA.
These rwo separate subunits join together around the mRNA strand to perform actual translation and protein
synthesis. Ribosomes are nonspecific and will translate any mature mRNA molecule present in the cytoplasm
into protein for as long as me mRNA exists.

Process
In a heal my cell about to perform protein synthesis, all the needed "ingredients" must be present along with
adequate amounts of me body's usual high-energy chemical adenosine triphosphate (ATP). Amino acids are
especially important ingredients. Wimout adequate amounts of each individual amino acid, protein synthesis
does not occur. For several reasons, cellular amino acids stay in me cytoplasm as individual amino acids for
only a short time. One reason is mat they are small molecules mat can move out of a cell and down a con-
centration gradient. Anomer reason is mat as individual molecules, amino acids contribute to the osmolarity
of a cell and would make me cytoplasm hyperosmoLar compared with me interstitial fluid and the plasma.
The hyperosmolarity could then disrupt cell fluid homeostasis. Under normal conditions, amino acids are
constantly replenished through dietary intake of protein, which is broken down into individual amino acids
and then transported into me cells as needed.

Starting
When me mature mRNA reaches the cytoplasm, rRNAs with the appropriate amino acids attached and acti-
vated ribosome are needed to begin translation. One large and one small ribosomal subunit form a complex
that fits together around me 5' (recall from Chapter 1 that' means "prime") ends of the mRNA, where me

ERRNVPHGLFRVRUJ
32 Unit I Basic Concepts From Molecular Genetics

translational start signal is located. The start signal tells the ribosome complex to move from the 5' ends toward
the 3' ends of the mRNA, decoding and uncovering each codon one at a time (Fig. 2-9). When the first
mRNA codon is uncovered, all the different tRNAs enter the open site and try to unload their specific amino
acids. For example, in Figure 2-9, the first codon in the mRNA that the ribosome has uncovered is for tyrosine
(UAU), which means that the next amino acid in this particular protein should be tyrosine. Although all the
tRNAs enter and each tries to unload its specific amino acid as the first one in the protein, only the tRNA
carrying tyrosine can transfer it into the ribosome. This tRNA has the anticodon that is complementary to
the tyrosine mRNA codon, AUA. The tRNA with the anticodon of AUA temporarily connects to the tyrosine
codon (UAU) and removes its tyrosine, leaving it in the ribosome complex to be added to the growing protein
chain. This tRNA then leaves the ribosome complex and is recycled by picking up a new tyrosine molecule

Figure 2-9 Initiation and continuation of protein syn- Growing peptide IRNA'''' _Amino
thesis through six messenger RNA (mRNA) codons /
IRNA'" acid
by ribosome 1.

5' 3'

tRNAphe

IRNA'"

[
t AAG

5' 3'

ERRNVPHGLFRVRUJ
 Chapter 2 Protein Synthesis 33

from the cell's supply of tyrosines. Next, the ribosome complex moves down the mRNA to the next codon (in
Fig. 2-9, the next codon is for leucine [VUG]) and uncovers it. Again, all the tRNAs come in, but only the one
with the anticodon AAC (complementary to the UUG codon) temporarily connects with the codon and
transfers the amino acid leucine into the ribosome complex. The ribosome complex then links the leucine
with a peptide bond to the previous amino acid, tyrosine. Now we have a peptide with tyrosine and leucine
in sequence. After linking the leucine to the tyrosine, the ribosome continues to move down the mRNA,
uncovering the codons and linking the appropriate amino acids together in the coded sequence (in this case,
the next amino acid is phenylalanine [VUC]), forming an ever-dongating peptide chain (see Fig. 2-9).

Stopping
The ribosomal complex continues to build the protein, one amino acid at a time in the correct order, until
a StOPsignal is reached. The stOp signal causes the ribosomal complex to separate from the mRNA into the
two original subunits, releasing the completely translated protein. Protein synthesis is an efficient process,
which means that one mRNA molecule can be translated more than once. In this way, if 100,000 molecules
of the protein insulin are needed, it is nor necessary to form 100,000 insulin mRNAs. Instead, perhaps
100 insulin mRNAs are produced, and each one is translated 1000 times. Not only can each mRNA molecule
be translated more than once, but also multiple ribosomal complexes attach and begin translation as soon as
the first ribosomal complex moves down the mRNA, away from the start signal.

Results
Synthesis of a specific protein continues as long as mRNAs coding for that protein are present, along with
adequate amounts of all other ingredients and energy. For this reason, mRNA transcription is rapid, as is
mRNA breakdown. For example, if a person's blood glucose level suddenly shoots up to 200 mg/dL, the beta
cells of the pancreas respond to the need to lower this level by very rapidly transcribing the insulin gene into
insulin mRNA. (After all, the pancreas does not know just how many candy bars the person ate to get the
blood glucose level that high, and it does not know if the person has stopped eating candy bars.) All of these
mature insulin mRNA molecules are rapidly moved into the cytoplasm for translation into insulin.
Once in the cytoplasm, mRNA molecules have a very short life span, only seconds, before they are degraded
by enzymes known as ribonucleases (RNases for short). This rapid degradation of mRNA is important in
preventing such an overproduction of insulin that the person's blood glucose level becomes dangerously low.
The idea is to make JUStenough active insulin to reduce the blood glucose level back into the normal range
without making the person become hypoglycemic, a tricky feat requiring continuous feedback of blood glucose
levels to the pancreatic beta cells. As the newly produced insulin does its job and blood glucose levels decrease,
transcription of new insulin mRNAs slows at the same time that degradation of the initially transcribed
bunch of mRNAs occurs. As a result, insulin synthesis decreases so that hypoglycemia does not occur. When
the person's blood glucose level reaches the normal range, further transcription of insulin mRNAs stops, and
existing ones are degraded so that no further insulin is produced at this time.
Another way that gene expression is regulated after transcription of a specific gene is through microRNA
activity. MicroRNA (miRNA) is a small, noncoding piece of RNA that regulates gene expression at the RNA
level. These 20 to 25 base segments of RNA can inhibit translation by binding to parts of specific (targeted)
mRNA molecules, making them partially double stranded, which cannot be translated. This effectivdy "silences"
the translation ability of selected mRNA molecules. It also increases the rate at which mRNA is degraded.
As a result, even when gene transcription overproduces specific mRNA, the presence of miRNA can prevent
overproduction of the final protein. This type of regulation is very important in controlling the cell cycle,
differentiating stem cells into a specific mature cell type, controlling viral replication, and modulating critical

ERRNVPHGLFRVRUJ
34 Unit [ Basic Concepts From Molecular Genetics

metabolic pathways. MiRNA appears to have a role in cancer development by selectively silencing the synthesis
of some suppressor-gene products. Chapters 4 and 5 discuss some of the ways in which mutations affecting
miRNA function interfere with health.
All protein synthesis appears to work in a similar manner. Although some proteins are stored to a greater
extent than insulin-for example, thyroid hormones are stored in large amounts-each protein is produced
when an appropriate signal indicates that more of that specific protein is needed.

PosttranslationalModification
Primary, Secondary, Tertiary, and Quaternary
Protein Structures
Getting the right amino acids in the right order through translation is the protein's primary structure. However,
most proteins are not in their final forms for active function when they are first synthesized and thus require
posrrranslational modification. This is the further processing of the newly translated primary protein Structure
into the secondary and tertiary structures (and sometimes even a quaternary structure) needed to make it fully
functional. Although further processing leads to these formations, correct secondary, tertiary, and quaternary
protein forms all depend on an accurate primary structure.
Secondaryprotein structure is a twisting of the linear primary structure from the interaction of amino acids
located near each other. Thus, the sequence of amino acids does not change, but now the structure has more
three-dimensional depth as parts of individual amino acids project out differently from the main structure.
Tertiary structure is the folding of the linear structure and occurs as the result of remote amino acids interacting
with each other. These interactions allow parts of the linear structure to draw closer together in some areas
and have greater distances in other areas. Folding often creates a "pocket" within the protein that becomes an
"active site," able to interact with other structures or substances. Folding in some proteins is enhanced when
"bridges" are formed that connect distant amino acids. The most common bridges are formed by linking two
sulfide molecules (known as disulfide bridges). Some proteins are active after proper folding into the tertiary
structure; others require associations with additional protein molecules to be active. For example, one tertiary
beta globin molecule cannot carry oxygen. It must associate properly with another beta globin molecule, twO
alpha globin molecules, and a heme molecule to form the oxygen-carrying compound hemoglobin. Thus, a
protein's quaternary structure is its needed association with one or more specific ocher proteins for effective
functioning.

Additional Modification
Other types of posrtranslarional modification may be needed for protein activity. Some amino acids may need
to be removed to activate a protein. For example, the protein insulin is first translated into a "preprohormone"
that contains more than the 51 amino acids that compose active insulin. The pre parr of the preprohormone is
a signaling peptide that is removed in the endoplasmic reticulum shorrly after insulin is translated, converting
it to a prohormone that contains 84 amino acids. (The 33-amino-acid pro part of the prohormone is later
removed in the liver right before active insulin is present in the blood and binds to its membrane recepror.)
Another type of posttranslational modification involves adding other substances to the protein to make it
functional. These other substances may include various types of sugar molecules, lipid molecules, or additional
peprides, Once again, the proper order of amino acids in the primary structure is important for these other
substances to be correctly arrached in order to result in the most functional form of a protein.
In addition, many proteins need to leave the cell in which they were synthesized to produce a functional
effect. For example, if insulin remained in pancreatic beta cells, it would not be able to change membrane
permeability to glucose and reduce blood glucose levels. One common way of processing proteins synthesized

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 Chapter 2 Protein Synthesis 35

in one cell for use in other body areas involves packaging the new protein within a secretory vesicle in the
Golgi apparatus of the cell. This processing surrounds the new protein with plasma membrane components
that allow the vesicle to fuse with the cell's plasma membrane. Afrer the vesicle membrane fuses with the cell's
plasma membrane, the vesicle opens on the outer aspect of the cell, and the newly synthesized and processed
protein is released inro the circulatory system. Once in the blood, the protein can travel to other body areas
for final function.

MUTATIONS
Overview
A mutation is an alteration in the base sequence of DNA or RNA. Although mutations can occur anywhere
in the DNA or RNA, they are most noticed when they occur in a gene-coding region. When a mutation
becomes a permanent part of one cell's DNA, it can be passed on to or inherited by other generations of
cells. Some mutations occur daily within one person and do not produce problems, especially if only a few
cells or tissues are affected. Mutations that occur after birth in general body cells (somatic cells) are known as
somatic mutations. Because these mutations are present only in a person's somatic cells, somatic mutations
cannot be passed on to offspring. One problem associated with somatic mutations is an increased risk for
cancer in cells with such mutations.
Germline mutations occur in germ cells (sex cells, sperm, or ova) and can be passed on to offspring (chil-
dren) at conception. When a child inherits a germline mutation, each of that child's cells contains the mutated
DNA, including the child's sex cells. This means that the mutation can be passed to many generations as long
as the mutation does not interfere with the person's fertility.
More is known about gene mutations that result in serious health problems; however, some gene mutations
do have beneficial results. An example of a helpful mutation is the one that prevents a person from producing
a specific receptor on the white blood cells known as helper/inducer T lymphocytes (CD4-positive cells). Without
this receptor, the white blood cell is not invaded and destroyed by HIV Thus, people with this mutation
who have been infected with HIV do not develop the progressive immunosuppression associated with HIV
disease and AIDS. So, mutations that result in gene variations may cause one person to have a higher risk
for developing a disease, whereas a different mutation in the same gene may cause another person to have a
lower risk for developing the same disease. Discussions of specific mutations affecting health are presented in
the clinical chapters (Chapters 10-15) of this textbook.

Point Mutations
Point mutations are substitutions of one base for another and can occur in DNA or RNA. This eype of
change does not result in an extra base or a lost base, just a substitution. Thus, the DNA triplets remain intact,
although one may be incorrect. This change mayor may not alter amino acid posicion or protein synthesis,
depending on where it occurs. When a single point mutation occurs in a DNA coding region or in mature
RNA, the result can change one amino acid in the protein's primary structure, with a resulting change in
protein function, but it also may have little or no effect. When a point mutation has little or no effect on a
protein's function, it is known as a benign mutation or a normal variation.
Think of the following sentences as an analogy to a point mutation. The top sentence represents the correcr
reading sequence for a specific gene:
THE RED BUG BIT THE DOG
THE RED BUG BIT THE HOG

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36 Unit I Basic Concepts From Molecular Genetics

A point mutation, as seen in the bottom sentence, has substituted the Din dog with an H. The coded message
is similar but not exactly the same.
Can a point mutation alter protein function or protein synthesis? No, some, and yes. First, point mutations
occur much more often in noncoding regions of DNA rather than in coding regions because non coding regions
make up about 95% of total nuclear DNA. This makes the noncoding regions bigger targets for mutational
events. Point mutations and other types of mutations in these noncoding regions are actually responsible for
making one person's DNA different from another person's DNA and thus identifiable. Even identical twins
(monozygotic twins) do not have absolutely identical DNA by the time they are born, although they probably
did when the embryo first split into twO embryos. By the time identical twins are born, they usually have at
least 100 base pairs that are different from each other in the noncoding regions. As they live their lives, each
twin continues to accumulate more and different rnurations, so as they age, so-called identical twins become
less identical in their DNA.

Silent Point Mutations

Even when a point mutation is part of a gene-coding region, it may have no effect, a mild effect, or a major
effect on synthesis of the protein coded by that gene. Sometimes a point mutation does not alter the final
amino acid sequence of the protein because the substitution occurs in the third base in the triplet, and the
resulting RNA codon still codes for the same amino acid. This type of point mutation is known as a silent
point mutation (Fig. 2-10).

Missense Point Mutations

A point mutation that does change the amino acid sequence is a missensepoint mutation and does affect protein
function, usually reducing it to some extent (see Fig. 2-10). Some missense point mutations reduce protein

Figure 2-10 Comparison of the effects of Normalsequence

a silent point mutation, a missense point
DNAcode ACA GAC CCC CAC
mutation, and a nonsense point mutation
on protein synthesis. Arninoacid Cys Leu Gly Val

A silent mutation with a single base change in the DNA

but no change in amino acid sequence
DNAcode ACA GAC CCG CAC

Arninoacid Cys Leu Gly Val

A missensemutation with a single base change that causes

a diHerentamino acid to be placed within the protein
DNAcode ACC GAC CCC CAC

Arninoacid Trp Leu Gly Val

A nonsensemutation with a single base change that results

in a "stop signai that haltsprotein synthesis
DNAcode ACT GAC CCC CAC

Arninoacid Stop Leu Gly Val

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 Chapter 2 Protein Synthesis 37

function only slightly, and others cause a more profound change in protein function. For example, in normal
adult beta globin, the sixth amino acid in the sequence is glutamate (glutamic acid), as described earlier. This
is the correct sequence for hemoglobin A (HbA), and the beta globin folds are proper, aLlowing hemoglobin
to maintain its shape and bind weLlwith oxygen. In people who have sickle cell disease, a single base substitu-
tion in the DNA changes the sixth amino acid to valine instead of glmamate, creating hemoglobin 5 (Hb5).
Although this form of beta globin (when combined with twO alpha globin molecules and a heme molecule)
can still carry oxygen, its folds are different, which make it less functional than HbA. In addition, under
conditions of low levels of tissue oxygen, the folds become more abnormal, causing the blood ceLlto form a
"sickle" shape. The protein produced as the result of this missense point mutation has significantly reduced
function.
Another genetic problem with the beta globin gene is hemoglobin C disease, which is a type of sickle cell
disease. In this disorder, instead of substituting a valine for glutamate in the sixth amino acid position, the
mutation places a lysine in that position. The disease is much milder than sickle cell disease, and it is ofren
not diagnosed until adulthood. 50, mutated hemoglobin with a substituted lysine in place of glutamate func-
tions better than mutated hemoglobin with a substituted valine in place of glutamate.

Nonse nse Point M utatio ns

A point mutation that results in an inappropriate placement of a Stop signal is known as a nonsensepoint
mutation, which has a negative effect on protein function. This type of mutation, also shown in Figure 2-10,
prevents the completion of a protein. The protein may not be synthesized at all if the StOPsignal is present
early in the reading sequence. If it is present later in the sequence, protein synthesis StOPSprematurely and
results in a short, or truncated, protein that usually has little, if any, function.

Single-Nucleotide Polymorphisms
The correct sequences for every gene are not yet known. Among those that have been sequenced, most people
have the same DNA sequence for most genes. However, some of the known gene sequences have small varia-
tions from the most common sequences in some groups of people. (The most common k.nown sequence
of a gene in a population is known as the wild-type sequence rather than the normal sequence.) Usually,
these variations are the result of missense point mutations, and they may affect protein function to varying
degrees. These differences or variations are known as single-nucleotide polymorph isms, or SNPs ("snips").
An example of a group of genes with considerable personal variation that results in protein function changes
is the cytochrome P450 enzyme system.
The cytochrome P450 system of enzymes is coded for by a l O-gene family that may have subsets of as
many as 100 genes. The genes in this family all have names that begin with CYP. These genes are large, and
there are many variations in the exact sequence of these genes, making some more active and others less active
than "normal" or the "wild type." The function of the proteins produced by these genes is very important in
drug metabolism. Chapter 17 provides a more in-depth discussion of the issues related to 5NPs in these genes.

Frameshift Mutations
Frameshift mutations are disruptions of the DNA reading frame from having one base or a number of bases
that are not multiples of three added or deleted. (A frameshifr mutation involving only one base is a specific
type of point rnutation.) When this type of mutation occurs in gene-coding regions, it always disrupts the
reading frame from the starr of the mutation to the end of the gene. The result is complete alteration of amino
acid position and prevention of synthesis of a functional protein. A normal protein cannot be made from a
gene with a frameshifr mutation.

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38 Unit [ Basic Concepts From Molecular Genetics

Think of the following sentences as an analogy to a frameshift mutation. The top sentence represents the
correct reading sequence for a specific gene:
THE RED BUG BIT THE DOG
THR EDB UGB ITT HED OG
THE RED GBU GBI TTH EDO G
A base-deletion mutation, as seen in the middle sentence, has removed the E in the first THE, shifting the rest
of the bases to the left {for the three-base codes} and disrupting the reading frame. A base-addition mutation,
as seen in the bottom sentence, has added a G to BUG, shifting the three-base reading codes to the right
from that point and disrupting the reading frame. The coded message from either a deletion or an addition
is essentially useless, and no functional protein can be generated.
Sometimes a mutation involves the deletion or insertion of a number of bases, and the n umber is one that
is a multiple of three. When these deletions or insertions occur in a gene-coding region, the actual reading
frame is not disrupted, but either some amino acids will nor be present in the final protein synthesized or
other unneeded amino acids will be present somewhere within the final protein. So, even though the reading
frame is not shifted, the final protein synthesized is not normal and may not be functional.
One example of this type of mutation is the founder mutations in the BRCAJ gene. This very large gene
codes for a protein that controls cell growth and protects against cancer development, especially breast and
ovarian cancer. Mutations that eliminate function in this gene are several large areas of base deletions causing
the loss of many amino acids, although much of the rest of the amino acid sequence in the synthesized protein
remains intact. When a person inherits the mutated form of this gene in one gene allele and produces a non-
functional protein, her or his risk for cancer greatly increases because the protection provided by the protein
is not in place. More information about this specific gene mutation is presented in Chapter 14.

Mutational Events
Mutations can occur at any generic level and in any genetic process. Thus, mutations can involve individual
nucleorides, DNA segments, genes, RNA, chromosomes, or the genome, and they can occur in any step of
the various processes involved in DNA replication, cell division, and protein synthesis. Although some causes
of mutations appear random, the location of uncorrected mutations appears less random. This means that
some areas and some processes are more susceptible to the development of mutations. Individuals vary in
their susceptibility to mutation development and mutation retention. In addition, both internal and external
environmental conditions influence mutation susceptibility and consequence. Some known causes of muta-
tions include the following:
• Spontaneous DNA replication error
• Poor DNA repair function
• Exposure to environmental mutagens (biological, chemical, physical, viral)

Mutation Mechanisms and Repair

Mutations have many causes and mechanisms. The most well-studied mechanism is spontaneous DNA replica-
tion error. Recall from Chapter 1 that with evety cell division, the entire genome within the cell must replicate.
The average human produces about a trillion new cells daily through mitosis, providing lots of opportunity
for spontaneous mutational events. Although DNA synthesis is a process with high fidelity. meaning that errors
are relatively few because replication of the new strand is faithfully complementary to the template strand,
errors do occur. If an incorrect base were placed in the new DNA strand at a rate of 1 our of every 1,000 bases

ERRNVPHGLFRVRUJ
 Chapter 2 Protein Synthesis 39

(and who among us can do the same thing over and over again 1,000 times correctly each timer), the overall
result would be 1,000,000,000,000,000,000 mutations daily (1 trillion cells x 1 billion base pairs + 1,000 =
I quintillion). This rate is nor compatible with health. With "anrirnucarion" mechanisms in place, however,
one mutation for every million base pairs is estimated to be the final daily average spontaneous mutation rate
during cell division. This basal rate varies with personal and environmental conditions.
As DNA synthesis during mitosis progresses, various DNA repair processes help discover and correct errors.
In a sense, a backup "editing" or "spell-checking" function occurs, with enzymes comparing the sequence of
the template DNA strand to the newly synthesized strand. Recall that the newly synthesized strand should
be complementary to the template strand, Thus, the sequence A-G-T-C in the template strand should be
T-C-A-G in the new strand. What happens if, instead of a G, a T is placed in the new strand (T-C-A-T)?
The DNA repair system of enzymes should recognize that the T is incorrect, clip it out, and insert a G as the
correct base in the sequence. Mutation fixed! Still, the process is not perfect, allowing for about 1 in every
1 million base errors to remain and to be passed down to the next cell generation. When these mutations
occur in the vast areas of DNA noncoding regions, they have little effect on overall body function but do
account for increasing DNA variations from one person to another as people age.
Even the effectiveness of DNA repair mechanisms is an inherited trait. Most people have "average" repair
function that can correct or manage well the day-to-day spontaneous replication error mutations and even
the mild-to-moderate mutations that occur from exposure to environmental mutagens. A mutagen is any
substance or event that can inflict temporary or permanent changes in the normal DNA sequence. Other
people have inherited repair mechanisms with greater-than-average function that serve to protect them from
allowing excessive mutational events to result in permanenr DNA mutations. Still others have inherited a
poor repair mechanism that does not recognize DNA mutations or that makes additional mistakes during the
repair process. For example, instead of correcting the error of placing a T instead of a G in the new strand
complementary to A-G-T-C (T-C-A-T), it replaces the incorrect T with an incorrect C.
Even the most outstanding repair mechanisms can be overwhelmed if environmental exposure to mutagens
is excessive. Consider the person who has a huge mutagen exposure by smoking four packs of cigarettes daily,
drinking a liter of whiskey daily, mining asbestos for a living, and lying out in me sun without protection for
hours daily. Then consider that this same individual has a house that was built in an area where radon gas is
very high. Not only will there be a greater rate of spontaneous errors that become permanent. but also other
direct damage to the DNA can occur, such as the creation of extra bonds or cross-links between dsDNA
so that it cannot separate for synthesis. This damage results in large areas of DNA deletions in some of the
new cells made daily. Health problems are likely, especially different types of cancer and birth defects in any
offspring produced by this individual.

Mutation Locations
At one time, mutations were thought to occur only in DNA and be totally random. We now know that
mutations can occur in many places. not just in the DNA. and mat the process is less random. "Hot spots"
for mutations exist. These are largely areas where extra events or processes are needed for normal function.
Recall, for example, that DNA replication is not a continuous process during cell division. Rather, synthesis
of new DNA strands complementary to the original strands in a cell occurs in many sites along the length of
the template. After these individual new DNA pieces have been synthesized. they must be spliced together.
These splice sites are areas that are more susceptible to the occurrence and retention of mutations. This is also
true during mRNA maturation. The splice site areas where introns are removed and exons spliced together
also provide hot Spots for mutations. Also consider that misreading can cause an intron to remain when it
should have been removed or, conversely, can cause an exon to be removed when it should have remained.

ERRNVPHGLFRVRUJ
40 Unit [ Basic Concepts From Molecular Genetics

Starr and stop codes can be misplaced or deleted. tRNAs can be synthesized incorrectly and not bind with
the appropriate amino acid. Any of these mutational events can disrupt protein synthesis; however, unless the
disruption is widespread within a person, a problem may never develop.

SUMMARY
Protein synthesis is an essential process for all life-forms. It is complex and requires precision in all steps for
proper outcomes. Changes in protein synthesis are a common factor in many health problems. These changes
can occur as the result of somatic cell mutations, which are a problem only for the person who developed
the mutation. Protein synthesis changes also can occur from germline mutations and thus may be inherited.
Specific health problems associated with changes in protein synthesis form the foundation of the clinically
focused chapters of this text.

GENE GEMS

• All hormones, enzymes, growth factors, and other protein-based chemicals needed for normal hwnan
physiologic function are protein gene products that are produced when the correct genes are activated
and expressed.
• The sequencing order of the amino acids is what makes one protein different in Structure and function
from another protein.
• Only about 5% of nuclear DNA contains gene-coding regions, and these are largely the same from
one person [0 another.
• DNA noncoding regions are different from one person to another, even between identical twins.
• DNA sequences are read from the 5' to the 3' direction.
• The transcription phase of protein synthesis takes place completely within the nucleus.
• The DNA antisense strand is read by RNA polymerase to make a complementary mRNA strand during
transcription.
• DNA sequences of one gene are in pieces within a coding region and are separated by areas of DNA
that are not part of that gene.
• RNA is single stranded (ss) and serves as the interpreter of information stored within the genes of DNA.
• RNA contains the base uracil in place of thymine.
• When messenger RNA is first constructed, it contains segments of the gene to be expressed (exons), as
well as noncoding segments (inrrons).
• Introns must be removed from mRNA before protein synthesis can occur properly.
• The translation phase of protein synthesis rakes place in the cytoplasm, often in an organelle known
as the endoplasmic reticulum.
• Translation requires sufficienr amounts of amino acids, ribosomes, mRNA, and tRNAs.
• Each tRNA is specific for only one amino acid and can be used more than once.
• Each mRNA is translated multiple times for as long as it is present.
• Molecules known as microRNA can regulate the translation of mRNA by either binding to it so that
translation does not occur or by increasing the rate at which mRNA molecules are degraded.
• The initial translation that produces a peptide with all the amino acids in the correct order is a protein's
pnmary structure.

ERRNVPHGLFRVRUJ
 Chapter 2 Protein Synthesis 41

• Further modification of a protein's primary structure is needed for function.

• Alchough DNA synthesis is a process with high fidelity, errors do occur.
• Mutations can involve individual nucleorides, DNA segments, genes, RNA, chromosomes, and genomes
and can occur during any seep in DNA replication, cell division, and protein synthesis.
• Not all mutations have deleterious results.
• A new somatic cell mutation cannot be inherited by offspring.
• Germline mutations occur in sex cells and can be inherited by offspring.
• A silent point mutation does not change protein function, a missense point mutation usually reduces
protein funcrio», and a nonsense mutation often eliminates protein function.
• A normal protein cannot be made from a gene with a frameshift mutation.
• Many cellular repair mechanisms exist to correct mutations or prevem them from becoming permanent.

•
Self-Assessment Questions. .
1. Which structure serves as an interpreter of DNA informacion stored in the genes?
a. cRNA
b. mRNA
c. microRNA
d. ribosomal RNA
2. Why is it useful for mRNAs to have only a short life span?
a. Energy is conserved by avoiding mRNA maintenance activity.
b. Their components can be reassembled into new mRNAs.
c. Protein synthesis can be more tighcly controlled.
d. The precision of RNA maturation is increased.
3. Which starernenr regarding the tertiary structure of a protein is true?
a. It is direccly coded for within the gene.
b. It is created by remote amino acids interacting for protein folding.
c. It requires assembly with other additional proteins for final activity.
d. It makes the protein resistant to external mutagens and other mutational events.
4. A strand of recently transcribed mRNA contains the following components: exon (I), intron (2),
intron (3), exon (4), imron (5). Which sequence represents the mature mRNA?
a. 1,4
b. 2,3,5
c. 2,3,4
d. 1, 2, 3, 4, 5
5. How does microRNA (miRNA) disrupt protein synthesis?
a. By com peeing with mRNA for ribosomal attachment
b. By inhibiting amino acid detachment from [RNAs
c. By covering translational scan signals on mRNA
d. By binding to mRNA, preventing translation
Continued

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42 Unit I Basic Concepts From Molecular Genetics

6. What would be the effect on protein synthesis if the DNA sense strand were used as the template for
transcription into RNA?
a. Improper placement of introns
b. Increased rate of mRNA degradation
c. Incorrect translation of the gene product
d. Inability of translation to recognize stOp signals
7. What is the expected result of a "missense" point mutation?
a. Replacement of one amino acid with another in the final gene product
b. Total disruption of the gene reading frame and no production of protein
c. Replacement of an amino acid codon with a "stop" codon, resulting in a truncated protein product
d. No change in amino acid sequence and no change in the composition of the protein product

Self-Assessment Answers
1. b 2. c 3. b 4. a 5. d 6. c 7. a

ERRNVPHGLFRVRUJ
 Chapter 3_-
Genetic Influences on Cell
Division, Cell Differentiation,
and Gametogenesis
Learning Outcomes
1. Compare the characteristics and growth regulation of normal cells and early embryonic cells.
2. Analyze the influences of membrane receptors, signal transduction pathways, and transcription factors in
the regulation of cell division.
3. Explain the role of apoptosis in normal physiologic function and in embryogenesis.
4. Describe the influence of gene expression in cell differentiation.
5. Compare the processes, timing, and outcomes of mitosis and meiosis.
6. Compare the processes and outcomes of meiosis I and meiosis II in spermatogenesis and oogenesis.

Key Terms
Anaplastic Gametes Phosphorylation
Apoptosis Gametogenesis Pluripotent cell
Cell adhesion molecules Hyperplasia Signal transduction
(CAMs) Hypertrophy Spermatogenesis
Contact inhibition of mitosis Meiosis Suppressor genes
Cyclins Meiotic cell division Teratogen
Cytokinesis Nucleokinesis Transcription factors
Differentiation Oncogenes Tyrosine kinase ITK)
Ferti lization Oogenesis Zygote

43

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44 Unit [ Basic Concepts From Molecular Genetics

INTRODUCTION
Normal cell growth and development have strict genetic controls to coordinate the activity of all tissues and
organs so the entire body can function efficiently and correctly. This coordinated functioning is important
for optimal health throughout the life span. Genetic regulation interprets signals from the person's internal
environment to determine when cells divide, when they die, and how or if they are replaced. The process
of normal cell division is orderly, complex, and common, occurring millions of times every minute. Genetic
regulation ensures that the process occurs at the right time, in the right place, and at the right rate. Interfer-
ence with genetic regulation of cell division can result in abnormalities of anatomy and function and is a
major factor in cancer development.

NORMAL CELL BIOLOGY

Overview
Some human organs continue to grow and increase in size after development is complete by hyperplasia,
mitotic cell growth in which the tissue or organ increases in size by increasing the number of cells within it
(Fig. 3-1). (Recall from Chapter I that mitosis is a duplication cell division that results in two new daughter
cells that are identical both to each other and to the parent cell that began the mitotic cell division.) Examples
of tissues and organs that continue to grow or replace cells that are destroyed, damaged, or nonfunctional by
mitosis and hyperplasia throughout the life span include the skin, liver, bone marrow, and the linings of the
intestinal tract and blood vessels. Some human cells no longer grow by mitosis after tissue or organ maturation
in fetal life or infancy. Examples of tissues and organs that do not usually grow by mitosis after maturation
include cardiac muscle cells, skeletal muscle cells, and neurons. Instead, these tissues increase from infant size to
adult size ("grow") by hypertrophy, the expansion of the size of each individual cell rather than by generating
new cells to increase the number of cells (see Fig. 3-1). A disadvantage of organs that have attained their final
size by hypertrophy is that when these nondividing cells die, they are usually replaced by scar tissue cells rather
than by the same type of cells that were losr. For example, if a person had a myocardial infarction and 30%
of the ventricular myocardial cells died from ischemia, the dead cells slough. Rather than leave the ventricle
with a hole, these dead myocardial cells are replaced with collagen and fibrous connective tissue that forms a
scar or patch in the area. The scar tissue cells are not cardiac muscle tissue and do not contract or contribute
to cardiac OUtput-they merely keep the chamber from leaking. Whenever normal cells within an organ are
replaced with scar tissue, some organ function is reduced. The degree of function lost is proportionate to the
amount of scar tissue present.

Figure 3-1 Tissue growth by hyperplasia and

hypertrophy,
••••• • • • •
•••••
•••• ••••• • • • •
•••• ••••• •• • •
•••• •••••
Originaltissue Tissue growth by lissue growth by
hyperplasia hypertrophy

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 Chapter 3 Genetic Influences on Cell Division, Cell Differentiation, and Gametogenesis 45

Other tissues and organs continue to grow when needed by mitotic cell division throughout the individual's
life span, although the rate of cell division decreases with age. These tissues and organs are generally located
where constant damage or wear occurs, and continued cell division is needed for replacement. A major advan-
tage of tissues and organs retaining mitotic ability is the replacement of dead, aged, or damaged cells with
new cells, thus ensuring optimal tissue or organ function. In those tissues and organs that do retain mitotic
ability, the growth of new cells is well controlled so that the optimum amount of maximal-functioning cells
is present. (Control also keeps the size of the organ within the correct limits for the size of the person.) For
example, unlike the heart, the liver is composed of cells that retain mitotic ability. The liver cells in a 90-year-
old healthy person are much younger than 90 years old. Each liver cell performs its physiologic function, ages,
and eventually dies. Cell aging in tissues capable of mitosis is determined by the number of preprogrammed
cell divisions it can undergo. As a person's liver cells age, wear out, are damaged, or become less functional
in some way, they undergo a process of programmed cell death or cellular suicide, known as apoprosis. These
poorly functional cells are removed from the liver, making room for new liver cells to generate by mitosis so
that the liver continues to be populated throughout life by optimally functional cells without increasing in
size. If apoptosis did nor occur, the liver would contain tOO few functional cells to perform its work efficiently
and effectively. For optimum function, mitosis must be balanced with apoprosis, Normal cell function requires
strict genetic regulation over both processes.

Characteristics of Normal Cells

Appearance
Each eype of normal cell has a distinctive or differentiated appearance, including size and shape. The structure
and appearance of normal cells reflect their function. Normal cells have a relatively small nuclear-to-cytoplasmic
ratio when they are not undergoing mitosis. (Note that the drawing of cells in Fig. 3-1 shows nuclei that take
up less than half of the volume of each ceil.)

Function
All normal cells perform at least one specific job, called a differentiated function, that helps whole-body function.
For example, skin cells synthesize keratin, testicular cells secrete testosterone, skeletal muscle cells contract,
neurons generate action potentials, and adrenal cortex cells secrete cortisol. Some cells, such as liver cells, have
more than one differentiated function.

Adherence
Normal cells have several different cell surface proteins that allow normal cells of the same eype to adhere
tightly rogether. These proteins are known as cell adhesion molecules (CAMs). Some of the most well-known
CAMs include fibronectin, the cadherins, and a variety ofinregrins to ensure cells within one organ are bound
together and do not migrate. Thus, normal cells do not leave their parent organ or tissue. (So, regardless of
how smart you feel or do not feel on any given day, you do not have brain cells in your feet! They are all in
your brain.) On the other hand, erythrocytes and leukocytes, although they are normal, do not adhere tightly
together and can move about the body as part of their function. These cells do not produce fibronectin or
other CAMs.

Ploidy
Normal human somatic cells have a nucleus and are diploid, containing 23 pairs of human chromosomes (or
46 individual chromosomes), a condition known as euploidy. The only normal mature human cells that are
not diploid are erythrocytes, which have extruded the nucleus and do not contain any chromosomes, and sex

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46 Unit [ Basic Concepts From Molecular Genetics

cells (oocytes or eggs and spermatocytes or sperm), which are haploid, containing only half of each pair of
chromosomes (23 total chromosomes).

Cell Growth
Normal cells that have retained mitotic ability are inhibited from mitosis when their membranes are com-
pletely in contact with the membranes of other cells, a condition known as contact inhibition of mitosis.
The presence of cell surface membranes that are untouched by the membrane of another cell is a signal that
mitosis is needed. Once a normal cell is completely surrounded by other cells and its membrane is contacted
directly on all surface areas with the membranes of other cells, it no longer undergoes mitosis. Another term
for this characteristic is density-dependent inhibition of cell growth. The purpose of this feature is to prevent
inappropriate tissue overgrowth. Think about what would happen if you skinned your knee and the remain-
ing normal cells were nor contact inhibited. They could continue to divide after wound closure and form
excess (and unsightly) skin Raps or folds on your knee that would serve no purpose. (Keloid formation is a
type of abnormal and excessive cell growth in which cell division does not completely respond to signals for
contact inhibition.)
Cells that retain mitotic ability have choices to make. They can divide, perform differentiated functions,
or undergo apoprosis. Which choice is made depends on age (both the person's age and the cell's age), body
conditions, and body needs that are communicated as signals to the cell.
Normal cells have well-regulated mitosis in response to the need for cell division. Mitosis in all cells that
retain mitotic ability occurs in a well-recognized pattern described by the cell cycle. The length of the cell
cycle varies by tissue and by the person's age, but the process and its regulation are the same. The phases and
normal regulation of the cell cycle are described in detail in the next section, "Controlled Mitosis."
Even cells that retain mitotic ability are restricted from entering the cell cycle unless new cells are essential
for growth and develop men t or when cells that are damaged or dead must be replaced. These restrictions are
part of the genetic regulation of cell growth. Specific gene products are needed to promote celJ division, and
other gene products inhibit cell division. Normal cells are able [Q respond appropriately to the signals gener-
ated by the presence of these products. Normal cell populations are regulated by a balance between products
produced by oncogenes, which promote entering and completing the cell cycle, and products produced by
suppressor genes, which restrict or inhibit emering and moving through the cell cycle. Thus, oncogene prod-
ucts are promitotic and induce cells to enter and complete the cell cycle to divide. Suppressor gene products
inhibit all aspects of mitosis and also trigger apoprosis.
Compare the control of cell division to controlling the movement of a car. The controller is the person
driving the car (the suppressor gene). To move, the car's accelerator (oncogene) is activated, and enough
fuel reaches the engine for the car to go. When the car needs co stop, the driver stops pressing the gas pedal
(inhibits it) and steps on the brake so that the brakes slow and srop the wheels. The driver is responsible for
preventing the car from moving when movement is not needed, for determining when movement is needed,
for allowing the car to move when movement is needed, and for maintaining the right speed for driving
conditions. A car set in motion without a driver or brakes is a disaster (consider cancer development as cell
division set into motion without any controls). (For information of the consequences when this control is lost,
see Chapter 14.)

Controlled Mitosis
As discussed earlier and in Chapter 1, cells not actively reproducing (undergoing mitosis) are outside of the
cell cycle in Go, the reproductive resring state, and continue to perform all their usual differentiated functions.
Cells that retain mitotic ability must exit the Go state to enter the cell cycle.

ERRNVPHGLFRVRUJ
 Chapter 3 Genetic Influences on Cell Division, Cell Differentiation, and Gametogenesis 47

Among all normal cells capable of mitosis, the step of leaving Go and entering the first phase of the cell
cycle, GI> is severely restricted. This restriction includes the presence or absence of external and internal signals,
many of which are gene products. Once a cell enters the cell cycle, it responds only to internal signals. Cells
in the cycle must either progress through the cycle or be arrested at some point in the cycle. Cells that are
arrested are nonfunctional and usually die.
Recall from Chapter 1 that mitosis allows one cell to divide into twO new cells that are identical to each
other and to the original cell that started the mitotic cell division (Fig. 3-2; also see Fig. 1-7). The steps of
entering and completing the cell cycle are tightly controlled by suppressor gene products. These genes are
activated at checkpoints and determine how much oncogene expression and prornitotic proteins are needed
to allow sufficient cell division to occur for events such as normal wound healing without leading to excessive
cell division.
Some of the checks, known as restrictionpoint controls. that are placed on a cell before it can enter the cell
cycle include the following:
• The cell has retained its mitotic ability.
• A need exists for cell division in the specific tissue where the cell resides. Are more cells needed in this
tissue from previous cell damage or loss? Are more ceLIsneeded in this tissue because the tissue needs to
increase in size (as in normal development)?
• Adequate nutritional Stores are present (especially protein. glucose. and oxygen) to suppOrt existing and
new cells.
• The cell has a sufficien t energy supply or can produce enough energy to participate in cell division and
synthesize additional membranes. proteins. and organelles.
Information on the presence of external events that inform the cell of a need for cell division is sent to the
cell's nucleus through a process known as signaJ transduction. This communication system allows information

Cell replicates DNA

(under the influence of
cyclin-NCDK)
(Progression under the
~Iuence of cyclin-B)

More protein

Cell enlarges, protein

synthesis

Beginning of cycle
(entering the cell cycle
M
= (under the influence
of cyclin-B/Cdc2)

Cell prepares to divide

(under the influence of
cyclin-NCdc2 and
under the influence of
cyclin-D/CDK)

0 1
Restrictions
aurora kinase)
Cell divides
(mitOSis)
Original cell in
reproductive
resting state
8 O 1
Figure 3-2 Events occurring during progression within the cell cycle.
Two new
cells

ERRNVPHGLFRVRUJ
48 Unit [ Basic Concepts From Molecular Genetics

about events, conditions, and substances external to the cell to reach the nucleus and then influence whether the
cell divides, undergoes apoprosis, or performs its differentiated functions. Many signal transduction pathways
are within cells that have retained mitotic ability. These pathways have multiple feedback loops and commonly
interconnect with each other. Some pathways are promitotic, and others transfer signals to suppress cell division.
Known factors that are external prorniroric signals include growth factors (such as epidermal growth factor
[EGF] and vascular endothelial growth factor [VEGF]); CAMs; steroid hormones; and cell-to-cell contact
through direct touching, chemical transmission, and electrical interactions. Most of these pathways involve
the occupation or activation of membrane receptors. Most cells have multiple receptor types and complicated
interconnecting signal transduction pathways. Not all pathways have been completely characterized, and dif-
ferent cell types express and activate different pathways, making control of cell division very complex.
Figure 3-3 presents a single prorniroric signal transduction pathway in a cell segment that, when activated
because of external conditions, leads to oncogene activation and the promotion of cell division. Any of several
conditions can initiate activation of this pathway, including growth factors that bind to receptors, the interac-
tion of drugs with the cell plasma membrane, the presence of adhesion proteins, changes in ion movement
(especially sodium and calcium), ligand binding, and other cell-to-cell interactions. When the pathway is

ligand-associated

-,
\o~\~e~
Cell plasma
membrane
-<.~~ ~e
i\~1>

Activation of
transcription --....
1 +---
13010'" ~

Figure 3-3 An example of a single promitotic signal transduction pathway that can be activated
by anyone of several external factors or conditions.

ERRNVPHGLFRVRUJ
 Chapter 3 Genetic Influences on Cell Division, Cell Differentiation, and Gametogenesis 49

activated, one of the first responses is the activation of enzymes that increase the intracellular concentration of
a variety of tyrosine kinase (TK) enzymes. The end result of the activation of any promitotic signal transduc-
tion pathway is increased production of transcription facrors. Transcription factors are proteins that enter a
cell nucleus and regulate transcription for a specific gene or set of genes. (Returning to the car analogy, these
transcription factors are reminding the driver of all the errands he or she needs to run and are helping the
driver prioritize thern.)
The remaining discussion about cell cycle control may appear complicated because of the many different
gene products that interact to control the process. Memorizing the activity of these different gene products is
less important for health-care professionals than is understanding the following concepts:
• Suppressor gene products control the expression of oncogene products.
• Oncogene products are always prornitoric. r-------------------_
• Control is exerted at every phase of the cell cycle. Still Having Trouble Understanding the
"Big Picture" of Nonnal Genetic Control
• Activation 0 f most 0 f t he prornirotic gene pro d ucrs
Over Cell Division?
requires the addition of a phosphate group to their
structures. Read the fol/owing sections, which describe the
activities that occur during the phases of the cell
• These prornitotic products can be deactivated by
cycle.
removing a phosphate group from their Structures.

G, Phase
When external promitotic signals reach the cell's nucleus and the checkpoint information indicates that the
resources are adequate, the cell exits Go and enters G .. the first phase of the cell cycle. Progression to the next
phase is determined by the presence of cydins. Cyctins are a group of prornitotic proteins produced by specific
oncogenes that, upon activation, propel the cell forward through all phases of the reproduction cycle. (Think
of the cyclins as the gas released into the engine by the accelerator that allows a car to move.) Normally, the
oncogene expression of cyclins is carefully regulated by suppressor gene products. Cyclin activation requires
the attachment of a phosphorous molecule to the cyclin structure, a process known as phosphorylation.
Phosphorylation is performed by a variety ofTKs. TKs activate many transcription factors at different steps
in the signal transduction pathway, and they activate cyclins in the cell cycle. A wide variety of TKs exists,
most of which are products of oncogenes. Some are unique to the cell type; others are produced only in cancer
cells that express a specific oncogene mutation.
Cyclins are activated by cyclin-dependenr kinases (CDKs). The CDKs combine with cyclins to form com-
plexes that start the cellular reproductive processes. In normal cells, cyclins and CDKs are carefully regulated by
suppressor genes (the driver) so that cell division occurs only when it is needed and to the degree it is needed.
(The driver keeps the car at the correct speed and the correct direction when it needs [Q move.)
The type of cyclins present in a cell during mitosis varies by the phase of the cycle. Differences in cyclin
types determine whether the cell progresses through the phases of the cell cycle and whether the cycle is com-
pleted so that two new cells are generated. More than 20 different families of cyclins have been identified (A
through T). The A, B, and D cyclin families are the most well characterized. The most common signal for
leaving Go and entering G1 is the formation of the cyclin-D/CDK complex, which is formed by combining
cyclin-D with its specific CDK. Additional complexes of other cyclins and their specific CDKs form to allow
progression through each phase of the cell cycle. All cyclins and CDKs are made in the cell in response to
specific oncogene activation. Figure 3-2 shows the activity of various cyclin complexes in the cell cycle.
Late in G1, additional cyclin/CDK complexes form to move the cell into S phase. These complexes promote
DNA transcription and protein synthesis. The resulting response is a greater expression of prornitotic cyclins
by oncogenes and a reduced expression of suppressor gene products that inhibit cell division. Progression into

ERRNVPHGLFRVRUJ
50 Unit [ Basic Concepts From Molecular Genetics

S phase requires that regulator proteins be phosphorylated to work with transcription factors. All of these
processes are under genetic control. A major regulator of the cell cycle for many types of normal cells is the
Tp53 suppressor gene product. It is known as the "guardian of the genome," and its activation restricts the
progression of cells from G1 into S phase. Anything that damages the Tp53 gene results in less restriction for
progression of the reproductive cell cycle.

S Phase
DNA replication is the major activity of S phase. The result is two complete sets of DNA. The cyclin-
E/CDKl complex drives DNA replication by activating the enzymes needed to produce nucleorides. Another
complex, the cyclin-A/CDK complex, then permits the synthesis of all substances needed for DNA replication.
After DNA is replicated, cyclin-B activates other kinases for completion of S phase and progression into the
G2 phase.

G2 Phase
This phase of the cell cycle is characterized by intense protein synthesis for proteins that are important in
M phase and for those that provide routine cell maintenance. The cyclin-B/Cdc2 complex drives these actions
and then moves into the nucleus to trigger gene expression for the production of other complexes and proteins
of cell structures needed for M phase (e.g., centrioles and spindle fibers).

M Phase
M phase is the part of the cell cycle in which true mirosis, which results in two new daughter cells, occurs.
During this phase, DNA is organized into chromosomes. As discussed in Chapter I,the subphases ofM phase
are prophase, prometaphase, metaphase, anaphase, and telophase (see Fig. I-II). Microtubular spindle fibers
form from the centrioles due to the interaction of cyclins and an activating enzyme called aurora kinase. As
each chromosome forms, it moves to the center of the cell and attaches each chromatid to one end of a spindle
fiber under the inAuence of aurora kinase and the protein survivin. At this point, nudeokinesis occurs, in
which each chromosome is pulled apart at the centriole so that the two sets of chromosomes are separated
within the single large cell. This process is immediately followed by cytokinesis, which is the separation of
this cell into two new cells that each have a complete set of chromosomes.

Apoptosis
As discussed earlier, some cells must die for the optimum function of a tissue and the human body, a process
known as apoptosis or programmed cell death. Cells are programmed to undergo this cellular "suicide" after
a specified number of rounds of cell division. When cells are damaged, apoprosis is triggered at earlier cell
ages. (Sometimes even a new car is totaled, damaged beyond the point that repair is possible and JUSthas to
be junked.)
A major signal for normal apoptosis is the shortening of the relorneric DNA at the tips of the cell's chro-
mosomes, which occurs with each round of cell division (see Fig. 1-3). When the cell is healthy, relorneric
DNA is maintained by the enzyme telomerase that was produced in the cell during fetal life. The cell has
achieved its preprogrammed number of cell divisions when relomerase is depleted and the telomeric DNA
is completely gone. Loss of the relorneres leads to chromosomal unraveling and fragment formation. This
response triggers a variery of generic and intracellular signals for self-destruction.
A major protein for apoprosis is the product of the Tp53 rumor suppressor gene. This gene is expressed
when cells reach their preprogrammed age or are damaged. The response to this protein is either apoptosis or

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 Chapter 3 Genetic Influences on Cell Division, Cell Differentiation, and Gametogenesis 51

the arrest of these cells at the G] or G2 phases of the cell cycle. Other substances synthesized and released in
response to the Tp53 gene product include cytochrome c and the p21 protein, both of which are important
. .
In apoptosls.
The sequence of events in which apoproric signals are received by normal cells starts with endonuclease
enzymes degrading the cell's DNA and mitochondria, thereby releasing cytochrome c. This substance activates
apoproric protease activation factor (Apaf-I), which then activates the enzyme caspase 9. Activation of caspase
9 starts a cascade reaction to activate the whole family of caspases, resulting in the degradation of the cell's
internal structures and fracturing of the cell membrane. The cell breaks into smaller fragments (apoptotic bodies)
that are eliminated as debris by white blood cells. Thus, the genetically controlled processes of apoptosis bal-
anced with the strict controls of cell growth ensure that organs remain optimally functional.
When cell division is nor needed, external signals (such as growth-factor inhibitors and the surrounding of
a cell plasma membrane with other cells) are sent that inhibit the prornirotic cell division signal transduction
pathways (Fig. 3-4). This inhibition leads to low levels ofTKs and reduced levels of prorniroric transcription
factors. Suppressor gene activity is increased, resulting in the production of more suppressor gene products
that inhibit the synthesis of cyclins and CDKs by oncogenes.

Growth
factor
inhibitor Ligand-associated

Cell membrane
~ contactedon all
sides by other cells

Actl~n
1 ors
01
trans ption
1.....
1 __
-e-

1
Decrea.se~.productlon;;(l-+ Less cell
01cycllns; Increased division
production of suppresso
gene products

Figure 3-4 External signals that inhibit the sample signal transduction pathway, resulting in
greatly reduced cell division.

ERRNVPHGLFRVRUJ
52 Unit [ Basic Concepts From Molecular Genetics

Growth
factor Ligand-associated
receptor

Cell plasma
membrane

Activation01
• --- suppressor
gene products

Decreased production -'L..... Less cell

of cycllns; Increased ~ division
production of suppressor
gene products

Figure 3-5 Suppressor gene activity inhibiting the sample signal transduction pathway, result-
ing in greatly reduced cell division.

Internal cell conditions, such as poor cell nutrition and reduced energy stores, can trigger the activation
of suppressor genes to disrupt the promitoric signal transduction pathways, even when external conditions
indicate a need for cell division (Fig. 3-5). Thus, healthy and active suppressor genes guard against cell divi-
sion when it is not in the body's best interest.
Thus, apoprosis is regulated by different gene produces, particularly suppressor gene products. Many sup-
pressor genes exist, and although all are present in every cell type, specific suppressor genes may be more
active in selected types of tissues. For example, the BRCAI suppressor gene appears most active in suppressing
excessive cell division in breast, ovary, and genitourinary tract tissues.

EARLY EMBRYONIC CELL BIOLOGY

Early embryonic cells are normal cells; however, in the first 8 days after conception, they more closely resemble
cancer cells in their growth panerns. In fact, some of what has been learned about the genetic origins of cancer
has come from studying early embryonic cells.

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 Chapter 3 Genetic Influences on Cell Division, Cell Differentiation, and Gametogenesis 53

Characteristics of Early Embryonic Cells

Appearance
Early embryonic cells have an anaplastic appearance, which means "without a specific shape" (morphoLogy).
They have not differentiated into a specific cell type. At this stage of development, the embryo is a ball of
cells that look like each other rather than like the mature cells they will eventually become (Fig. 3-6). They
are all small and rounded, with a larger nuclear-to-cytoplasmic ratio. The large size of the nucleus indicates
continuing DNA replication.

Function
Early embryonic cells do not perform any specific differentiated functions because they have not yet differenti-
ated into any mature cell type. At this point in development (up to day 8 in humans), they have unlimited
potential for differentiation, a feature known as pluripotency. A pluripotent cell can, under the right condi-
tions, become any cell type in the human body. These are the original "stem" cells. (Differentiation is the
process by which a cell leaves the pluripotent stage and acquires the maturational features and functions of
a speci fic cell type.)

Adherence
Early embryonic cells do not produce cell adhesion molecules; therefore, they adhere loosely to each other.
As a result, early embryonic cells migrate within the early embryo.

Ploidy
When early embryonic cells are generated from normal germ cells (the sex cells of one mature ovum and
one mature spermatozoon [plural, spermatogonia]), they are diploid. This is the only characteristic that early
embryonic cells share with normal differentiated human cells.

Figure 3-6 Appearance of early embryonic cells.

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54 Unit [ Basic Concepts From Molecular Genetics

Cell Growth
Early embryonic cells do not display contact inhibition of cell growth, even when all sides of these cells are
in continuous contact with the surfaces of other cells. These cells perform rapid and continuous cell division,
with a minimal amount of time spent in Go. They reenter the cell cycle nearly as soon as they leave it and
do not respond to signals for apoptosis. These cells have long relorneres that do not shorten with each cell
division, and they have a relatively large amount of the enzyme relornerase. (Later in fetal life, apoptosis is
needed for normal development; however, it is not a characteristic of early embryonic celis.) The only job for
an embryo during the first week after conception is to increase the number of cells within it.

COMMITMENT AND DIFFERENTIATION

Obviously, early embryonic cells must change in some way so that humans are not born as large balls of
undifferentiated cells. That would make performing almost any human function impossible, such as eating,
walking, computing, and so on (as well as make clothing very hard to fit). The change that occurs is known
as commitment and involves adjusting the activity of the promitoric oncogenes and the genes that regulate dif-
ferentiation. At about day 8 after conception in humans, early embryonic cells each commit to a differentiation
pathway and are no longer pluripotent. At this stage, cells have not yet taken on any differentiated features,
but they begin to position themselves within the embryo in areas that will eventually become specific organs
or tissues. So, cells scattered throughout the early embryo that are destined to become heart cells migrate and
join together in the area that will eventually become the chest. Thus, migration continues on a limited basis
after commitment.
Suppressor gene activity increases so that greater control and limits are placed on oncogenes, usually slowing
cell division somewhat. In addition, whatever genes are important for structure and function within specific
organs are selectively expressed. Thus, the genes for heart structure and function are expressed within the
cells destined to become heart muscle cells and are not expressed in ceLIsdestined to become liver cells. This
selective gene expression directs the normal growrh and differentiation into specific body tissues and organs.
With commitment comes strict regulation over cell division. The genes that control cell division in the
embryo and during fetal life are the same ones that control cell division for normal differentiated cells that
retain their mitotic ability. The differences are in timing and the degree of expression. Figure 3-7 shows the
stages of prenatal development.

Early Embryo Stage

Just after conception and for the next 14 days, an unborn baby is known as an early embryo. The cells in this
early embryo have not yet started to differentiate into specific organs or tissues, and they all have essentially the
same appearance (see Fig. 3-6). Because the placenta has not yet completely formed, very few drugs affect an
unborn baby at this stage unless the mother is harmed. However, toxins and infectious organisms can damage
the early embryo and can cause a spontaneous abortion (miscarriage). More commonly, though, genetic issues
that disrupt commitment and differentiation are responsible for miscarriage at this stage.

Embryonic Stage
From the third week of pregnancy to the eighth week of pregnancy (days 15 through 60), the unborn baby
is called an embryo. In this developmental stage, most of the important organs are beginning to differentiate
and form, and some, such as the heart, begin to function. If a pregnant woman is exposed to a teratogen
(a drug; toxin; or infectious agent, such as the Zika virus, that can cause birth defects) during this stage, the

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 Chapter 3 Genetic Influences on Cell Division, Cell Differentiation, and Gametogenesis 55

Very Embryo Fetus Birth

early
embryo Figure 3-7 The three stages of prenatal devel-
-- RiskfOf opment and risk for birth defects from maternal
birth defects
exposure to drugs or other teratogens.

embryo's organ development may be interrupted. This embryonic stage is the time of pregnancy when external
or internal conditions are most likely to induce birth defects. Unfortunately, some women in this stage are
not yet aware they are pregnant.
Failure of a pregnancy to progress from the embryonic stage (week 3 through week 8) to the fetal stage
is a very common feature of many genetic problems, especially inheriting more than or less than the correct
amount of genetic material. In fact, a high number of spomaneous abortions may be the first due that one
member of a couple has a genetic or chromosomal abnormality that affects his or her germ cells.

Fetal Stage
From the ninth week of pregnancy until birth, the unborn baby is called a fetus. In this stage, the organs
have most of their structures organized from selected expression of structural genes. These structures, for the
most part, just continue to grow and get larger. However, tight regulation by suppressor gene products over
oncogene expression is still needed to ensure that organ development continues to proceed at the right rate
and does not overgrow. Although these organs are less likely co be damaged during middle and late pregnancy,
teracogens such as drugs and toxins can still disrupt gene activity and development. At this stage, most birth
defects are attributable to such environmental exposures rather than to genetic issues. However, variation in
gene sequencing and expression can alter (increase or decrease) the susceptibility of the embryo or fetus to
this damage.
The interplay of all genes is a keystone for development. The timing of gene expression and suppression
is critical for development to proceed normally. As strange as it may sound, even apoptosis (programmed cell
death) is an absolute requirement for normal development but must occur within a narrow time frame. For
example, when the face and head structures begin to form, the right half and the left half first develop sepa-
rately. Thus, early in development, we all have a deft palate (in fact, we have a cleft face). The two halves of
the palate first grow vertically in the head rather than horizontally. For the palate to develop correctly as a
single, closed structure, the two halves must rotate upward into a horizontal position. Then the cells on the

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56 Unit [ Basic Concepts From Molecular Genetics

very middle edges of the two halves become "sticky" because of limired apoprosis in this region. The stickiness
of the twO halves allows tissue fusion to occur. The timing here is critical. The edges are sticky for only about
24 hours. So, if the twO halves of the palate rotate a day later than usual, they will not fuse. This results in
the palate remaining as a deft rather than as a fused single palate. (This is just one mechanism responsible
for the development of a deft palare.) The timing of gene expression determines which day the palate halves
rotate and when apoprosis occurs to make the edges sticky.
Another example of the need for apoprosis in normal development is the growth of separate fingers and
toes. Before these digits first form, the hands and feet are "paddles." The areas between the digits are solid
tissue. This tissue must undergo apoptosis for the digits to separate and function individually. If apoptosis
occurs tOOearly, the digits will be underdeveloped. If it occurs tOOlate, one or more digits may be fused, a
condition called syndactyly.
Think about prenatal development as a very complex dance with thousands of participants each simultane-
ously performing separate steps and maneuvers that interact. The choreography and timing of all actions must
be precise for the outcome to appear as a unified performance. Think how unfortunate it would be for one
performer to leap out from a balcony with no other performers present below at the right time to catch him or
her. Various genes control the expression and the timing of all events related to development. Although external
conditions can influence how well development proceeds, genetic influences determine whether it proceeds.

GAMETOGENESIS
Overview
Gametogenesis is the conversion of diploid germ cells into haploid gametes that are capable of uniting at
conception to stan a new person. It represents a specific rype of cell differentiation and maturation. Convert-
ing precursor diploid germ cells into haploid gametes requires the process of meiosis. Meiosis or meiotic cell
division is a special rype of cell division occurring over several steps in which the chromosome number per
cell is reduced to half This type of cell division occurs only in germ cells. The process of meiosis for gamete
formation involves only one episode of DNA synthesis and twO separate rounds of meiotic cell divisions.
This process takes time and occurs at differem rates for the ova compared with the sperm. The outcome in
terms of gamete numbers also differs between the ova and sperm. For sperm, one precursor diploid germ cell
undergoing meiosis results in the eventual formation of four haploid marure sperm, each capable of causing
fertilization. For ova, one precursor diploid germ cell that completes meiosis results in the formation of only
one haploid mature ovum capable of being fertilized, along with up to three haploid small cells, known as
polar bodies, that contain almost no cytoplasm. Table 3-1 summarizes the key differences in meiosis between
spermatogenesis and oogenesis.
The term haploid during the process of gametogenesis refm to both chromosome number and DNA content.
This distinction is important in understanding how we can have haploid numbers after both meiosis I and
meiosis II. The two cells resulting from meiosis I are haploid for chromosome number (23), but because each
chromosome at that point has twO chromatids that have not separated, the DNA content is still diploid. At
meiosis II, the chromatids of each of the 23 chromosomes separate. Thus, the two cells undergoing meiosis
II do not replicate either chromosomes or DNA, and each produces two cells that are haploid for both chro-
mosome number and DNA content.

Spermatogenes is
Immature male germ cells, known as spermatogonia. are produced in the seminiferous tubules of the testes
late in fetal development. These cells are nonfunctional (dormant) throughour late pregnancy and childhood.

ERRNVPHGLFRVRUJ
 Chapter 3 Genetic Influences on Cell Division, Cell Differentiation, and Gametogenesis 57

.'!':jlll~t:IIl\ ..

Comparison of Spermatogenesis and Oogenesis

Spermatogenesis Oogenesis
Converts diploid precursor germ cells into mature Converts diploid precursor germ cells into
haploid sperm mature haploid ova
Requires the process of meiosis Requires the process of meiosis
Begins at puberty and continues throughout the life Begins in fetal life and stops when menstruation
span stops
Is a continuous process Is a cyclical process
Completion of meiosis I and meiosis II takes days to Completion of meiosis I and meiosis IItakes
weeks. years and is not complete until after fertilization.
Prophase I is hours to days long. Prophase I is years long.
One diploid precursor cell can ultimately result in the One diploid precursor cell can result in the
formation of four haploid sperm capable of fertilizing a formation of one haploid ovum capable of being
mature ovum. fertilized by a mature sperm and up to three
haploid polar bodies.

The conversion of the diploid spermatogonia into mature sperm, spermatogenesis, does not begin until the
individual enters puberty. At that time, the spermatogonia exit dormancy under the influence of a variety of
hormones and start to develop further. They also become mitotically active, greatly increasing their numbers.
At anyone time after puberty, the seminiferous tubules contain hundreds of millions of spermatogonia in
various stages of development. The final developmental stage before the process of meiosis is the primary
spermatocyte, which is still diploid.

Meiosis I
The primary spermatocyte, which has 46 chromosomes (23 pairs), enters meiosis I, which is the type of
cell division that reduces the chromosome number and has multiple stages or steps. Some of these stages
resemble those in mitosis, whereas others are unique to meiosis. (See Chapter 1 to review the stages of mirotic
cell division.) Figure 3-8 shows an overview of the ploidy changes that occur during spermatogenesis, and
Figure 3-9 shows details of the stages of the process of meiosis. (Stages that are also part of meiosis II are
labeled with a Roman numeral I when the stage occurs during meiosis I and with a Roman numeral II when
the stage occurs during meiosis II.) The primacy spermatocyte enters the cell cycle and progresses through the
phases of G, and S in the same way as for mitosis, including DNA replication during S phase. However, Gz
phase does not really happen in meiosis. Shortly after S phase, M phase for meiosis begins and has additional
steps compared with M phase of mitosis.
Prophase I
On entering M phase, the spermatocyte has double the DNA and chromosome content from DNA replica-
tion during S phase, JUStlike in mitosis. Because each chromosome has sister chromatids, rerraploidy (4N)
now exists, just like in mitosis. During prophase I, the DNA of the replicated chromosomes continuously
condenses. Remember that the metaphase of mitosis is a relatively rapid process. However, in meiosis, it is
much longer. For spermarocyres. the prophase of mitosis is days long (for oocytes, prophase is years long).

ERRNVPHGLFRVRUJ
58 Unit [ Basic Concepts From Molecular Genetics

Spermatogenesis

DNA replication

Maturesperm

Figure 3-8 Overview of ploidy changes during

spermatogenesis.

LEPTOTENE STAGE. The leprotene stage of prophase I resembles the early prophase of mitosis. During this
phase, the four chromatids of each chromosome pair are long, thin threads. These threads become looser and
slightly unwind.
ZYGOTENE STAGE. Chromosome movement occurs during the zygotene stage. The chromosome pairs, with a
total of four chromatids each, line up next to and even on top of each other. For example, the pair of chromo-
some number 3 gets very close to each other, lining up the entire length of the four chromatids along their
axis, a process called synapsis.
PACHYTENE STAGE. Because the four chromatids of each chromosome pair are lined up lengthwise and touch,
the exchanges of chromosome material occur through breaks and rearrangements. The exchanges are called
crossing over, and they occur not just between chromatids from one parent but also among the four chromatids
for both the maternal and paternal chromosomes of the pair (Fig. 3-10). This results in a huge but usually
even "shuffling" of genetic material; therefore, at the end of the pachytene stage, the two chromosomes (with

Figure 3-9 Detailed activity of spermatogenesis from the primary spermatocyte through sperm maturation
using one pair of number 3 chromosomes to show the steps. (Blue = paternally derived chromosome 3;
pink = maternally derived chromosome 3.)

ERRNVPHGLFRVRUJ
 Nucleus of one Meiosis I
primary spermatocyte
NUClear

®
membrane

23 pairs of chromosomes
• G, phase S phase

DNA replication has occurred

(46 chromosomes) Cell is now tetraploid (4N) tor
Diploid (2N) for chromosome chromosomes and DNA content
number and DNA content

Diplotene stage: MP_~

crossing over stops;

'~om@'...
chromosomes separate;

'~.ed
.. __ ~
Pachytene stage Zygotene stage

Tetraploid (4N) tor Tetraploid (4N) tor Tetraploid (4N) tor Tetraploid (4N) tor
chromosome number and chromosome number chromosome number chromosome number
DNA content; maternal and DNA content and DNA content and DNA content

rmb,"'"
and paternal material
total

Diakinesis: nuclear Metaphase Anaphase I Telophase I

membrane disappears

Sister chromatids Two secondary Nuclear membrane

are bound spermatocytes re-forms; sister chromatids
each haploid (1 N) no longer connected at tips
Tetraploid (4N) tor together at the Chromosomes line up,
chromosome number centromere and spindle fibers torm for chromosomes and
and DNA content and the tips diploid (2N) for DNA Each is haploid (1N) for
tetraploid tor chromosome
Ready to move number and DNA content content chromosomes and diploid
into metaphase (2N) for DNA content

~
Meiosis II

About 8 weeks
0,· \.l/
\l./ O,·

Four mature sperm, each haploid

for chromosomes and DNA content,
GG
Four spermatids, each haploid
(1N) for chromosomes and
capable of fertilizing a mature ovum DNA content (just showing for
chromosome number 3)

ERRNVPHGLFRVRUJ
60 Unit [ Basic Concepts From Molecular Genetics

8
--_._../0
Crossoverpoints

Homologouschromosomeso~~
one pair,one from the father -
:.••~.. 'IIiIIII__ •
-
-:~
and one from the mother ::._~
...~--.

Recombined
chromosomes

~
Gametes
Figure 3-10 Crossing over of homologous chromosomes during meiosis I of gametogenesis.

two chromatids each) are now combinations of maternal and paternal genes, rather than one purely mater-
nally derived chromosome and one purely paternally derived chromosome. Think about what that means for
anyone person and how that person receives bits and pieces of genetic material in combination from many,
many parental ancestors (Fig. 3-11). The result is that it is extremely unlikely that any two mature gametes
from the same person will have exactly the same gene alleles at ali loci. It is amazing that often siblings do
look very much alike!
DIPLOTENE STAGE. At the diplotene stage in spermatogenesis, the recombined chromosome pairs now separate,
but the chromatids for each chromosome remain connected. Crossing over halts, and the two-armed (bivalent)
chromosomes coil and condense in preparation for segregation.
Diakinesis
At this point, the 46 chromosomes are coiled inro very compact structures. The two chromatids of each
chromosome are firmly attached at the cenrer and at the terminal areas. The nuclear membrane disperses, and
these chromosomes move into the cytoplasm.
Metaphase I
The homologous chromosome pairs move to the center of the spindle area of the cell, much like what occurs
in mitosis. Spindle fibers form and attach to each chromosome.
Anaphase I
Complete separation of whole chromosome pairs (not the chromatids) occurs during this phase, resulting in
two secondary spermatocytes mat are now haploid for chromosome number (23 individual chromosomes) and
diploid for DNA content, Those recombined chromosomes that are each a mixture of maternal and paternal
genes sort randomly into the two secondary spermatocyres.

ERRNVPHGLFRVRUJ
 Chapter 3 Genetic Influences on Cell Division, Cell Differentiation, and Gametogenesis 61

Paternal grandparents Maternal grandparents

CID®®®
~ ~ ~ ~
Father ~ / Mother

(ill You
Figure 3-11 Consequence of crossing over for one chromosome in
gametogenesis for two generations.

Telophase I
The telophase I stage of meiosis I resembles the interphase stage of mirosis. The coiled single chromosomes
(with two chromatids) in each secondary spermatocyre relax somewhat. These two secondary spermarocytes
are structurally alike in terms of chromosome number, cytoplasm, and intracellular organelles. Their genetic
material is very different in terms of which gene alleles came from which parenr. Under normal circumstances,
these two secondary spermatocytes will each enrer meiosis II without further DNA synthesis or replication.

Meiosis II
For both ova and sperm, meiosis II is a relatively rapid process. This division is sometimes called an equational
division because the number of chromosomes remains the same (23). In many ways, meiosis II resembles
mitosis. Within each of the two secondary spermarocytes, the individual chromosomes line up in the center,
spindle fibers attach to the kinerochores, and the chromatids are pulled apart. Each chromatid segregates
independently, so each secondary spermatocyte produces two spermatids that are haploid both for chromo-
some number and DNA content,

Sperm Maturation
Although the spermatids generated at the end of meiosis II are genetically correct, they are not yet mature
gametes capable of fertilizing an ovum. (Fertilization is the union of one mature haploid sperm with one
mature haploid ovum to form a diploid zygore.) Over a period of about 2 months, these sperrnarids continue
to develop and change. Changes include losing most of the cytoplasm, condensing the nucleus, developing a

ERRNVPHGLFRVRUJ
62 Unit [ Basic Concepts From Molecular Genetics

functional tail (flagellum), and acquiring the acrosomal material and cap. These mature sperm are stored in a
tubular environment just outside of the testes called the epididymis before exiting the male reproductive system.
After puberty, men produce mature sperm throughout their ~re spans. The rate of sperm production decreases
with age but does not Stop. Even though the sex chromosomes in a male are not completely homologous,
they do line up as a pair during meiosis I and meiosis II. The final result of normal, complete spermatogenesis
from one spermatogonium is the generation of four haploid spermatocyres, with two having 22 autosornes
and 1 X and two having 22 autosornes and 1 Y.

Oogenesis
Oogenesis is the process oHorming oocytes from precursor germ cells. Although oogenesis, like spermatOgen-
esis, requires converting diploid cells into haploid cells through the process of meiosis, the timing and overall
results differ significantly. Figure 3-12 shows an overview of the ploidy changes that occur during oogenesis,
and Figure 3-13 shows details of the stages in the process of meiosis.
Immature female diploid germ cells, known as oogonin, undergo quite a lot of cell division in both embry-
onic and fetal life. At 9 weeks after conception, the early ovary contains at least half a million oogonia. By

Figure 3-12 Overview of ploidychanges during oogenesis. Oogenesis

8 ooqcnum

~ DNA replication

8 Primary oocyte

oocytes V~
Secondary ~2N ~ F'm polar body

~ J
One mature
ovum
G) Three polar bodies

Figure 3-13 Detailed activity of oogenesis from the primary oocyte through maturation of one mature ovum
using one pair of number 3 chromosomes to show the steps. (Blue = paternally derived chromosome 3; pink
= maternally derived chromosome 3.)

ERRNVPHGLFRVRUJ
 Nucleus of primary oocyte Meiosis I
Nuclear

®
membrane

G, phase S phase

23 pairs of chromosomes DNA replication has occurred

(46 chromosomes) Cell is now tetraploid (4N) for
Diploid (2N) for chromosome chromosomes and DNA content
number and DNA content

Mphase ~
Diplotene stage
Crossing over continues for years.

-(] III@
@....
__
Cell synthesizes more proteins, Pachytene stage Zygotene stage Prophase I

c:~~~~:I)°"'·III.les ... __

Tetraploid (4N) for chromosome Tetraploid (4N) for Telraplold (4N) for Tetraploid (4N) for
number and DNA content; chromosome number chromosome number chromosome number
matemal and paternal material and DNA content and DNA content and DNA content
totally recombined. Cell stays at
this stage for years, then
prepares for metaphase

First polar body Telophase I

Metaphase

"

Nuclear membrane re-forms; sister

Chromosomes line up One secondary oocyte and chromatids no longer connected at tips
and spindle fibers form the first polar body, each
tetraploid for chromosome haploid (1N) tor chromosomes Each is haploid (1N) for chromosomes
number and DNA content and diploid (2N) for DNA content. and diploid (2N) for DNA content
The secondary oocyte retains the
cytoplasm, proteins, fats, and
organelles.
~
Meiosis II

One mature ovum forms with up to

three polar bodies. Each is haploid
(1N) for chromosomes and DNA content
Oust showing for chromosome number 3).
At fertilization, the polar bodies separate
from the ovum.

ERRNVPHGLFRVRUJ
64 Unit I Basic Concepts From Molecular Genetics

the fifth month, several million diploid oogonia are present in each of the two ovaries. Many of these diploid
cells undergo degeneration without further maturation. Those that progress to mature ova begin this journey
by entering meiosis I during the fetal period.

Meiosis I
For the early part of meiosis I, oogonia undergo the same processes at the same rate as spermatogonia. They
first start by entering the cell cycle and proceeding through 5 phase with DNA replication. Like spermato-
gonia, they bypass G2 and enter prophase of metaphase I. The leptotene, zygotene, and pachytene stages
continue, and the events that occur in these stages are very similar to those that occur during prophase I for
spermatogenesis.
However, the eventS in the diplotene stage for oogenesis differ from those occurring during spermatogen-
esis. The four chromatids per chromosome pair lengthen rather than COntract, and the nucleus becomes quite
large. The chromatids become very loose, taking on a brushlike appearance. The threads of DNA unwind at
many points, and much more crossing over among homologous chromatids occurs. Not only is more DNA
in close contact for crossing over, but also this stage lasts for years, at least until puberty. Thus, prophase I
of meiosis I is arrested for a prolonged period during oogenesis. By birth, most female infants have about a
million primary oocytes trapped in meiosis I in both ovaries, and no further proliferation of these cells occurs.
The majority of primary oocytes will regress and degenerate so that by the time a girl begins puberty, only
about 40,000 oocyres remain.
During the diplotene stage, other nonnuclear but essential growth of the oocyces occurs, especially of the
proteins, fats, developmental information, and cytoplasmic organelles. (This content is critical for proper
development after fertilization occurs.) So, the extended diplotene stage is not truly dormant, although the
process of meiosis is on hold.
After puberty, groups of primary oocyres continue meiosis I because of hormonal influences. In these cells,
diakinesis occurs, with events similar to those in spermatogenesis. In anaphase I, however, the results are differ-
em. Complete separation of the chromosome pairs (not the chromatids) occurs during this phase, resulting in
one secondary oocyte and the first polar body (see Fig. 3-13). Both new cells are now haploid for chromosome
number (23 individual chromosomes) and diploid for DNA content. Those recombined chromosomes thar are
each a mixture of maternal and paternal genes sort randomly into the two new cell structures. However, they
are not equal in terms of cytoplasm and size. The secondary oocyte has all the extremely important cytoplasm,
and the first polar body has minimal cytoplasm. The cytoplasm of the secondary oocyte and eventually of
the ovum is important because it contains the mitochondria, the organelles responsible for chemical energy
production in the form of ATP (adenosine triphosphate). This ATP is needed to drive cell division and all the
other energy-requiring actions involved in cell growth. Sperm have very little cytoplasm and cannot contribute
to the nonnuclear ATP and proteins needed to continue cell division after conception.
Another difference at this point is that the polar body usually does not separare completely from the sec-
ondary oocyte but remains connected by the plasma membrane.
Completion of meiosis I of the primary oocyte into a secondary oocyte and a polar body does not happen
until jusr before ovulation. This means that if a girl begins mensuuating at age 10 years and has her first
ovulatory cycle that year, the ova released at ovulation that year have been trapped in prophase of meiosis I
for more than 10 years. If she continues to menstruate and is ovulatory until age 50, rhe last ovum released
at ovulation has been trapped in prophase of meiosis I for that entire time! During that long time, plenty of
opportunity exists for chromosome breaks and rearrangements. Therefore, in women, oogenesis is a limited
process that occurs cyclically only during the menstrual years. By the time a woman StopS menstruating, she
may have fewer than 1,000 primary oocyres left in both ovaries. On average, a woman forms only about
400 secondary oocytes in her lifetime.

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 Chapter 3 Genetic Influences on Cell Division, Cell Differentiation, and Gametogenesis 65

Meiosis II
In theory, meiosis II occurs in both the secondary oocyte and the first polar body. Researchers have speculated
that the first polar body might not always undergo meiosis II (it certainly is not needed because the polar
body should not be capable of being fertilized).
Meiosis II of the secondary oocyte occurs only if fertilization takes place. The result of meiosis II of the
secondary oocyte is the maintenance of chromosome number (23) and reduction of DNA so that the ovum
is haploid for both the chromosome number and the DNA content. Another polar body is formed and also
is haploid for chromosome number and DNA content. If the first polar body also undergoes meiosis II, the
outcome of meiosis of one oogonium is the formation of one mature haploid ovum that is fertilized and three
haploid polar bodies that are nor capable of supporting fertilization (see Fig. 3-13).

Ferti lization
Each month, usually one ovum matures and gets larger under the influence of several hormones. This mature
ovum has a plasma membrane that is surrounded by a thicker membrane (zona pefLucitk) and a layer of fol-
licle cells within a "shell" that also contains a gelatinous fluid. At ovulation, this entire mature ovum and its
shell are released from the ovary. The sheU separates from the ovum, although some follicular cells remain,
surrounding the ovum like a halo known as the corona radiata. At fertilization, the sperm must penetrate this
halo of cells, liquids, and the zona pellucida before penetrating the ovum's plasma membrane. The acrosomal
area of the sperm head contains enzymes that allow the corona radiata to be penetrated (and the acrosome
falls off the sperm). When the sperm binds with and then penetrates the plasma membrane of the ovum,
several different processes occur. The ovum's plasma membrane changes its electrical charge, preventing any
other sperm from entering. The sperm's tail and midsection drop off and do not enter the OVWTI. The sperm's
haploid nucleus fuses with the haploid nucleus of the ovum. The result of this action is a zygote (a single
diploid cell formed from fertilization that is capable of developing into a multicelled embryo). At the same
time, the polar bodies separate completely from the oocyte.

SUMMARY
Strict genetic control over cell division is required throughout a person's lifetime, from conception to death,
to ensure optimal physiologic function. Loss of genetic control not only forms the basis for many anatomic
and physiologic problems, but it is also the source of all types of abnormal cell growth, such as cancer.

GENE GEMS

• Whenever normal cells are replaced with scar tissue, some tissue or organ function is reduced.
• The maintenance of healthy tissues and organs is dependent on the proper balance of cell division
with apoptosis .
• Suppressor gene products limit cell division by controlling the expression of oncogenes so that mitosis
occurs only when it is needed and to the extent it is needed
• Oncogenes are normal genes, and their products are prorniroric, The controlled expression of oncogenes
is needed for normal cell division.
Continued

ERRNVPHGLFRVRUJ
66 Unit [ Basic Concepts From Molecular Genetics

• Oncogenes are heavily expressed during early embryonic development.

• Apoprosis of differentiated cells ensures that a greater number of optimally functional cells populate a
tissue or organ that retains its mitotic ability.
• Commitment is an event critical to the development of an embryo that has the potential to differenti-
ate into a fetus.
• Tight genetic regulation of cell growth is essential for health throughout the life span, not JUStfor
prenatal development.
• The mature ovum is the largest single cell in the human body and contains all the cytoplasm necessary
to suppOrt the initial growth of the zygote.
• The mature sperm is the smallest single cell in the human body.
• The process of meiosis for gamete formation involves only one episode of DNA synthesis and two
separate rounds of meiotic cell divisions.
• The end result of meiosis I is rwo pregameres that each are haploid for chromosome number (23) and
diploid for DNA content.
• Meiosis II does not involve any additional replication of DNA or chromosomes.
• The end result of meiosis II is the formation of four cells that are totally haploid for chromosome
number and DNA COntent.
• The entire process of meiosis for spermatogenesis occurs after puberty, takes days, and continues through-
out the life span.
• The entire process of meiosis for oogenesis begins in fetal life, is not completed until fertilization occurs,
and StOpSwhen menstruation StOps.
• "Crossing over" makes it unlikely for any twO mature gametes from the same person to have exactly
the same gene alleles at all loci.
• Teratogens are substances (drugs, toxins, infectious organisms) that, when exposure occurs during
pregnancy, can disrupt development and cause minor and major birth defects.
• The embryo is most susceptible to the effects of teratogen exposure between days 15 and 60 after
conception.

...
Self-Assessment Questions .
1. Which statement most closely defines the term teratogen?
a. Programmed cell death necessary to ensure optimally functional cells within a tissue
b. A single diploid cell formed from fertilization that can develop into a multicelled embryo
c. A drug, toxin, or infectious agent capable of disrupting development and causing birth defects
d. The process of chromosomal reduction cell divisions required during gametogenesis to ensure that
gametes are haploid
2. How are gametes different from zygotes?
a. Zygotes are fertilized ova with 46, XX karyorypes, and gametes are fertilized ova with 46,
XY karyorypes.
b. Zygotes are fertilized ova with 46, XY karyorypes, and gametes are fertilized ova with 46,
XX karyorypes,
c. Zygotes are the cells that result from fertilization, and gametes are the mature sex cells of both genders.
d. Zygotes are usually haploid, whereas gametes are usually diploid.

ERRNVPHGLFRVRUJ
 Chapter 3 Genetic Influences on Cell Division, Cell Differentiation, and Gametogenesis 67

3. How are "anaplasia" and differentiation interrelated?

a. The more anaplastic a cell appears, the less differentiated it is.
b. The greater the anaplasia, the more differentiation is present in a cell.
c. Differentiated cells avoid apoptosis, whereas anaplastic cells respond to apoproric signals.
d. Anaplastic cells are inhibited from entering the cell cycle, whereas differentiated cells never leave
the cell cycle.
4. What would be the potential outcome of excessive suppressor gene expression?
a. Increased risk for eventual cancer development
b. Reduced ability to replace nonfunctional cells
c. Reduced response to signals for apoptosis
d. Loss of differentiated functions
5. What structure, substance, or process preventS normal differentiated cells from migrating away from
their parent organs or tissues?
a. Cell adhesion molecules
b. Restriction point controls
c. Plasma membrane growrh-facror receptors
d. Increased amounts of transcription factors
6. Which tissue grows only by hypertrophy after maturation is complete?
a. Skin
b. Liver
c. Intestinal lining
d. Skeletal muscle
7. Why is crossing over a more amplified process in oogenesis than in spermatogenesis?
a. The outcome of oogenesis is the formation of one mature ovum, whereas that of spermatogenesis
is the formation of four mature sperm.
b. Prophase 1 in spermatogenesis is hours to days in length and is years in length for oogenesis.
c. Women undergo the process of meiosis for less of their lifetimes than men do.
d. The completion of meiosis II in oogenesis occurs after fertilization.
S. What change is the first result of commitment?
a. Loss of pluriporency
b. Loss of migratory ability
c. Reduced time spent in Go
d. Appearance of differentiated features

Self-Assessment Answers
1. c 2. c 3. a 4. b 5. a 6. d 7. b 8. a

ERRNVPHGLFRVRUJ
ERRNVPHGLFRVRUJ
Gene Expression

69

ERRNVPHGLFRVRUJ
 pier ~ _ ___.
Patterns of Inheritance
Learning Outcomes
1. Analyze the characteristics of autosomal-dominant, autosomal-recessive, sex-linked-recessive, and sex-linked-
dominant parrerns of inheritance for monogenic trairs.
2. Explain how penerrance and expressiviry change the expected expression of some autosomal-dominant
traits and disorders.
3. Explain why X-linked-recessive disorders are expressed at a higher rate in males than in females.
4. Use a Punnert square to predict the probability of transmitting a monogenic trait to offspring.
5. Explain how complex diseases differ from diseases that are transmitted following Mendelian parrerns.
6. Describe the impact of modifier genes on expression of a genetic trait.
7. Explain how the liability model is used to describe genetic risk in complex disease.

Key Terms
Carrier Kindred Polygenic traits
Codominant expression Liability model Recurrence risk
Complex traits Mendelian inheritance Regression to the mean
Expressivity Modifier genes Risk alleles
F generations Monogenic trait Segregate
Genetic resistance P I generation Threshold
Genetic susceptibility Penetrance Transmission
Hemizygosity Pleiotropy Twin concordance

INTRODUCTION
Mendelian inheritance refers to the rules for inheritance of monogenic traits as first recognized by Gregor
Mendel in the 19th century. These rules help explain how traits can be inherited from remote ancestors as
well as more directly from our parenrs. A monogenic trait or single-gene trait is one in which the expression is
determined by the input of the twO alleles (one from each parent) of a single gene. Because alleles segregate,
meaning that normally only one allele of a pair is rransmirred from each parent to any child, a single gene

70

ERRNVPHGLFRVRUJ
 Chapter 4 Patterns of Inheritance 71

remains distinct and does not combine with alleles from other genes. Thus, inheritance patterns from one
family generation to another can be traced. Family history information in the form of a pedigree is essential
ro recognizing patterns of Mendelian inheritance of single-gene traits and disorders. Although information for
constructing and interpreting pedigrees is presented in Chapter 8, pedigrees that exemplify specific panerns
also are used in this chapter.
Mendelian rules and patterns do nor apply to traits or structures that involve the input of more than one
gene, known as polygenic traits. In addition, other types of inheritance exist, and other factors influence the
expression of monogenetic gene traits and polygenetic gene traits.

MENDELIAN INHERITANCE
Overview
Mendel first worked out pattems of inheritance for what we now know as single-gene traits using plant
models in the 19th century. These pattems were then applied using animal models rather than humans.
Plants were used in this early work because they demonstrated the inheritance of certain characteristics over
many generations in a single year. Obviously, waiting to observe inheritance from one generation to the next
in the human situation would rake many years and would make drawing conclusions more difficult. Some
of Mendel's conclusions regarding the patterns of inheritance for single-gene traits were quite remarkable and
accurate considering he never saw a chromosome or DNA.

Dominant and Recessive Expression

Mendel's work explained the concepts of dominant traits and recessive traits. His observations over 10 years
of different types of garden peas led him to determine that specific varieties of peas had unique traits. For
example, one variety of peas always produced wrinkled seeds when fertilized with pollen from the same pea
type, whereas another variety of peas always produced smooth seeds when fertilized with pollen from its same
pea type.
Modeling out this information yielded the patterns shown in Table 4-1, in which PI generation indicates
the initial parental generation of a family or group (in this case, peas) being observed for a specific trait or traits.
For example, if you were examining your family history, starting with your great-grandparents, they would be
the PI generation. The F generations are the succeeding generations of offspring or progeny produced from
the parental generation. Each succeeding generation is designated by a numeric subscript (F" F2, F3, etc.), so F,
is the first-generation offspring or progeny after the parental generation, F2 is the second-generation offspring
or progeny, FJ is the third-generation offspring or progeny, and so forth, for succeeding generations. So, if
your great-grandparents are the PI generation, your grandparents are the F" your parents are the F2, you and
your siblings are the F j, and your children are the F4 generations. In Mendel's famous pea experiment, after
the parental generation, each generation of progeny was fertilized with pollen from the same generation. (So,
this was an incestuous pea family!)
When Mendel experimented with cross-pollination (crossbreeding) of the tWOpea varieties, the expected
response was that the F, generation would have 50% smooth seeds and 50% wrinkled peas. However, the
inheritance of seed texture came out differently than expected. Table 4-2 shows Mendel's results of using a
smooth-seed pea variety fertilized with the pollen of a wrinkled-seed pea variety. Note that the F, generation
showed only smooth seeds, although wrinkled-seed peas were half of the parental generation used in the
fertilization process. Not until the second F generation do wrinkled-seed peas finally appear, and even then,
they are not present as 50%.

ERRNVPHGLFRVRUJ
72 Unit II Gene Expression

.'!.1:i.:::tr!!!!IIII
Mendel's Observations of Seed-Texture Inheritance With Self-Pollination
Generation Seed Texture Seed Texture
P, (parental generation) Smooth seeds pollinated with Wrinkled seeds pollinated with
smooth seeds wrinkled seeds
F, (first generation after All smooth seeds produced All wrinkled seeds produced
parental generation) Self-pollination of F, seeds Self-pollination of F, seeds
F2 (second generation) All smooth seeds produced All wrinkled seeds produced
Self-pollination of F2 seeds Self-pollination of F2 seeds
Fa (third generation) All smooth seeds produced All wrinkled seeds produced
Self-pollination of Fa seeds Self-pollination of F3 seeds
F4 (fourth generation) All smooth seeds produced All wrinkled seeds produced

Mendel's Observations of Seed-Texture Inheritance With Cross-Pollination

Generation Seed Textures
-
P, (parental generation) Smooth seeds cross-pollinated with wrinkled seeds
F, (first generation after parental generation) All smooth seeds produced
Self-pollination of F, smooth seeds:
F2 (second generation) Smooth and wrinkled seeds produced in a ratio of three
smooth seeds to one wrinkled seed

From this and other experiments, Mendel correctly concluded that two elements control the inheritance
of a trait (one from each parent)-in this case, seed rexrure=-and that the elements were not always equal in
strength (in this case, the ability to be expressed). We now know that these two hereditary elements are the
two alleles of a single gene. As described in Chapter I, variation in allele "strength" is responsible for the vari-
able expression of a single-gene trait when the pair of alleles is mixed (heterozygous). When both parent pea
seeds have the same hereditary element or genotypes (homoz.ygous), all offspring in succeeding generations have
the same appearance or phenotype expression. For homozygous pairs, the phenotypes and the genotypes are
identical. When the parent seeds are heterozygous for seed texture alleles, the first-generation offspring express
only the stronger or dominant allele even though both alleles are present in all offspring. In this situation,
the appearance or phenotype is different from the genotype (the appearance of the peas in the FI generation
is smooth even though the seed-texture alleles consisted of one gene allele for smooth texture and one gene
allele for wrinkled texture).
The mixed seed textures in the F2 self-fertilized generation led Mendel to determine that the hereditary
element (gene allele) for smooth texture was dominant, and the hereditary element for wrinkled texture was
recessive. He predicted that dominant traits could be expressed in the phenotype when the genorype for that
trait was either homozygous or heterozygous, but recessive traits could only be expressed in the phenorype
when the genorype for that trait was homozygous.

ERRNVPHGLFRVRUJ
 Chapter 4 Patterns of Inheritance 73

.'!':'IIII~='t
Mendel's Observations of Flower Color With Cross-Pollination Showing
Codominant Expression
Generation Flower Colors
P1 (parental generation) White flowers cross-pollinated with red flowers
Fl (first generation after parental generation) All pink flowers produced
Self-pollination of Fl pink flowers:
F2 (second generation) White, red, and pink flowers produced in a ratio
of one white to two pink to one red

Codominant Expression
Mendel also defined the issue of incomplete dominance or codominant inheritance using cross-pollination of
the colorful four-o'clock flower. In cross-pollinating red Rowers with white Rowers in the parental generation,
Mendel predicted that only the dominant color trait would be expressed in the FI generation, with both
colors being expressed in the F2 generation (in a 3: I ratio). Because red was a stronger, bolder color, Mendel
expected that the first-generation flowers from this cross-pollination would all be red. Instead, as shown in
Table 4-3, the flowers in the first-generation progeny were all pink, indicating that the gene allele for red and
the gene allele for white (flower color being a single-gene trait) were equally expressed, known as codorni-
nant expression. Flowers in the second generation of this cross-pollination were red, pink, and white in a
1:2: 1 ratio. Thus, in codorninant inheritance, the phenotype accurately expresses the genotype. Red flowers
must have two red gene alleles (homozygous), pink flowers must have one red gene allele and one white gene
allele (heterozygous), and white flowers must have two white gene alleles (homozygous).

Pleiotropy
Many single genes control the expression of just one trait. However, some single genes have effects in more
than one tissue or organ. This type of influence is known as pleiotropy. Usually, the pleiotropic gene codes
for a substance or a structure that is found in more man one tissue or organ. Thus, a problem with that gene
will result in changes that are expressed in more man one organ or body area. One example of a gene with
pleiotropic influence is the CFTR (cystic fibrosis transmembrane conductance regulator) gene, which codes for
a membrane chloride channel that controls how chloride and bicarbonate move through specific membranes.
Mutations in this gene are responsible for me disease cystic fibrosis (CF), which is discussed in Chapter 11.
The manifestations of this disease are seen in a variety of tissues and organs in which chloride transport is
important (e.g., lungs, pancreas, liver, testes, and salivary glands). So, although this gene codes for only one
protein, mutations in the gene are expressed in multiple tissues and organs. Pleiotropy or pleiotropic effects are
seen in genes that have autosomal-dominant transmission panerns and in those that have autosomal-recessive
transmission patterns.

Transmission of Monogenic Inheritance Patterns

Expression of any monogenic trait depends on the inheritance of dominant or recessive alleles as well as whether
the gene is located on an autosome or on a sex chromosome. The specific inheritance patterns of a monogenic
trait can be assessed based on family history without knowing a person's genotype. Transmission is the term

ERRNVPHGLFRVRUJ
74 Unit II Gene Expression

used to describe how a trait is inherited or passed from one human generation to the next. Transmission
patterns are determined by examining the way a trait is expressed through several generations of a family. A
common method of examining emerging transmission patterns is by pedigree analysis of a kindred. A kindred
(sometimes termed a kinship) is the extended family relationships over several generations.
As described in Chapter 8, a pedigree is a pictorial or graphic illustration of family members' places within
a kindred and their history for a specific trait or health problem over several generations. The pattern of
inheritance for a single-gene trait can be identified by examining the expression of the trait as it is transmit-
ted over several family generations. At least three family generations must be explored to draw supportable
conclusions about trait transmission. (Remember that Mendel examined hundreds of plant generations to
develop the rules regarding specific patterns of inherirance.)

Autosomal-DominantTransmission
Autosomal-dominant (AD) single-gene traits have the controlling gene alleles located on an autosomal chromo-
some. The trait is expressed regardless of whether the person is homozygous or heterozygous for the dominant
allele. Criteria for AD patterns of inheritance include the following:
• The trait is found in about equal distribution between male and female family members.
• The trait has no carrier status (the person with even one dominant allele expresses the trait).
• The trait appears in every generation, with clear transmission from parent to child.
• The risk for an affected person who is heterozygous for the dominant allele to pass the trait to his or her
child is 50% with each pregnancy.
• The risk for an affected person who is homozygous for the dominant allele to pass the trait to his or her
child is 100% with each pregnancy.
• Unaffected people do not have the allele and have essentially zero risk for transmitting the trait to their
children.
Figure 4-1 shows a typical pedigree with the transmission of an AD trait. Table 4-4 lists common physical
characteristics and disorders that have AD transmission. A key feature of AD traits is that they are expressed
whether both alleles are dominant or only one allele is dominant. Thus, when a dominant allele is paired with
a recessive allele, only the dominant allele is expressed.
One important discinccion must be made between normal traits with an AD transmission and disorders
with an AD transmission. A person can be homoz.ygous for the dominant alleles of a normal trait with an AD

Figure 4-1 Pedigree showing a typical autosomal-

dominant pattern of transmission for a monogenic
(single-gene) trait.
II

III

o Unaffected female • Affected female

D Unaffected male • Affected male

ERRNVPHGLFRVRUJ
 Chapter 4 Patterns of Inheritance 75

Three Most Common Mendelian Patterns of Inheritance for Monogenic Traits

and Disorders
Pattern of Inheritance

Autosomal Dominant Traits

Blood type A
Blood type B
Free earlobes (not attached to head)
Taste sensitivity to phenylthiocarbamide (PTC)
"Widow's peak"
Disorders
Achondroplasia
Diabetes mellitus type 2·
Ehlers-Danlos syndrome
Familial adenomatous polyposis
Familial melanoma
Familial hypercholesterolemia
Hereditary non polyposis colon cancer (HNCC)
Huntington disease
Long OT syndrome and sudden cardiac death**
Malignant hyperthermia (MH)
Marian syndrome
Myotonic dystrophy
Neurofibromatosis (types 1 and 2)
Polycystic kidney disease** (types 1 and 2)
Polydactyly
Porphyria
Retinitis pigmentosa**
Syndactyly
von Willebrand disease
Autosomal Recessive Traits
Earlobes attached to head
Middle finger shorter than second or fourth finger
Lack of taste sensitivity to phenylthiocarbamide (PTC)
Disorders
Albinism
AJpha-l antitrypsin deficiency
Ataxia telangiectasia
Beta thalassemia
Bloom syndrome
Cystic fibrosis
Gaucher disease
Hereditary hemochromatosis
Hunter syndrome
Hurler syndrome
Continued

ERRNVPHGLFRVRUJ
76 Unit II Gene Expression

.f!1:t'~~I.~
Three Most Common Mendelian Patterns of Inheritance for Monogenic Traits
and Disorders-cont'd
Pattern of Inheritance
Lesch-Nyhan syndrome
Phenylketonuria (PKU)
Sickle cell disease
Tay-Sachs disease
Xeroderma pigmentosum
Sex-Linked Recessive Duchenne muscular dystrophy
Fragile X syndrome
Glucose-6-phosphate dehydrogenase deficiency
Hemophilia
Red-green colorblind ness
Severe combined immune deficiency (SeIDI**

'Some disorders haveboth a genetic and a nongenetic form.

.••Some disorders have more than one genetic form and can also be aUlosomalrecessive.

transmission pattern, such as taste sensitivity or "widow's peak." However, many health problems that have
an AD transmission pattern do not show homozygous genotypes. For these disorders, the homozygous AD
genotype appears lethal, with loss at the embryonic or feral pregnancy Stages or within the first L2 months after
birth. Examples include Huntington disease (HD) and achondroplasia. Living people with these disorders are
heterozygous for the mutated dominant allele. This distinction slightly changes the predictability of the disorder.
Some health problems inherited as AD single-gene traits are not apparent at birth but develop as the person
ages. Two examples are HD and some forms of hearing loss among older adults. Even when a single-gene
trait is present at birth, variation in expression is possible. Two factors that affect the expression of some AD
single-gene traits are penerrance and expressivity.
Penetrance
Penetrance is how often a gene is expressed within a population when it is present. Penetrance is calculated
by examining a population of people known to have the gene mutation and determining the percentage of
people within that population who ever express the condition coded by the gene. Some AD genes have greater
penetrance than others. For an AD genetic disorder that has high penetrance, among L 00 individuals who
have one allele, nearly L 00% will express the disorder. For example, the gene for HD, which is a degenerative
neurologic disorder, has an AD pattern of transmission with a high degree of penetrance. Therefore, the risk
for a person who has one HD allele to develop this disease approaches L 00%, although gender differences and
other factors influence the age of disease expression and the rate of neurologic deterioration.
Some dominant gene alleles have "reduced" penetrance. This means that a person who has the gene muta-
tion has a risk of less than L 00% for expressing the gene. One example of an AD gene allele with reduced
penetrance is polydactyly, a condition in which a person has one or more extra digits on the hands or feet.
This gene has a penetrance rate of about 80%, which means that of 100 individuals who have the gene, only
about 80% have one or more extra digits. However, even those individuals who have the gene mutation but
do not express it can transmit the gene to their children, who then may express the trait and have extra digits.

ERRNVPHGLFRVRUJ
 Chapter 4 Patterns of Inheritance 77

So, having a gene mutation does not absolutely predict that the person will express the health problem, but
the risk is higher than for a person who does not have the gene mutation.
Expressivity
Expressivity is a personal issue (rather than a population issue) in which the degree of gene expression varies
by the person who has a dominant gene for a health problem. The gene is always expressed, but some people
have more severe problems than do others. For example, the gene mutation for one form of neurolibrornarosis
(NF 1) is dominant. Some people with this gene mutation express it as only a few areas of light brown skin
tone known as caje-au-fait spots. Other people, even within the same family, who have the same gene mutation
may develop hundreds of tumors (neurofibromas) that protrude through the skin. A person with low expression
of this problem can transmit the gene to his or her child, who then may have high expression of the disorder.
The reverse also is true. A person with high expression can transmit the gene to his or her child, who then
may have low expression of the disorder. So degree of expressiviry is not predictable.

Autosomal-Recessive Transmission
Autosomal-recessive (AR) traits have the controlling gene alleles on an autosomal chromosome. These traits
are expressed only when both alleles are present. Table 4-4 lists some AR traits and disorders. Figure 4-2
shows a typical pedigree with the transmission of an AR disorder. The trait is expressed only when the person
is homozygous for the recessive alleles. Criteria for AR patterns of inheritance include the following:
• The trait is found in about equal distribution between male and female family members.
• The trait often appears first in siblings rather than in the parents of affected children.
• The trait may not appear in all generations of anyone branch of a family.
• The risk for the children of twO affected parents to also be affected is close to 100%.
• About 25% of the members of a family with an AR trait will express the trait or disorder.
• AR traits do have a carrier status in which those individuals who have only one affected allele may not
express any level of the trait .
• Unaffected carriers of AR traits can transmit the trait [0 their children if their parmer is either a carrier
oris affected .
• An AR allele may be present in a family for many generations without overt expression.
An example of an AR trait is type 0 blood in which both alleles must be type 0 (homozygous) for the
person [0 express type 0 blood. If only one allele is a type 0 allele, and the other allele is either type A or
type B, the dominant allele will be expressed, and the 0 allele, although present, is not expressed and cannot
be detected by standard blood type analysis. The phenotype and genotype are the same for expressed AR
traits and disorders.

Figure 4-2 Pedigree showing a typical autosomal-

recessive pattern of transmission for a monogenic
(single-gene) trait.

II

III

ERRNVPHGLFRVRUJ
 78 Unit II Gene Expression

Carrier Status
A person who has one mutated allele for a recessive genetic disorder is a carrier. A carrier, even though he or
she has one mutated allele, does not usually have any manifestations of the disorder but can pass this mutated
allele on to his or her children. For some AR disorders, a carrier may have very mild manifestations. One
example is sickle cell trait. A person with two sickle cell gene alleles for the beta chain of hemoglobin (beta
globin) expresses all the health problems associated with sickle cell disease. However, a person who has only
one sickle cell gene allele and one normal gene allele for beta globin usually has about 50% normal hemoglobin
and rarely expresses sickle cell health problems. This carrier has sickle cell trait and can transmit the mutated
allele to his or her children. (Chapter II provides a full discussion of sickle cell disease.) Figure 4-3 shows
an AR pedigree with affected individuals, unaffected individuals, and carriers identified. Remember, that the
child of a person who expresses an AR trait will have at least one of the (WO recessive alleles. This person is
termed an obligate carrier of (hat trait even if he or she does not express it.
Gene Survival
Many have wondered how it is that recessive gene alleles in humans have survived for hundreds or even
thousands of years when they are not expressed in the heterozygous state. The most reasonable explanation
for this gene allele survival is that the recessive allele is not expressed when paired with a dominant allele.
This lack of expression allows a recessive allele to "hide" for many generations without expression. So, what
does this really mean for humans?
Human beings can think, assess their surroundings, and make choices. In many cultures, humans choose
with whom to have children, and usually, the selection is made from outside one's family. Think about a
scenario in which family A has rwo or more developmentally delayed siblings in every generation, which
suggestS a genetic cause that has an AD transmission. Some people would likely avoid having children with
members of family A to prevent such an OCCUHencein their Own offspring. But what about family B, many
of whose members carry a recessive allele for severe developmental delay? Because it is not expressed in the
heterozygous form, no one is aware of this possibility. Perhaps as many as 10 generations have passed without
any child expressing developmental delay.Thus, outsiders (and current family members) would have no reason
to believe such a problem is possible. Then, if a carrier from Family B has children with a carrier for the same
problem from family C, a child is born with the severe developmental delay. If only one child expresses the
problem, it could be perceived as a random event, not one associated with a familial disorder. Thus, some-
times a true genetic problem can go unrecognized as one that can be transmitted. This "hiding," or lack of
frequent expression, has allowed AR mutations co continue to exist. Now that genetic testing is possible and
being used, the frequency of AR transmission of genetic problems could change.

Figure 4-3 Pedigree showing affected. unaf-

fected. and carrier status for an autosomal-
recessive monogenic (single-gene)trait.

II

III

I Carrier male [!] Carrier female 01

ERRNVPHGLFRVRUJ
 Chapter 4 Patterns of Inheritance 79

Sex-Linked Inheritance
The sex chromosomes (the X and the Y) have some genes that are not present on other chromosomes. The
Y chromosome is small and has less than 300 protein-encoding total genes. Most of these genes are important
for male sexual development and are transmitted only from father to son. Only a very few gene alleles, located
at the tips of the Y chromosome, pair with homologous alleles on the X chromosome. The X chromosome
is much larger than the Y chromosome (Fig. 4-4) and has about 1,500 single gene alleles, most of which are
not present on the Y chromosome or on any autosome. Some of these genes are specific for female sexual
development, but there are also several hundred gene alleles on the X chromosome that code for nonsexual
functions for both males and females.
Normally, men have one X and one Y chromosome. Mature sperm cells are haploid and contain only one
chromosome of each pair, including the sex chromosomes. Thus, each sperm contains either one X chromo-
some or one Y chromosome, not both. Normally, a woman's ova also contain only one chromosome of each
pair, but each has only an X chromosome for the sex chromosome and never a Y chromosome. When a sperm
fertilizes an ovum (egg), the resulting cell should contain 46 chromosomes (23 pairs), including one pair of sex
chromosomes. If the sperm that fertilized this ovum had a Y chromosome, the new cell would be male, with
an X from the mother and a Y from the father. If the sperm that fertilized the ovum had an X chromosome,
the new cell would be female, with an X from the mother and another X from the father.
Y-Linked Transm ission
Genes on the Y chromosome are termed Y-linked. All males inherit their Y chromosomes from their fathers
(because mothers, being female, do not have them). Thus, the unique genes on the Y chromosome are all

X chromosome Figure 4-4 Comparison of the X and Y chromosomes

for size and loci.

Y chromosome

25
26
27
28

ERRNVPHGLFRVRUJ
80 Unit II Gene Expression

paternal in origin and are expressed only in males. Most of these unique genes are important for male sexual
development and fertility. This includes penis size and relative fertility in terms of the amount of different
types of testosterone produced and rate of spermatogenesis (development of mature, fertile sperm). The timing
of the onset of puberty in males also appears related to Y-linked inheritance.

X-Linked Transmission
The number of X chromosomes in males and females is not the same, with females having twice the number
of X chromosomes than males have, making the number of X-Linkedchromosome gene alleles unequal between
males and females. Because males have only one X chromosome, they have only one allele for every gene on
the X chromosome and thus have only half of the X gene alleles that a female has. Because these alleles have
no corresponding (balancing) allele on the Y chromosome. any X-linked allele in a male is expressed as if it
were a dominant allele. a condition known as hemizygosity. As a result. X-linked-recessive genes have dominant
expression in males and recessiveexpression in females. This difference in expression occurs because males do not
have a second X chromosome to balance the presence of a recessive gene allele on the first X chromosome.
X-LINKED RECESSIVE.X-linked-recessive traits and disorders are relatively common and sometimes called sex-linked
recessivebecause no Ylinked-recessive issues exist. Expression of X-linked-recessive monogenic traits occurs differ-
ently for males than females. For such a disorder to be fully expressed in females. the gene allele must be present
on both X chromosomes (the female must be homozygous for (he rrait), In males. expression of an X-linked-
recessive allele occurs when the allele is present on only the X chromosome. Table 4-4 lists traits and disorders
associated with X-linked-recessive transmission. Figure 4-5 shows a typical pedigree for an X-linked-recessive
trait or disorder. including carrier status. Features of a sex-linked-recessive pattern of inheritance include the
following:
• The incidence of the trait (or disorder) is much higher among males in a family than among females
(and may be exclusive to males).
• The trait cannot be transmitted from father to son.
• Transmission occurs from an affected father to all daughters (who will be obligate carriers) and from a
carrier mother to both sons and daughters.
• Female carriers have a 50% risk for transmitting the gene ro their children with each pregnancy.
• If no sons are born ro carrier mothers. the trait may not be expressed overtly for many generations.
• If no daughters are born to affected fathers who have children with noncarrier mothers. the trait is not
transmitted further.
• Depending on the disorder. females who are homozygous for an X-linked-disorder gene allele may not
survive pregnancy or will have more severe disease.
X-LINKED DOMINANT. X-linked-dominant disorders are rare. Two examples include hypophospharernic rickets
(males and females) and Rett syndrome (females only). Females do express the disorder in the heterozygous state
and have a 50% chance of transmitting the trait with each pregnancy co children of either gender. Males who
are hemizygous for the allele are more profoundly affected than are heterozygous females. For some disorders,
the severity is so strong for males that the disorder is lethal. and they die in utero or shortly after birth. The
most outstanding feature of X-linked-dominant disorders is that an affected father transmits the disorder to
all his daughters (who then express the disorder) and co none of his sons. An affected woman generally has
unaffected daughters. affected daughters. unaffected sons, and affected sons in equal proportions. The most
notable feature that distinguishes this transmission from that of autosomal recessive is the complete lack of
father-co-son transmission.
X-CHROMOSOME INACTIVATION. A special genetic feature is present in the somatic cells of females related to
the issue of unequal gene alleles for the 1,500 or so genes on the X chromosome. Most of the genes on

ERRNVPHGLFRVRUJ
 Chapter 4 Patterns of Inheritance 81

III

IV

C!) Obligate carrier (2) Possible carrier, status not verified • Deceased

Figure 4-5 Pedigreeshowing typical X-linked-recessivemonogenictransmission.

the X chromosome code for somatic cell functions important to both males and females, and relatively few
genes code for female sexual differentiation. To prevent XX females from having an excessive "dose" of the
X chromosome genes coding for somatic cell function, one X chromosome in every somatic cell is randomly
inactivated. This random inactivation means mat, in some cells, the paternally derived X chromosome is
inactivated, existing as a Barr body, and only the maternal genes are expressed in those cells. In other cells,
the maternally derived X chromosome is inactivated, existing as a Barr body, and only the paternal genes are
expressed in those cells (Fig. 4-6).
An interesting result of this random X inactivation is that, for any particular organ, the majority of cells may
express more of one parent's X chromosome, which can affect the function of the organ. This phenomenon
can be seen in examining the genetics of fur color (coat color) for calico cars. Calico cats have black (or gray)
fur patches intermixed with orange fur patches and some white fur areas. The gene for fur color (black and
orange) is on only me X chromosome. The gene for white fur is located on a different chromosome. When
a male cat with black fur mates with a female cat mat has orange fur, me female offspring of this union will
express both black fur and orange fur along with some white fur (Fig. 4-7). The orange fur patches represent
areas where the maternal X chromosome is active and me paternal X chromosome is inactive. The black fur
patches represent areas in which the paternal X chromosome is active and me maternal X chromosome is
inactive. The male offspring of this union will only express me orange fur (and white) from the X chromo-
some inherited from the mother and not the black fur from the father because there is no fur-color gene on
the Y chromosome. The reverse is also true when me mother cat has black fur and me father cat has orange

ERRNVPHGLFRVRUJ
82 Unit II Gene Expression

Older embryo after X chromosome inactivation;

note unequal dlstrlauuon of paternal X active cells
and maternal X active cells

Multicelled embryo with

New zygotewith active all active X chromosomes
paternaland maternal
X chromosomes

~_.
Paternally
derived
Maternally
derived
X chromosome X chromosome /
Area of embryo from which
X-inactivatedcells differentiate
into kidney cells

J
Maternal inactive
X chromosome
~ (Barr body)
Paternalinactive

0 X chromosome
(Barr body)

Mature kidneyshowingmajority Mature heart showing majority

of cells containingactive paternal of cells containingactive
X chromosomeand inactive maternalX chromosomeand
maternal Barr body inactivepaternal Barr body

Figure 4-6 Demonstration of embryonic random X chromosome inactivation with unequal distribution
to differentiated tissues.

fur. Female offspring will show black and orange patches (along with white fur areas), and the male offspring
will express only black fur with white trim.
Abour 1 in 3,000 calico cats are male. So, essentially all calico cats are female. The origin of me few male
calico cats rums out to be a chromosomal disorder in which me male car has two X chromosomes (insread of
just one) and one Y chromosome. This condition also exists as a chromosomal abnormality in human males,
as well, and is known as Klinefelter syndrome (see Chapter 7). (By me way, men with Klinefelter syndrome
do not have orange and black fur.) So, the few male calico cats have Klinefelrer syndrome.

ERRNVPHGLFRVRUJ
 Chapter 4 Patterns of Inheritance 83

Figure 4-7 Femalecalicocat expressingorange

patches and black patches alongwith white fur
areas.

In humans, random (and unequal) X chromosome inactivation can have health consequences. For example,
the gene for the muscle protein dystrophin is on the X chromosome. When this gene is mutated, the person
may express Duchenne muscular dystrophy. a sex-linked-recessive disorder of progressive muscle weakness. A
grandmother who is a carrier for this disorder transmits
the X chromosome with the mutation to her daughter. So, How Does It Happen That This Woman's
The daugh ter also inherits a normal X chromosome from Heart Has More Inactivated Patemally Derived
her father. This daughter is now a carrier and transmits X Chromosomes and More Functionally
the affected X chromosome to her son. Because the dys- Active Matemally Derived X Chromosomes if
the Process Is Random?
trophin gene is on the X chromosome. her son expresses
the disorder even though his carrier mother. who has Given the large number of cells in the heart, why
two X chromosomes, does not. However, if most of the are the percentages of maternal and paternal X
inactivation not equal (50-50)? The answer to these
mother's cardiac muscle cells from her paternally derived
questions lies in the timing of embryonic X inactiva-
X chromosome are inactive. these cells will express the
tion and in the fact that the inactivation is "fixed,"
mutated maternally derived dysrrophin gene. and her meaning that it is an irreversible event.
heart function will be reduced below normal.
In Figure 4-6, notice that when the fertilized egg first forms a zygote, both parental X chromosomes are
active. As the zygote becomes an early embryo and the cells divide co increase in number, both X chromosomes
are still active. Within the first week of embryonic lire, and before commitment occurs, these cells will randomly
inactivate one X chromosome in every cell. At this point. the maternal-co-paternal ratio of X inactivation
within the early embryo is nearly equal. However. as cells each commit to become a specific type of tissue or
organ, the early organ contains only a few cells. Usually, this small number of cells does not reflect an equal
distribution of maternal and paternal X inactivation. Figure 4-6 shows mat, after X inactivation has occurred,
equal numbers of maternal and paternal X chromosomes are inactivated, but they are not evenly distributed
throughout the embryo. So, if 10 of these cells are committed to becoming heart muscle and only 2 of the

ERRNVPHGLFRVRUJ
84 Unit II Gene Expression

10 (20%) express the active paternal X chromosome, then 8 of the 10 (80%) are expressing the active maternal
X chromosome. As these future heart cells continue to divide and form the heart muscle, these percentages
(20% paternal X chromosome active and 80% maternal X chromosome active) remain in the same unequal
distribution, and this person's adult heart will have mostly maternal X chromosome influence. In the case of
the woman who is a carrier for Duchenne muscular dystrophy, 80% of her heart muscle cells do not make
functional dystrophin, and she will have very serious heart function problems. If she had a greater percentage
of heart muscle cells actively expressing her father's X chromosome, her heart muscle function would be berrer.

PUNNETT SQUARE ANALYSIS AND PROBABILITY

Mendelian rules for patterns of inheritance apply to only those traits or characteristics that are regulated by a
single gene with at least two possible alleles. The relationship between genotype and phenotypic expression as
well as predictability can be explained with the use of the Punnert square. This model involves plotting the
known maternal genotype of a specific monogenic trait against the known paternal genotype for the same
specific trait. The example provided at the tOp of Figure 4-8 uses blood type. The allele for type 0 blood is
recessive, and the alleles for either type A or type B are dominant. The mother is phenotypically and genotypi-
cally type B (BB), whereas the father is phenotypically and genotypically type 0 (00). The expected genotype

Mother
B B

0 0 B 0 B
B = blood type B. a dominant allele
o = blood type B, a recessive allele
Father
Because both parents are homozygous for their blood type alleles,
0 0 B 0 B any child they produce has a 4-in-4 chance (100%) of having
an 0 B genotype with a phenotype expression of type B blood.

Mother (normal hearing)

d d d or d = recessive allele for normal hearing
o or 0 = dominant allele for deafness
0 0 d 0 d Because the mother is homozygous for normal hearing and the father is
Father heterozygous with one dominant allele for deafness, any child they
(deaf) produce has a 2-in-4 chance (50%) of being homozygous for normal
d 0 d 0 d hearing and a 2-in-4 chance (50%) of being heterozygous with a
dominant allele for deafness (and will be deaf) and a recessive allele for
normal hearing.

Mother (deaf)
0 d
Because both parents are heterozygous with one dominant allele for
0 0 0 0 d deafness (and are both deaf), any child they produce has a 1-in-4
Father chance (25%) of being homozygous for normal hearing, a 2-in-4
(deaf) chance (50%) of being heterozygous with a dominant allele for deafness
d d 0 d d and a recessive allele for normal hearing (and will be deaf but could
produce a child with normal hearing), and a t-In-e chance (25%) of
having two dominant alleles for deafness (will be deaf and all of his or
her offspring would also be deaf).

Figure 4-8 Examples of Punnett square analysis of probability for offspring genotypes and expressed
phenotypes when parental genotypes are known.

ERRNVPHGLFRVRUJ
 Chapter 4 Patterns of Inheritance 85

for all first-generation offspring is BO, with the expressed phenotype for all first-generation offspring expected
to be type B blood. The probability of this genotype and phenotype among the children born to this couple
is four Out of four (100%) with each pregnancy.
The middle section of Figure 4-8 shows Punnett square prediction for hearing in which D is an autosomal-
dominant allele for deafness and d is a recessive allele for normal hearing. In this case, the probability is
that two out of four pregnancies (50%) will have the Dd genotype and express deafness, and two out of
four pregnancies (50%) will result in the dd genotype and have normal hearing. The bottom section of
Figure 4-8 shows the Punnen square prediction for hearing when both parents are heterozygous for a dominant
D (deafness) allele and a recessive d (hearing) allele. The results indicate that with each pregnancy, the allelic
risks are one out of four (25%) with a DD genotype and deaf phenotype, two out of four (50%) for a Dd
genotype and deaf phenotype, and one out of four (25%) with a dd genotype and normal hearing phenotype.
One problem with Pun nett square analysis for probability is that the model is less reliable for smaller
numbers. If a Punnert square were used to predict the probable incidence of a single-gene trait for 2 mouse
parents that would eventually have 100 offspring, the model would be close to correct. However, human couples
do not have 100 children. Think about tossing a coin 100 times and counting the number of times "heads"
versus "tails" appears. With JUStthe 2 possibilities (heads or tails), the probability with each tOSSis 50% heads
and 50% tails. Tossing the coin 100 times will result in close to 50 heads and 50 tails in reality. However,
tossing the coin only 4 times makes 50-50 heads and tails less likely. So, when the couple in the middle of
Figure 4-8 has only three pregnancies, they have a 50% chance with each pregnancy that anyone child will be
deaf, but with such a small number of children, the probability and the actuality may not be the same. Thus,
all three children could be deaf, all three children could have normal hearing, two children could be deaf
with one child having normal hearing, or one child could be deaf with twO children having normal hearing.
A probability is only a chance based on statistics-it is not an absolute--and many people misinterpret
probabilities. For example, a couple with one child who has a genetic health problem is told that the risk is
50%. Their interpretation may be that the next child will not have the problem because the first child already
does (50% of the twO children). Importantly, these parents should be reminded that these probabilities apply
to eachpregnancy, not to the family as a whole.
Another issue with Punnett square analysis is that it does not take into account any other factors that may
influence the expression of monogenic traits. Other factors that can modify the expression of a monogenic
trait or problem include the presence of modifier genes, the environment, and epigenetic influences.

CHROMOSOMAL INHERITANCE
Normally, individuals inherit one copy of each chromosome pair from their mothers and one copy from
their fathers. Problems can occur when a child inherits more than or less than twO copies of a chromosome,
or parr of a chromosome, from his or her parents. Such inheritance represents a disproportionate or unbal-
anced inheritance of the gene alleles on that chromosome and usually results in abnormalities in anatomical
development. A complete discussion of chromosomal inheritance for autosornes is presented in Chapter 6.
Chapter 7 discusses inheritance patterns for sex chromosomes.

COMPLEX (MULTIFACTORIAL) DISEASE

Overview
Complex traits and diseases are sometimes referred to as multifactorial traits and diseases because they result
from the actions of several genes working together (polygenic) andlor the combined influences of both genes

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86 Unit II Gene Expression

and environment. Most people who will require hospitalization for a generic or genomic problem have complex
diseases, such as some forms of diabetes mellitus, atherosclerosis, obesity, and cancer.
Complex or polygenic traits are not dominant or recessive. Each gene variant adds to or takes away from
the actual expression of the trait (phenotype). Sometimes the contributions of a particular gene variant are
large, and sometimes they are small. For example, nearly 20 different regions of the genome have been associ-
ated with the onset of multiple sclerosis, and another 24 regions have been associated with the development
of type 2 diabetes.
Many complex traits are considered quantitative. Height is a good example because it can be measured on
a numerical scale. People are taller when they inherit more alleles that add to height, and many of the genes
involved in height are on the X chromosome. If an individual's parents are both tall, more tall aLlelesare
available for him or her to inherit than if both parents were shore With the random assortment of genes that
occurs during the formation of mature sex cells, however, an individual may end up with many or few of the
alleles contributing to greater height. Not all children of tall parents will be tall, but they are more likely to
be tall than are the children of short parents.
Environment is also important in the final phenotype of a complex trait. Imagine someone who has a
larger-than-average number of tallness alleles but who is severely malnourished during his or her growth
years. That person may end up being much shorter than someone who has the same genomic constitution
but consumed a diet providing plenty of nutrients and calories. Some of these nongenetic influences that call
affect gene expression have been found to be inherited and to affect more than one generation. This exciting
and complex area of genetics is known as epigeneticsand discussed further in Chapter 5.
Francis Galton was a British aristocrat who lived around the time of Mendel and was Charles Darwin's
cousin. Galton studied multifactorial inheritance and noticed the phenomenon of what he called "regression
to mediocrity." This idea today is called regression to the mean. Extremes of a condition or trait tend to
become more average over time in successive generations. For example, a very tall father tends to have sons
who are shorter than he is (closer to average height), and a very short father tends to have sons who are taller
than he is (again, closer to average height). Galton applied his ideas to aLIquantitative (continuous) heritable
traits, including intelligence. He was the founder of the very controversial eugenics movement in l883 (see
Chapter 19).

Modifier Genes
Genes that contribute to the phenotype but are not the primary cause of its expression are considered modifier
genes. Even in single-gene diseases, other genetic influences can be present in addition to the predominant
mutation. For example, two children in the same family (with the same primary mutation) may have cystic
fibrosis (CF), but one might be much sicker than the other. Assuming they are both receiving the same quality
of care, some difference probably exists in their modifier genes. Perhaps one has a gene variant that is somewhat
protective, whereas the other has a gene variant that makes things worse. Evidence of the actions of modifier
genes is seen in disorders such as Gaucher disease, hemochromatosis, beta-thalassemia, and polycystic kidney
disease, although not ali modifier genes involved have been identified.

Liability Model and Threshold

People carry differing numbers of risk alleles for a given complex trait, such as hypertension. Risk alleles are
gene variants that increase a person's risk for developing the phenotype. In graphing a population's risk, the
combination of genetic and nongenetic factors would be normally distributed in the population, resulting in
a bell-shaped curve. The population numbers (from few to many) would be on the y-axis, and the liability
risk (from less [Q more) would be on the x-axis (Fig. 4-9). The top of the bell curve represents the mean of

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 Chapter 4 Patterns of Inheritance 87

Distribution of liability in Threshold value

the general population of liability

Affected people

Liability

Distribution of liability in the

siblings of affected people

Affected siblings

Figure 4-9 The distribution of liability and

the concept of threshold requirement for
problem expression.

the population, or the liability (risk) of most of the population. Regarding risk for hypertension, some people
would be at the low end of the curve because they have very few alleles that increase their risk for becoming
hypertensive. A few other people will be at the high end of the curve because they have lots of alleles that
increase their risk for becoming hypertensive. Most people would fall somewhere near the middle of the curve;
the dotted line represents the average number of risk alleles carried by most of the population.
For every trait, there is a theoretical point called the threshold, which indicates the point at which the
number of risk alleles needed [Q express the disorder has JUStbeen mer. In Figure 4-9, all points to the right
of the threshold line are designated as "affected." The threshold for expression of a complex trait or health
problem varies with each individual, even within one family.
A model of the liability threshold for a complex trait indicates how high the risk is in the general population
and at what point risk is high enough so that having the disease or trait is likely. Thus, a liability model is an
estimate of the risk an individual has for experiencing a complex disease based on the number of risk alleles
in his or her kindred. In a family with a high incidence of disease, more risk alleles are likely to be present
than in the average family from the general population. For example, in a family with many tall people, lots
of gene variants that confer tallness are probably present, so the mean for the people in that family is much
higher than for the population in general. If someone comes from a family with lots of hypertension, the
chances are good that he or she has more risk alleles for hypertension than the general population. Thus, the
liability model can be used to plot out the risk for someone who has siblings with hypertension. Although
the threshold is at the same place in the population (of siblings of an affected person), the mean has shifted
to the right, so more people from the population now have sufficient risk alleles to express hypertension.
A point to consider regarding why the liability model is used to calculate risk only within a kindred rather
than for the general population is the issue of the degree of genetic susceptibility co the expression of a disorder

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88 Unit II Gene Expression

versus the degree of genetic protection or resistance to the expression of a specific disorder. Much more is
known about susceptibility than about resistance. These issues are discussed later in this chapter.

Twin Concordance
Twin concordance can help determine how much genetic factors contribute to disease development. If twins
are monozygotic (identical), they share nearly identical genomes. If one twin has a disease that is completely
due to genetic variants, then the likelihood of the other twin having the same disease is nearly 100%. If
environment plays a role, the likelihood of the second twin having the disease goes down a bit. It also goes
down if environment is important and the monozygotic twins were raised apart because they did not share
the same environment after birth. Dizygotic (fraternal) twins share only about 50% of their genomes. Most
are raised together and so share much of their environment. If the incidence of a trait being shared by twins
is equal for monozygotic and dizygotic twins, it is likely to have a strong environmental component and
some genetic contribution. For example, consider a trait like diabetes mellitus type 2 (DMT2). Studies have
demonstrated that this disorder has a higher twin concordance for monozygotic than dizygotic twins, so the
genetic contribution must be Stronger than the environmental conrribution in DMT2. Chapter 12 has a more
in-depth discussion of this issue.
Heritability estimates (the proportion of the variance accounted for by genetic factors) tell us how important
genetics is in creating disease risk. Of course, some of these estimates will vary from study to study, depending
on the variations in a number of factors, such as the background of genetic traits or variations in the environ-
ment being considered; however, looking at a heritability estimate provides a general sense of how heritable
something is (Table 4-5).

Recurrence Risk
Families that already have one child with a genetic disorder may be concerned that future children will have
the same disorder, which is known as the recurrence risk. Providing families with this information is an
important service provided by generic counselors who are educated in both the statistics involved in making

.'.:.,:J.=ll!!!!o'
Heritability Estimates of Common Health Problems I
Disorder Heritability Estimate

Schizophrenia 85%
Asthma 80%
Cleft lip/cleft palette 76%
Pyloric stenosis 75%
Coronary artery disease 65%
Hypertension 62%
Congenital hip dysplasia 60%
Anencephaly/spina bifida 60%
Peptic ulcer 37%
Congenital heart disease 35%

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 Chapter 4 Patterns of Inheritance 89

accurate estimates and the skills required to counsel worried families. When the disorder follows a clear
dominant or recessive pattern, providing families with numbers that convey the likelihood that another child
will be affected becomes easier. Remember that if both parents are carriers of a recessive trait, the risk of
having an affected child is 25% with each pregnancy. Things are much more complicated when the disorder
is complex.
Some facrors can help in estimating the recurrence risk for a specific family. For example, the risk is higher
if more than one family member is affecred, The risk for having a second child with a ventricular septal defect,
when a couple already has one affected child, is 3%; however, if this family already has two affected children,
the risk for another child being affected goes up to 10%. The risk increases because, with two affected chil-
dren, the parents must be carrying a fairly large number of risk alleles. The family is also at the higher end
of the liability curve if their child is severely affected, making it more likely that a sibling will be affected. If
the disorder is found more commonly in one sex than the other and the child with the problem is of the less
commonly affected sex, the risk to another sibling is also higher. Pyloric stenosis is five times more common
among males, so if the child with pyloric stenosis is female, the family probably has a high liability for having
other children with this problem. Of course, the more distant the affected relative is, the lower the risk of a
child being born with the disorder. For example, if the affected person is a cousin, the risk is lower than if
the affected person is a sibling.

GENOMIC VARIATION INFLUENCING

SUSCEPTIBILITY AND RESISTANCE
TO HEALTH PROBLEMS

Overview
The section of clinical chapters discusses how the inheritance of certain gene changes and allele variations
increases the risk for developing certain health problems. Rarely is the risk as high as 100%, but it can be
substantial. Some of these variations have been identified by exploring families who have a higher incidence of
single-gene disorders, and others have been identified by performing genome-wide association studies (GWASs)
to begin to identify groups of changes that together may increase disease risk. In addition to genomic varia-
tions that increase risk, scientists believe that some genomic variations exist that actually decrease the risk for
disease develop men t. Some of the evidence suggesting this possibility includes the observation that longevity
seems to "run in some families," just like specific diseases appear to run in others.
Over the years, attention has focused largely on idemifying individuals and families at an increased risk
for a health problem or birth defect because such disorders commonly require significan t health-care effort
and reduce individual productivity (not to mention quality of life and life span). Attempting to identify a
gene for a specific disorder, such as cancer, can be compared to looking for a needle in a haystack-starting
with a haystack known to contain needles helps. Similarly, performing genetic studies on family groups who
had higher-than-average incidences of a specific disorder was a good start and has led to the identification of
many genomic variations that increase the risk for a specific disorder.
Because some families appear to remain free of common disorders and health problems, even when living
in geographic areas in which specific problems are common, some inherited genomic variations must protect
against disease development. Think about the person who has smoked cigarettes since the age of 12 and now
continues to smoke four packs daily at the age of 100 with no evidence of lung cancer or chronic obstructive
lung disease! Do such people exist? Yes, they do; however, they are in the minority and should not be used
as role models for healthy living. Their longevity occurs despite their personal choices and environmental

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90 Unit II Gene Expression

influences, not because of them. Clearly, some choices and environmental hazards are worse for some people
than for others.

Suscepti bi lity
Variation in allele sequences for single genes does increase the risk for a person to develop a specific disease;
therefore, the individual's susceptibility to the disease is greater than that of the general population. For example,
having one mutated allele in the BRCA2 gene increases the risk for a woman who carries that mutation to
develop breast cancer from an overall 12% lifetime risk to a lifetime risk of25% to 50% as well as her overall
risk for ovarian cancer from less than 1% to 40% to 80%. Because such gene mutations are known to greatly
increase risk, they are termed susceptibiLil)!genes. Thus, a genetic susceptibility is having one or more gene
variations that increase the risk for disease expression. Having a specific mutation that works as a susceptibility
gene only increases the risk for disease but does not (often) guaramee it. One exception is mutation of the
Huntington disease (HD) gene allele, in which the person who has the mutation has nearly a 100% risk for
HD if she or he lives long enough and does nor die of something else first. Even when the risk for developing
a specific health problem is very high due to inheriting one or more susceptibility genes, whether the disease
ever occurs appears to be partly determined by the presence of other genetic variations that modify the risk
and may have some protective influence.
Many susceptibility genes have been identified that increase disease risk, including those that result in sickle
cell disease, colorectal cancer, familial hypercholesterolemia, hereditary hemochromatosis, long QT syndrome,
hemophilia, and cystic fibrosis. (The inheritance patterns, pathophysiology, and genetics of these disorders
are presented in the clinical chaprers.) The susceptibility genes that have been identified are most often those
for single-gene disorders that may be inherited in an autosomal-dominant, autosomal-recessive, or sex-linked-
recessive manner. Many more variations probably exist as multiple gene effects that require interaction to
increase susceptibility to disease. Through GWASs, some susceptibility variations have been identified in genes
that regulate enzyme activity, inflammation and immune responses, and metabolism.

Resistance
Scientists have termed genes that can protect against the development of a specific disease resistance genes or
modifier genes, which confer genetic resistance. Because not many such genes have been identified to date,
they are largely considered "theoretical," but few genetic professionals doubt their existence.
For many decades, health-care professionals and scientists had observed that disease-free longevity was a
feature of some families and appeared to be a good predictor of healthy aging. Environmental studies of long-
lived individuals do not show consistent lifestyle choices, other than a diet low in animal fat, that contribute
to disease-free exceptional longevity. (Remember the centenarian=« person who lives to be at least 100 years
old-who smoked his way through life.) Although this may represent JUStgood luck, it more likely represents
a yet-to-be identified genetic difference or differences that confer protection or resistance to common health
problems often associated with aging, such as hypertension, diabetes, and cardiac disease. Of course, the best
combinations for healthy aging probably include both a good genetic predisposition to disease-free longevity
coupled with a lifestyle that avoids known risky behavior (e.g., sedentary habits, dietary challenges, chemical
or radiation exposures, andlor activities associated with a greater possibility of trauma).
For some complex disorders with a strong genetic component, such as diabetes mellitus type 2 (DMT2),
disease expression may represent an imbalance among susceptibility genes that promote expression, resistance
genes that protect against expression, and personal environmental (lifestyle) choices. Consider, for example, a
32-year-old woman who has JUStbeen diagnosed with gestational diabetes. Although the disorder will resolve
within a few weeks after she delivers, it greatly increases her risk (90%) for later developing DMT2. In

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 Chapter 4 Patterns of Inheritance 91

examining her family history without performing any genetic studies, her mother and older sister were both
diagnosed with DMT2 by age 40. What does this mean for our pregnant woman?
Having gestational diabetes indicates she has inherited the predisposition for DMT2 and may have few, if
any, resistance genes or factors to modify her risk (Fig. 4-10). When the resistance genes and the susceptibility
genes are added together, susceptibility wins (Fig. 4-11). Does this mean that her development of DMTI is
inevitable? Not really, because the gene-environment interaction is also in play.
Figure 4-12 shows that, in considering the risk for developing any disorder, some people have more sus-
ceptibility genes with fewer resistance genes, others have more resistance genes than susceptibility genes, and
still others have equal input from susceptibility and resistance genes (like offsetting penalties). If people could
know their susceptibility versus resistance to a specific disorder. manipulating their environments to suppOrt
resistance and reduce susceptibility could be possible. So, how would this work for the pregnant woman with
gestational diabetes?

GENETIC RISK FOR TYPE 2 DIABETES MELLITUS Figure 4-10 Susceptibility and resistance to type

+-----......_.
Low risk High risk 2 diabetes.

• = Diabetes resistancegene • = Diabetes susceptibilitygene

GENETIC RISK FOR TYPE 2 DIABETES MELLITUS Figure 4-11 The interaction of susceptibility

+-----......_.
genes and resistance genes for diabetes mel-
Low risk High risk
litus type 2. The top section shows the ratio
of one person's susceptibility and resistance to
type 2 diabetes. The bottom section shows that
combined genetic susceptibility to type 2 dia-
betes greatly overwhelms the person's genetic
resistance to the disease .

• = Diabetes resistancegene • = Diabetessusceptibilitygene

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92 Unit II Gene Expression

Genetic
susceptibilly
Genetic
susceptibility
Genetic
susceptiblity

Genetic
resistance
Genetic
resistance
Genetic
resistance

Genetic susceptibility Genetic resistance Geneticsusceptibility

greatly exceeds greatly exceeds and genetic resistance
genetic resistance. genetic susceptibility. are matched.Genetic
Likelihoodof Likelihoodof influencefor disease
Figure 4-12 Differences in the risk for disease
disease expression disease expression expressionis negligible.
expression based on the inheritance of specific is high. is low. Environmentalfactors
susceptibility genes and resistance genes. may be more influential.

The rwo most influential personal environmental factors for DMT2 developmenr among those who have
a genetic predisposition (susceptibility) to the disorder are a sedentary lifestyle and obesity. If our patient
participated in a lifestyle change for either one of these rwo factors, she might be able to delay the onset of
the disorder by as much as 10 years beyond the ages at which her mother and sister expressed overt diabe-
tes. If she changed both factors, she might delay the onset of the disease by 25 or more years, or she might
never develop overt DMT2. To illustrate this point, one of the authors of this text has a friend just like the
32-year-old described earlier who was diagnosed with gestational diabetes. This friend is now 72 years old
and still has a normal fasting blood glucose level and a normal hemoglobin Alc. She started running 5 miles
daily after the birth of her l l-pound daughter and has maintained her weight within 5 pounds of ideal for
her height (she is 5 foot 9 inches tall and weighs 150 pounds). Will she ever develop DMT2? Possibly, but
she has certainly delayed the onset of the disease and its complications by decades. Thus, "bearing our genes"
is sometimes possible by manipulating the disease risk input from the environment.

SUMMARY
Monogenic traits can be explained and shown to follow stable patterns of inheritance with strong panerns
of probability prediction. For traits and health problems associated with the input of more than one gene
(polygenic input), the probability of expression is more difficult. However, the expression of even monogenic
traits can be modified by other genes, the gender of the parent who transmitted the gene, interactions with
the environment, and factors that have yet to be identified. Therefore, some of the Mendelian rules can be
thwarted. In a sense, when we understand how these other factors interact with genetic facrors, we may be
able to "beat our genes." For example, DMT2, which is a multifactorial, complex disorder, shows a strong
autosomal-dominant pattern of inheritance, although no specific single gene has been identified as causative.
Environment clearly plays a role because those individuals who have the genetic risk can delay the onset of
the disease for two decades (or more) by maintaining a normal weight and participating in a lifelong program
of moderate-intensity exercise.

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 Chapter 4 Patterns of Inheritance 93

GENE GEMS

• Mendelian inheritance applies only [Q monogenic (single-gene) [fairs and disorders.

• Autosomal-dominant traits are expressed whether both alleles are dominant or only one allele is dominant.
• The genotype and phenotype for autosomal-dominant traits can be the same but do not have to be
the same.
• When a dominant allele is paired with a recessive allele, only the dominant allele is expressed.
• Having a gene mutation for a disorder does not necessarily mean that the disorder will ever develop.
• Many aurosornal-dorninanr disorders are lethal in the person who is homozygous for that allele.
• Autosomal-recessive traits usually are only expressed in the homozygous state.
• The child of a person who expresses an autosomal-recessive trait will have at least one of the two reces-
sive alleles and is an obligate carrier of that trait.
• The fact that autosomal-recessive alleles can go unexpressed for many generations contributes to the
survival or preservation of the trait.
• The Y chromosome is small, with less than 300 protein-encoding gene alleles.
• Only the tips of the Y chromosome have gene alleles that pair with alleles on the X chromosome.
• Y chromosome traits are all paternal in origin and transmitted only from father to son.
• Because males have only one X chromosome, they have only one allele for nearly every gene on the
X chromosome.
• The X chromosome has about 1,500 genes, most of which code for non-sex-related functions.
• In females, one of the two X chromosomes in every somatic cell is inactivated to preven t a "double
dose" of X chromosome alleles.
• Xvlinked-recessive traits and disorders are expressed more frequently in males.
• A man with an X-linked-recessive disorder transmits the allele to all daughters and to none of his sons.
• X-linked-dominant disorders are very rare, and males are more profoundly affected than females.
• Punnett square probability is less reliable with smaller numbers of offspring.
• The probability for offspring genotypes and phenotypes is calculated for each pregnancy and not for
families as a whole.
• Common disorders that are considered complex, multifactorial diseases include some forms of diabetes
mellitus, atherosclerosis, obesity, and cancer.
• Complex traits and disorders are neither dominant nor recessive but represent the influence of multiple
genes interacting with the environment.
• Complex traits are quantitative expressions that vary within families and within populations.
• Modifier genes are not responsible for an actual genetic feature or product but modify how the trait
is expressed.
• Each person has a unique distribution of risk alleles for any complex trait.
• The threshold of expression for a complex health problem or trait varies with each individual, even
within a family.
• Heritability estimates help determine how much of the expression of a complex trait is dependent on
genetic factors rather than environmental and Lifestylefactors.
• When the incidence of trait concordance is higher among monozygotic twins than for dizygotic twins,
genetic factors have a stronger influence than environmental factors.
• When the incidence of trait concordance among monozygotic twins is the same as among dizygotic
twins, environmental influences are at least equal ro or greater than genetic facrors.
• Recurrence risks are easier [Q calculate for monogenic traits or problems than for complex traits.

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94 Unit II Gene Expression

Self-Assessment uestions ....

1. How many alleles for the single gene trait of blood rype (A, B, 0) does a person with the normal
number of chromosomes inherit from his or her biological parents?
a. 1
b. 2
c. 3
d. 0
2. How are gene penetrance and gene expressiviry different?
a. With penetrance, the gene is either expressed completely or is not expressed at all; with expressiv-
iry, the gene is always expressed, but the degree of expression can range from minor to extreme.
b. Penetrance and expressivity are both related to "gene dosage." With penerrance, only one copy of
the gene is expressed; with expressiviry, more than one copy of the gene can be expressed.
c. Gene penetrance and gene expressiviry are different terms for the same concept, which is the exces-
sive expression of recessive alleles.
d. Penetrance refers co the actual gene structure in the DNA, and expressiuity refers to the chromo-
some locus of the gene.
3. Why are X-linked-recessive disorders expressed in males more frequently than in females?
a. Hemizygous X alleles in males have homozygous expression.
b. One X chromosome of a pair is always inactive in all female cells.
c. Females have more effective DNA repair mechanisms than do males.
d. Expression of genes from the Y chromosome does not occur among females.
4. Which types of traits or health problems cannot be predicted or explained using Mendelian rules?
a. Traits/health problems with high penetrance
b. Y-linked-dominant traits/health problems
c. Codorninant traits/health problems
d. Polygenic traits/health problems
5. Which disorder demonstrates a strong gene-environment interaction?
a. Marfan syndrome
b. Diabetes mellitus type 2
c. Neurofibromatosis type 1
d. Red-green color blindness
6. Which statement or condition best reflects pleiotropy?
a. A mutation in a single gene results in the expression of problems in a variety of organs.
b. The susceptibility to a problem is an inherited trait, but the development of the problem is related
to environmental conditions.
c. A mutated gene is inherited, but the results of expression of that gene are not evident until middle
or late adulthood.
d. Several genes are responsible for the mechanism of hearing, and a mutation in anyone of them
results in hearing impairment.

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 Chapter 4 Patterns of Inheritance 95

7. Which common health problem has the lowest heritability estimate?

a. Asthma
b. Hypertension
c. Pyloric stenosis
d. Congenital heart disease
8. Under which condition for a complex disorder is the problem more likely to recur in a family?
a. The mother's great-grandfather had a milder form of the problem.
b. The problem is found in only one child in a set of dizygotic twin boys.
c. The affected child is male, and the disorder usually occurs among females.
d. The problem has never been seen in the family going back five generations.

Self-Assessment Answers
1. b 2. a 3. a 4. d 5. b 6. a 7. d 8. c

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 Epigenetic Influences
on Gene Expression

Learning Outcomes
1. Describe how the epigenome is related to the genome.
2. Explain how epigenetic changes affect gene expression.
3. Provide three clinical examples demonstrating the impact of epigenerics.
4. Explain the processes of methylation.
5. Explain the process of histone modification.
6. Describe the role of microRNA. ,
7. Explain how epigenerics plays a role in the development of cancer.
8. Describe the microbiome.
9. Discuss the impact of specific environmental toxins on gene expression.

Key Terms
Agouti (Avy) gene Epigenetics Microbiome
Developmental plasticity Epigenomics microRNA (miRNA)
Developmental window Histone modification Nutrigenomics
Dutch hunger winter Methylation

INTRODUCTION
By the winter of 1944-1945, Europe had suffered from 4 years of war. The winter was bitter cold, and food
was scarce. The area of the western Netherlands was under control of the Nazi army, which created a blockade
that prevented food from getting to the area. People were surviving on about 30% of their normal caloric
intake. By the time food returned to the area, in May of 1945, about 20,000 people had died This was the
Dutch hunger winter.

96

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 Chapter 5 Epigenetic Influences on Gene Expression 97

It was horribly tragic, but it provided scientists with an interesting population, one that had experienced a
brief period of significant malnutrition. The survivors were studied to learn about the impact of this difficult
time. Scientists found that if the malnutrition took place during the last few months of gestation, the babies
that were born were small. That was not surprising because we know that babies put on weight during those
last few months of pregnancy. What surprised the scientists was that these children never really caught up.
They remained small throughout their lives, despite eating well and having plenty of food available to them.
They also demonstrated very low rates of obesity.
Babies who were conceived during the hunger winter and malnourished only during the first 3 months
of gestation caught up and were born at normal birth weights. They seemed healthy and fine at birth.
The strange thing about these children was that, as they grew, they had higher rates of obesity and more
health problems in general. Their rate of cardiovascular disease was twice that of a control group. Perhaps
the most interesting finding was that the children and grandchildren of people malnourished during the
first 3 months of gestation also showed these health problems. Something happened to these Dutch chil-
dren that was passed on to future generations. We now know that these heritable changes were due to
epigenetics.

Overview
Epigenesics is a term that may be new to many people, but it has been around for almost 40 years, although
its definition has changed over time. Discoveries in the last 10 years have underscored its importance, and
information about the impact of epigenerics is growing rapidly.
As with genetics and genomics, people use the terms epigenetics and epigenomics. Epigenomics is the broader
term, referring to heritable changes in the ways that genes are expressed, without changes in DNA sequence,
across the whole genome. Epigenetics is more specific and refers to specific alterations of gene expression,
which can be inherited but are not changes in DNA sequence. If these terms sound similar, that is because
they are and are often used interchangeably.
Epigenerics adds an interesting layer to our understanding of how generic information is transmitted and
the factors that affect it. The term makes good sense when we break it down into its parts: You already know
that the genome is the entire set of DNA in a cell, and the information needed for constructing every protein
needed by the body is contained within it. The word epigenome comes from the Greek and means "above"
or "on" the genome, just as the term epicardium refers to the outer layer of the wall surrounding the heart.
You also know that gene expression (resulting in protein production) varies with the physiologic needs of the
body and the specific tissue. Genes are turned on or off, depending on the needs of a particular cell. Different
proteins can be produced even though the DNA sequence remains the same.
Imagine that the DNA sequence is a song, such as "Born to Run" by Bruce Springsteen. To write that song,
particular notes were placed in a particular order, just like in a DNA sequence. When that song is played at a
concert, Bruce and his band might add different variations, holding one note longer or emphasizing different
phrases. The result is that the song is a little bit different each rime it is played, but the order of the notes is
always the same. Maybe some other band might cover the song, and then it might sound very different! The
added flourishes and changes placed on top of the sequence of notes are similar to the epigenetic changes that
result in differences in phenotype despite identical genotypes.
Another example is schizophrenia, a mental illness that affects about 0.5% to 1% of the population. When
it occurs in one fraternal (dizygotic) twin, the other twin has a 15% chance of also being affected. But, if those
twins are identical (monozygotic), they have virtually the same DNA sequence. If one identical twin is affected
with schizophrenia, the second twin has a 50% chance of being affected. If schizophrenia were entirely due
to genetics, the identical twins, who share the same genome, would both be affected.

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98 Unit II Gene Expression

Health endpoints
• Cancer
• Autoimmune disease Epigenetic
• Mental disorders factor
Epigenetic mechanisms
are affected by these factors • Diabetes Histone modification
and processes: The binding of
• Development (in utero, childhood) epigenetic factors to
• Environmental chemicals histone 'tails" alters
• Drugs/pharmaceuticals the extent to which
• Aging DNA is wrapped
around histones and
• Diet
the availability of
inthe DNAto

Histones are proteins

around which DNA can
wind for compaction and
gene regulation.

Chromosome
DNA methylation
Methyl group (an epigenetic factor found
in some dietary sources) can tag DNA
and activate or repress genes.

Figure 5-1 Mechanismsof epigenetics.

Identical rwins share rhe same genome as well as rhe same epigenome at birth. Most identical twins share
the same environment both in urero and shorrly after birth, but as they grow older, their environments differ.
Maybe they have differences in diet, exercise, or exposure to radiation, which could result in epigenomic
changes. Some identical rwins seem to look more alike when they are young and less alike as they age. Changes
in rheir epigenomes could derermine wherher both [Wins get schizophrenia (Carey, 2012).
The epigenome uses chemical tags that affect the structural packaging of DNA or mat silence parts of me
genome, thereby alrering gene expression and subsequent protein production (Fig. 5-1). Surprisingly, these
modificarions can be passed on from generarion to generation. As me cell divides, me chemical modifications
sray with me parental DNA; these modifications can be altered by interactions with the environment, includ-
ing factors such as parental dier and exposure to environmental toxins. The modifications that science knows
mosr abour are DNA methylation, hisrone modification, and the interaction of microRNAs wirh me genome.

Methylation
Methylation is the addition of a chemical tag called a methyl group to me cytosine base in me DNA sequence
irself (see Fig. 2-3). The presence of methylation turns off expression of me gene or genes mar are methylated,

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 Chapter 5 Epigenetic Influences on Gene Expression 99

Repeated studies of this process found that methylacion of a gene's promoter silences that gene's expression.
For example, some genes are expressed only if they are transmitted from the father, and some are expressed
only if they are transmitted from the mother. The chemical process of methylation silences the genes from
one parent. If a gene with a defect is the only active gene, or if there is a delecion and the needed gene is not
there, disease will result. (See Chapter 6 for a more detailed discussion of genomic imprinting.)
When a cell divides, methyl-copying enzymes add methyl tags to newly replicated strands of DNA, based
on the methyl tags on the template strand. The DNA sequence and the methyl tags are passed on to each
daughter strand. New studies of genome-wide methylation have revealed that methylation may be more
complex than originally thought. Methylation may have a profound impact on several regularory elements,
altering transcription in ways beyond JUStsilencing the promoter (Rodger & Chatterjee, 2017).

Histone Modification
The DNA double helix winds around histone proteins, which give it structure and stability, allowing the
DNA to form chromosomes. Histone (or chromatin) modification involves changes to the proteins around
which the DNA double helix winds (see Fig. 1-10). Chemical tags attach to the "tails" of the hisrones and
can alter how tightly the DNA is packaged by adjusting the tension with which it winds. When the DNA
is wound tightly around the histones, some sequences of DNA may not be available for transcription, so no
protein will be made from that sequence. The gene will appear "turned off." When the DNA is loosened, a
gene that was hidden may suddenly be able to interact with the cell's protein-making machinery and appear to
be "turned on." In this way, histone modification and DNA methylation can turn gene expression on and off
(Fig. 5-2).

DNA accessible
gene turned on

Figure 5-2 Histone modification.

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100 Unit II Gene Expression

MicroRNA
As discussed in Chapter 2, microRNAs (miRNAs) are small single-stranded pieces of RNA that can bind to
messenger RNA, making it double stranded and preventing protein production. miRNA can JUStturn off
gene expression. These single-stranded pieces of RNA are only 20 to 30 bases long, and they do not encode
protein. Sometimes they are included as contributing to epigenomic changes. The possibility that miRNA
plays a part in the development of cancer is currently being explored.
Epigenornic changes may be caused by a wide variety of environmental factors under prenatal influence,
including maternal diet, radiation exposure, foreign chemicals, and even behaviors. Both human and animal
studies suppOrt this idea, known as the "fetal basis of adult-onset disease" (jirrle & Skinner, 2007). As noted
earlier in this chapter, people with the same genotype (identical or monozygotic twins) often have some phe-
notype variability. One may have diabetes mellitus type 2 (DMT2), whereas the other twin does not. One
may get cancer, whereas the other twin remains healthy. These differences mayor may not be attributable to
differences in lifestyle. Both twins may exercise, have a great diet, and deal well with stress, yet one twin never-
theless gets sick. Epigenomic changes may provide clues about why this happens by altering what scientists
call developmental plasticity, or the ability of the environment to cause different phenotypes from the same
genotype (Jirtle & Skinner, 2007).

MICROBIOME
Another issue related to epigenetics is the microbiome. The microbiome is composed of all the microorganisms
and their genomes living in and on a person in peaceful coexistence. These various organisms, often called
"normal flora," are different in number and type for every human (even identical twins) and include those that
live in the mouth, the gastrointestinal tract, the nose and sinuses, the vagina, and on the skin. These organ-
isms collectively are unique to every person (Ursell, Metcalf, Parfrey, & Knight, 2012). The body has about
10 times more microbial cells than human cells. As long as these organisms are confined to the nonsrerile areas
of the body, they are generally considered nonpathogenic (non-disease causing). For example, Escherichia coli
in the intestinal tract are helpful in processing food for absorption and are nonpathogenic. However, E. coli
in the urinary tract are pathogenic and, in great enough numbers, cause a urinary tract infection.
We all begin acquiring our unique microbiomes from birth (the intestinal tract of a newborn is sterile), and
the specific profile of our microbiome changes somewhat almost daily over time. The microbiome represents all
our life-long actions and experiences of eating food, drinking water (and other substances), taking drugs, petting
or touching animals, and physically interacting with other people (especially kissing and sexual encounters).
Even [he different rooms we spend time in, such as a classroom or office, have unique organisms that interact
with us. These encounters add to or change our microbiomes. The degree to which microbiome changes occur
depends on our own genome and immune status. In mct, the developmenr of immunity requires interaction
with some external genomes. Thus, the microbiome is generally protective and performs such helpful actions
as helping with food digestion and keeping some pathogenic microorganisms from overgrowing sufficiently
to cause disease. The types of digestive tract organisms a person has can change how he or she responds to
immunotherapy for cancer.

Changes in the Microbiome

Changes in the types and numbers of microorganisms composing the microbiome can affect health adversely.
For example, long-term antibiotic therapy can reduce the normal intestinal microbiome, which then allows
overgrowth of more dangerous organisms such as Clostridium difficile (C difJ). When present in the intestinal

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 Chapter 5 Epigenetic Influences on Gene Expression 101

rract in large numbers, this organism causes chronic severe, bloody diarrhea and can damage the mucosal
epithelial cells of the intestinal lining. Another example of unhelpful flora is an overgrowth of Helicobacter
pylori, which is responsible for many cases of stomach ulcers (peptic ulcer disease). Apparently, some intestinal
microbiomes contribute to and perhaps cause irritable bowel disease (Ursell et at, 2012).
The ability of various organisms to live in rugged, hostile environments, such as the human intestinal tract,
is a function of their genomes interacting with the host's genome and immune system. People can change their
intestinal microbiomes over time by changing the diet. A 30-year-<>ldman who was always an omnivore (i.e.,
ate a diet composed of animal proteins, various grains, and dairy products, along with Fruits and vegetables)
and then changes to a vegan diet long term will have changes in the intestinal rnicrobio me. These changes
mayor may not be beneficial, but they will affect the microbiome.
In summary, as individuals, we and our cells are not alone. No matter how often an individual showers,
microorganisms and their genomes will persist on the skin and mucous membranes. The intestinal organisms
may change in organism type, but some will always be present even with regular "colon cleansing." The exact
role of the microbiorne and all its possible effects on gene expression are still being investigated. Analyzing
differences in the gene sequences of individuals' microbiomes is believed co be the key ro better understanding
of the microbiorne's role in health and disease (Ursell er al., 2012).

EPIGENETICS AND CANCER

As first discussed in Chapter 3, normal cell division (mitosis) and growth are regulated by a balance of gene
products. Genes that produce proteins promoting mitosis are called oncogenes; genes that produce proteins
limiting entrance into the cell cycle and mitosis are called suppressor genes (tumor-suppressor genes). Under
normal conditions, suppressor gene products control whether oncogenes are expressed. Having cells reproduce
only when they are needed is a balance of these two types of gene products.
Cancer represents a change in gene expression to the extent that regulation of cell division is damaged
or lost. Damage to or loss of expression of suppressor genes permits the expression of oncogenes, allowing
unregulated cell growth that can result in carcinogenesis (malignant transformation) of a normal cell into a
cancer cell. Damage or mutation of an oncogene can make it less susceptible to control by suppressor gene
products. In either case, the balance is lost, allowing cancer development to proceed and, over time, progress
to widespread malignant disease. Chapter 14 provides more details on the processes related to cancer develop-
ment and progression.
In addition to direct gene damage, epigenetic events also have been shown to change the expression of sup-
pressor genes and oncogenes. Much of the research that points to epigenetic influence in cancer development
and progress has been done with living cancer cells in cell culture situations and in tumors generated in animal
models. Although these studies suggest both causal and protective relationships, some of the results found
in humans with cancer have been conflicting (Hafner & Lund, 2016). In addition, of the three mechanisms
proposed for epigenetic influence, the one most studied in cancer development and progression is methylation-
induced silencing of gene expression.
A tumor cell line is a group of cells initially obtained
So, What Leads to These Changes in
from a human tumor and grown artificially in cell culture.
Methylation That Upset the Growth-
Normal cells have a limited life span in cell culture;
Controlling Balance of Tumor-Suppressor
however, cancer cells can become immortalized and live Gene Expression and Oncogene Expression?
(and divide) in cell culture indefinitely. Some of these
A known cancer-causing substance (carcinogen)
cell lines have been growing (and heavily reproducing)
provides clues.
in cell cultures for decades. One of the most famous is

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102 Unit II Gene Expression

the HeLa cell line of cervical cancer cells originally obtained from Henrietta Lacks during surgery in 1951.
Tumor cell lines of any type are invaluable for cancer research, and much has been learned about the cell and
gene changes that occur in cancer development and progression. In addition, these cells are often those used
to initially test various drugs and biological agents for their effectiveness in slowing or stopping cancer cell
growth.

Differences in DNA Methylation

In examining genetic material from new cancers, as well as that obtained from long-established tumor cell
lines, differences in DNA methylation have been noted. The areas in and around oncogenes are often hypo-
methylated, leading to an increase in their expression. Some of the hypomethylated areas also include promoter
regions for these oncogenes. On the other hand, the rumor-suppressor gene areas are ofren hyperrnerhylared,
thus silencing the expression of these genes.
A common cancer is head and neck cancer that arises from the squamous epithelial cells in the upper
aerodigestive tract. Among the general population, this cancer occurs ar the rate of I per 1,000 adul ts. Among
people who consume more than I oz. of alcohol daily, the rate goes up in proportion to the amount of alcohol
ingested (e.g., 2 oz. per day increases the rate to 2 per 1,000, 4 oz. per day increases the rate to 4 per 1,000,
and so on). In examining head and neck rumor ceLIsobtained from patients with head and neck cancer, as well
as from established cells lines, the tumor-suppressor genes themselves and their promoter regions were found
to be heavily methylated (Supic, Jagodic, & Magic, 2013). One consideration is that the alcohol may be the
methyl group donor in this case. These findings are not universal to all cancer cells, which may mean that the
influence of different environmental compounds on methylation may be tissue specific (Romani, Piscillo, &
Banelli, 2015; Supic et al., 2013). Thus, some tissue types exposed to one carcinogenic compound may not be
as susceptible to its methylation influence as another tissue type.

Using Epigenetics in Cancer Treatment

Another huge area of research is that of cancer prevenrion and cancer therapies. Epigenerics has been the
focus of much research in these areas for the past decade. Based on the premise that epigenetic influences are
reversible, whereas gene mutations probably are nor, examination of compounds to preven t methylation or
to cause oncogenes to be methylated rather than tumor-suppressor genes being methylated has been ongoing.
Drugs with mechanisms of action that inhibit enzymes that either increase methylation or change histone
influence are in clinical trials. Some of these drugs have been used previously for cancer therapy because of
their other influences as cytotoxic agents. Results show some promise but rarely as single agents. More likely,
these types of drugs may be more effective when combined with other treatment types and modalities. JUSt
like some other systemic cancer treatments (e.g., chemotherapy and biotherapy), having drugs exert their
effects only on the target cells rather than on normal cells as well as target cells is still a goal, nor a reality.
Antioxidant research examining the influence of plant-derived compounds on both methylation and histone
modification has shown promise in cell culture and animal models. Many of rhese compounds, when added to
cell cultures and administered in relatively high doses to animal models, reduced the expression of oncogenes.
Others increased the expression of tumor-suppressor genes. Again, results in the real-life human situation were
more conflicting. Even in cell cultures, compounds that reduced the expression of oncogenes in one cancer
cell type ofren had a promoting effect on another cancer cell type. These results point out the obvious need
for extreme caution in applying laboratory findings to the human situation.
Nevertheless, this information demonstrates that epigenetic events do influence cancer development. However,
cancer does not occur in isolation; many environmental, genetic, and other biologic factors play into car-
cinogenesis. Thus, reversal of epigenetic influences on cancer development and progression is nor likely to

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 Chapter 5 Epigenetic Influences on Gene Expression 103

be a single-focus task. Epigenetic therapy strategies combined with other methods for cancer prevention and
cancer treatment are nor yet a reality but are likely to be a part of the war on cancer in the future.

NATURE AND NURTURE WORKING TOGETHER

Because methylation can be altered by environmental influences such as diet, this process is thought to
provide the missing link between DNA sequence and the environment. We have known for a long time that
environment inAuences gene expression, but the way this happens has eluded understanding. Learning about
methylation has provided an important step forward in appreciating environmental contributions to our health
(jirrle & Skinner, 2007).

Toxins and Gene Expression

A number of environmental toxins can affect gene expression. Bisphenol A (BPA) is used in the manufactur-
ing of polycarbonare plastic products. You probably have noticed that you can buy water bottles and other
plastic items with large labels stating that they are BPA-free. Phrhalares are additives that help soften plastic.
They might have been used in the rubber ducky you played with as a child. Both BPA and phthalates are
known to alter DNA methylation. When human placental cells were exposed to BPA, it altered their miRNA
expression. These methylation alterations can affect gene expression and have been associated with disease. In
animal studies, a mixture of these plastics including BPA and phthalates was found to increase the incidence
of several adult-onset diseases, such as endocrine, kidney, and prostate disease (Manikkam et al., 2013).

Research Into Epigenetics

Research studies using agouti mice have taught us a lot about epigenomics and the inAuence of environmental
factors on DNA expression. Mammals, like us, carry the agouti gene (.4vy). Mice carrying twO copies of the
dominant agouti alleles are yellow and obese, but Au] can be methylated (or turned off) to varying degrees.
Mice born with variations in methylation vary in color according to the level of Av] activity. Mice with mottled
coats will be produced when Ary activity varies from ceU to ceU.
Epigenomic variations occurring while fetal mice grow in the mother's uterus produce offspring with a range
of coat colors, despite being genetically identical. In addition to causing variations in coat color, having the
Avy turned on makes the mice ravenously hungry, resulting in gross obesity. These mice are also at a higher
risk of cancer and DMTI. When the Ary gene is methylated, it is turned off, and mice have normal appetites
and a brown coat color (Fig. 5-3). Scientists have shown that this variation can be manipulated because of
the diet's effect on methylation.
In 1998, Craig Cooney and his team fed pregnant brown agouti mice different levels of nutrients that sup-
ported methylation. These included folic acid, zinc, and the amino acid methionine. The mother mice that
were fed higher levels of the supplements produced offspring that were browner in color, leaner, and healthier.
This surprising study result demonstrated that a mother's diet can affect the offspring's phenotype byalrering
Av] gene expression (Wolff, Kodell, Moore, & Cooney, 1998).
In 2006, Cropley and colleagues completed a study in which pregnant agouti mice were fed a diet rich in
methyl donors similar to what Cooney had used. High levels of a methyl-rich diet again produced offspring
with browner coats, and this affected not only the offspring of the mice fed by Cropley, but also their grand-
children. Clearly, these changes in methylation were being inherited from one generation to the next (Cropley
et al., 2006). The work by these and other scientists has demonstrated that epigenetic changes are maintained
through mitosis and are passed on in the germline during meiosis.

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104 Unit II Gene Expression

T T T T
IA
;. A
P T
I

Unmethylated DNA Methylated DNA

\ , , M"hylOroop

Yellow and obese mouse Thin and brown mouse

Figure 5-3 Agouti mice.

Epigenetics and Nutrition

The earlier discussion of me Dutch hunger winter showed me impact of malnutrition on gestating fetuses.
In me Swedish counry of Norrbotten, a similar natural experiment occurred. This region was very isolated
in the 19m century, and when me fall harvest was not sufficienr to supply enough food for me population,
the residents starved. Extreme famines occurred during me harvests of 1800, 1812, 1821, 1836, and 1856.
Researchers studying this community found mat those people who experienced a famine while they were
teenagers passed on health problems to their grandchildren, but this happened only when the grandchildren
were the same sex as me grandparent who experienced me episode of malnutrition. Researchers suggested
that developmental windows were responsible, in which having too little or too much food could result in
epigenetic changes mat cause disease, both in me person affected and their offspring.
Animal studies supported these ideas. For example, rats that were given a high-fat diet during gestation and
lactation had offspring that were more likely to be obese. Mice that were placed on a low-protein diet during
preimplanrarion of a fertilized egg had low-birth-weight offspring that later developed hypertension (Jang &
Serra, 2014). This work led to studies examining the ways in which diet and epigenerics work together (see
Table 5-1).
Regarding merhylarion (discussed earlier in this chapter), B vitamins, folic acid, and the nutritional supple-
ment SAM-e (Svadenosylmerhicnine) are considered methyl-donaring nutrients, They playa vital role in me
biochemical production of methyl groups. During early embryonic and fetal development, a diet high in these

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 Chapter 5 Epigenetic Influences on Gene Expression 105

Examples of FoodsThat Have Been Linked to Epigenetic Changes

Class of Food/ Nutrient Source Role in Epigenetics
Cruciferous vegetables Broccoli, Cauliflower, cabbage, etc. Methylation of a gene involved
in stomach cancer
Folic Acid Green leafy vegetables, peas, bean, Methylation of genes involved in
sunflower seeds, liver, fortified bread and bowel cancer
cereal, baker's yeast Methylation of a gene involved
in neck cancer.
Methionine Spinach, garlic, brazil nuts, kidney beans, Synthesis of SAM
tofu, chicken, beef, fish
Genistein Soy Products Increase in methylation
B12 Fish, Cheese, Milk, Meat. Liver Synthesis of Methionine
Resveratrol Red Wine Histone modification (removal of
acetyl groups)
Betaine Some (especially cheaper) wines Can interfere with folic acid and
methylation
Zinc (insufficiency) Meat, Shellfish, Oysters IL6 promoter demethylation

Source:Eating for your Epigenome.The Epigenome Network of E><eellence (NoE). Retrievedfrom; hnp;/Iepigenome.ewen/2,48.875
on July 18. 2017;Nutrition and the Epigenome. Genetics Sciencelearning Center. hnp:/lleam.genetics.lJIah.edwcoment/epigeneticsl
nutrition. Retrievedon July 18. 2017;.Carmen P. Wong. NicoleA. Rinald. Emily Ho. Zinc deficiency enhanced inflammatory response by
increasingimmune cell activation and inducing Il6 promoter demethylation. Molecular Nutrition & Food Research.2015;doi; 10.10021
mnfr.201400761
-

nutrients can alter gene expression (Genetic Science Learning Center, 2013). We know that pregnant women
wirh low levels of dierary folic acid are more likely to have babies wirh neural rube defects. Epigenerics has
been suggesred as the possible cause.
The study of the interaction of nutrition and the genome is called nutrigenomics. A lor of intriguing
research is going on in this field. It may not be long before patients will be given a diet prescription based on
their genomes and epigenomes!

THE FUTURE OF EPIGENETICS:

ARE THERE CLINICAL APPLICATIONS?
The research on epigenerics is very interesting, but clinicians always want ro know, "How can this information
improve people's health?" Is it possible to reverse disease by targeting epigenetic mechanisms? Research into
the development of epitherapeutic drugs that would affect methylation and histone modification is ongoing.
Studies are investigating how some of these might help in the treatment of cancer, HIV infection, diseases of
inflammation, and some metabolic diseases (Hafner & Lund, 2016).
Studying epigenetic changes throughout the genome is possible using high-throughput DNA analysis.
Epigenome-wide association studies (EWASs) provide researchers with a tool to link epigenomic changes to

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106 Unit II Gene Expression

particular disease phenotypes. More advanced techniques to Study epigenomic changes are being developed,
such as targeted epigenome editing, which applies a popular gene editing method (CRISPR/Cas9) to the
epigenome (Rodger & Chatterjee, 2017).
Although much has been learned about epigenerics and nutrition that can be applied to improve health by
improving diet, much more is still to learn. Discovering ways mat our knowledge of epigenetics can be applied
clinically is a field of great interest, but it is a long way from the research laboratory ro the patient's bedside.

GENE GEMS

• Epigenetic! refers to specific alterations of gene expression, which can be inherited but are nor changes
in DNA sequence.
• Nutrigenomics is the study of the interaction of nutrition and the genome.
• Epigenetic changes are maintained through mitosis and are passed on in the germline during meiosis.
• Three mechanisms of epigenetic changes are methylation, histone modification, and microRNAs.
• Methylation turns off expression of the gene or genes that are methylated.
• When the DNA is wound tightly around histories, some sequences of DNA may not be available for
transcription, so no protein will be made from that sequence.
• MicroRNAs bind to messenger RNA, making it double stranded; this binding prevents the process of
translation.
• Epigenetic events also have been shown to change the expression of suppressor genes and oncogenes.
• The areas in and around oncogenes are often hypomethylated, leading to an increase in their expression.
• Tumor-suppressor gene areas are hyperrnerhylared, which silences the expression of these genes.
• The microbiome is composed of all the microorganisms and their genomes living in and on a person
in peaceful coexistence.

Self-Assessment Questions. . '"

1. What did we learn from the Dutch hunger winter?
a. Nutrition events have impacts on furu.re generations.
b. Fetal development is affected by overnutrition.
c. Underfeeding an infant results in a low body mass index throughour life.
d. When food is limited, parents will choose to feed their children rather than themselves.
2. What happens in the process of methylation?
a. Histone proteins are rearranged.
b. Genes are silenced due to binding with micro RNA.
c. Oncogenes are activated.
d. Gene expression is turned off.

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 Chapter 5 Epigenetic Influences on Gene Expression 107

3. When the area around oncogenes is hypomerhylared, what happens to gene expression?
a. Gene expression increases.
b. Gene expression stays the same.
c. Gene expression decreases.
d. Genes are no longer expressed.
4. How does bisphenol A (BPA) cause epigenetic changes?
a. BPA directly increases gene expression.
b. BPA can alter the production of microRNAs.
c. BPA alters caloric intake, which can lead to epigenetic changes in future generations.
d. BPA contaminates drinking water directly, leading to kidney disease.
5. What did we learn from studies with agouti mice?
a. Mother mice exposed to plastics produced offspring more Likelyto get kidney disease.
b. Mice with the agouti gene turned off were yellow and obese.
c. When mother mice were fed higher levels of supplements, their offspring were browner, leaner,
and healthier.
d. Supplements such as folic acid, zinc, and the amino acid methionine result in lower levels of
methylation.
6. How does the microbiome interact with the environment?
a. The microbiome is similar to the genome in that it is stable from birth.
b. Major dietary changes can alter the microbiome.
c. Identical twins have virtually identical microbiomes.
d. Colon cleansing will eliminate the microbiome.

CASE STUDY

Aamuun and Asad are refugees from Somalia currently living in Albuquerque, New Mexico. Aamuun was
pregnant when the couple arrived. During the first 4 months of Aamuun's pregnancy, she lived on very
meager food portions. After arriving in the United States, her diet improved greatly. She gave birth to a
healthy girl of normal birth weight. The family is having some difficulty adjusting to their new home, but
they are receiving help and support from their new community. Fortunately, they will continue to have
access to health care as their baby grows and develops.
1. How might Aamuun's meager food intake affect the long-term development of their baby?
2. How does this case illustrate potential epigenetic changes?
3. Will Aamuun's and Asad's grandchildren be at an increased risk of disease due to epigenetic
changes? Why or why not?
4. What can health-care professionals do to support this family?

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108 Unit II Gene Expression

References
Carey. N. (2012). The ~pigmnics reuoltaion:How modern biology is rt:writingour Imdn-stalldillgof genetics,disease,and inheritance.
New York. NY: Columbia University Press.
Cropley. J .• Suter. C. Beckman. K.. & Martin. D. (2006). Germ-line epigenetic modification of the murine A(vy) allele by
nutritional supplementation. Procudings of tlJl'National Acndnny ofScimcN. 103(46). 17308-17312.
Genetic Science Learning Center. (2013. July 15). Nntrition and tbr ~pigl!llom~.Retrieved from hrrp:lliearn.genetics.urah.edul
con ten rIep igeneticslnurritionl
Hafner. S.• & Lund. A. (2016). Grear expecrations-Epigenetics and rhe meandering path from bench [Q bedside. Biomedical
journal. Retrieved from hnp:llcrearivecommons.orgllicenseslby-nc-nd/4.01
Jang. H.• & Serra. C. (2014). Nurririon, epigenerics, and disease. C/illit:alNutrition Research, 3. 1-8.
Jirtle. R.• & Skinner. M. (2007). Environmental epigenomics and disease suscepribiliry, Nature R~vi~11lS Genetics, 8(4). 253-262.
Manikkam, M .•Tracey. R.• Guerrero-Basagna. C .• & Skinner. M.K. (2013). Plastic derived endocrine disruprors (BPA. DEHP
and DBP) induce epigenetic rransgenerational inheritance of obesity. reproductive disease and sperm epimurarions. PLOS
One. 8{l). e55387
Rodger. E. j.. & Charrerjee, A. (2017). The epigenomic basis of common diseases. Clinical Epigmetics. 9(5). doi: 10.11861
s 13148-0 17-0313y. Retrieved from hnp:lldinicalepigeneticsjournal.biomedcenrral.com
Romani. M.• Pisrillo, M .• & Banelli, B. (2015). Environmental epigenetics: Crossroads between public health. lifestyle. and
cancer prevention. BioMed Resmrch lnternational. doi: 10.1155/20 151587983
Supic, G .. jagodic, M .• & Magic. Z. (2013). Epigenerics: A new link between nutrition and cancer. Nutrition and Cancer,
65(6), 781-792.
Ursell, L., Metcalf,J .• Parfrey,L. & Knight. R. (2012). Defining the human microbiome. Nutrition &vinus. 70(5uppl. I). 538-544.
Wolff, G. L., Kodell, R. L., Moore. 5. R.• & Cooney, C A. (1998). Maternal epigenerics and methyl supplements affect agouti
gene expression in Ary/a mice. F-ASEB[aurna]; 12,949-957.

Self-Assessment Answers
1. a 2. d 3. a 4. b 5. c 6. b

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 Chapter
Autosomal Inheritance
and Disorders

Learning Outcomes
1. Apply the basic information about chromosome structure, nomenclature, ploidy, and karyotyping presented
in Chapter 1.
2. Compare the developmental, functional, and reproductive consequences for a person who is a balanced
translocation carrier with those of a person who has an unbalanced translocation.
3. Identify the common features of people who have the following chromosomal disorders: trisomy 21,
trisomy 18, and trisomy 13.
4. Explain the consequences of duplicated areas and deleted areas of chromosomal material that contain
gene-codi ng regions.
5. Describe how genomic imprinting can affect the phenotype.
6. Explain how mosaicism of a chromosomal abnormality affects the phenotype.

Key Terms
Balanced translocation Nondisjunction Triploidy
Genomic imprinting Reciprocal translocation Trisomy
Monosomy Robertsonian translocation Unbalanced translocation
Mosaicism Translocation Uniparental disomy (UPD)

INTRODUCTION
Recall from Chapter 1 that chromosomes are large sections or chunks of DNA formed as temporary structures
during the metaphase of mitosis in the cell cycle. Although the tightly condensed chromosome structure is
temporary, the double-stranded DNA making up each chromosome is a permanent section of the total DNA
within one cell's nucleus. Small chromosomes may have as few as 80 to 90 genes, and larger ones may have

109

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110 Unit II Gene Expression

thousands. Chromosomes ensure the precise delivery of the correct amount of DNA to the two new cells
generated during mitosis. Please review the "Chromosomes" section of Chapter 1 to become familiar with the
basic issues of chromosome structure, nomenclature, ploidy, and karyoryping,
Of the human's 46 chromosomes (23 pairs) in each somatic cell's nucleus, 22 pairs are autosornes,
and 1 pair composes the sex chromosomes (see Fig. 1-12). One chromosome of each pair was inherited
at conception from the father, and the other was inherited from the mother. This means that in every
one of your cells, half of the chromosomes are paternal in origin from your father and half are maternal
in origin from your mother (see Fig. 1-1). The process of forming mature sex cells that are capable of
uniting at conception to start a new person is called gametogenesis. This process is described in detail in
Chapter 3.

CHROMOSOMAL INHERITANCE
We inherit one copy of each chromosome pair from our mothers and one copy from our fathers when each
sperm and each ovum have only half of each chromosome pair. This way, the result of fertilization of an ovum
by a sperm is one new cell with 23 pairs of chromosomes that can develop into a new person. The cells that
become the germ cells (sperm and ovum) start out diploid with 23 pairs of chromosomes (see Chapter 3).
During the formation of germ cells through the process of meiosis, the cells become haploid, containing half
of each chromosome pair. For ova, most of meiosis occurs in the fetal female ovary, so a girl is born with all
the ova she is ever going to have. For sperm, spermatogenesis (the forming of mature sperm) and meiosis
begin at puberty and continue throughout life. For both ova and sperm, the diploid cells become haploid.
When conception occurs, the twO haploid cells fuse, forming a single diploid cell called a zygote that contains
the entire human genome.
Although we do inherit half of each chromosome pair from our fathers and half from our mothers, these
chromosomes are a mixture of chromosome parts inherited from each of our four grandparents. During the
process of making mature gametes, pieces of homologous chromosomes are often exchanged between chroma-
tids, resulting in a "shuffling" effect of our paternal grandparent genes in our father's chromosomes and of our
maternal grandparent genes in our mother's chromosomes. This phenomenon is discussed in "Gamerogenesis"
section of Chapter 3.
The most important part of this beginning process in which a zygote is formed is that it inherits exactly the
right amount of genetic material from each parent-half from its father and half from its mother. The actual
location of the genetic material is less important for normal growth, development, and function. When the
location of some genetic material is translocated from one chromosome to another, normal development can
occur (so long as the correct amount of DNA is present), but reproductive issues often arise in the mature
individual.
A translocation is a chromosomal abnormality in which all or part of a chromosome is transferred to
another nonhomologous chromosome. (A nonhomologous chromosome is not parr of the normal chromosome
pair. For example, one number 13 chromosome and one number 15 chromosome are a nonhomologous pair,
whereas two number 13s or two number 15s are homologous pairs.) A translocation can be balanced or unbal-
anced. Regardless of the balance status, a translocation is first described by the rest of the karyotype and then
is described by a lowercase t and the chromosomes involved. For example, a female with a translocation of a
number 21 chromosome 011[0 a number 14 chromosome would be described as 45,XX,-14,-21,t(l4q;21q).
If the translocation involves only parts of chromosomes rather than whole chromosomes, the breakpoints also
are listed (ifknown). For example, a male with a translocation between 12q14 and 22q21 would be described
as 46, XY,t(l2;22)(q14;q21).

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 Chapter 6 Autosomal Inheritance and Disorders 111

Balanced Translocations
A balanced translocation is one in which the right amount of DNA is present (no more and no less), but
not all the DNA is located in its customary place. This type of translocation is very common in human
development. Because this translocation is balanced, no specific risk exists either for abnormal development or
miscarriage of this individual as a fetus. This individual has the translocation in all cells, and neither phenotype
nor physiologic function is affected. The tWOrypes of common balanced rranslocations are Roberrsonian and
reciprocal translocarions.

Robertsonian Translocations
A Robertsonian translocation is a specific type of balanced translocation created by the fusion of the en tire
long arms (q arms) of two acrocentric chromosomes with the loss of the short arms (p arms). (Recall from
Chapter 1 that acrocentric chromosomes have the centromere near the very tOp end of the chromosome; see
Fig. 1-13.) The acrocentric chromosomes are chromosome numbers 13, 14, 15,21, and 22. A Robertsonian
translocation is the most common type of balanced translocation, occurring in about lout of every 900 live
births. Because the very small p arms of acrocentric chromosomes carry no significant genetic material, their
loss does not affect development and normal phenotypic appearance, even though the translocation is present
in every somatic and germ cell. However, the person with such a translocation has a karyotype with only
45 chromosomes (Fig. 6-1). Whole chromosome translocations between acrocentric chromosomes are more
common than between metacentric or submeracenrric chromosomes. The reason for this is that the DNA of
the centro meres of two acrocentric chromosomes attract each other, whereas the tips of whole chromosomes
have no special attractive force. The presence of a Robertsonian translocation can be diagnosed by analysis
of plain stained karyotypes: however, identification of the specific chromosomes involved usually requires
banding or other more precise chromosome identification techniques (see Chapter 16). Figure 6-2 highlights
a t(13;21) Robertsonian translocation.

Reciprocal Translocations
Reciprocal translocations are a specific type of balanced translocation in which segments of two non-
homologous chromosomes break and are equally exchanged. Such rranslocations can occur between any two
chromosomes, not just between acrocentric chromosomes. Because genetic material is neither gained nor lost,
the translocation is balanced, and the person's development and normal phenotypic appearance are not affected.
Also, because this type of translocation involves only chromosome segments rather than whole chromosomes,
the person's karyotype shows 46 chromosomes (Fig. 6-3). Although reciprocal translocations can be found
incidentally among a small number of anyone's somatic cells, the individual is considered a translocation
carrier only if the translocation is present in all cells. Identification of the specific chromosome segments
involved in any reciprocal translocation requires banding or other more precise techniques for chromosome
identification (see Chapter 16).

Reproductive Consequences of Balanced Translocations

Although the person who has any type of balanced
So, What Are the Possible Outcomes for
translocation does not have abnormal development or
Gametes From a Person Who Is a Balanced
physiologic function from the translocation, significant
Carrier of a Robertsonian Translocation?
reproductive issues can result. Remember that the trans-
When the diploid precursor germ cells undergo
location is presenr in all the person's somatic cells as
meiosis, four possible outcomes result.
well as the cells that are or will become germ cells. The

ERRNVPHGLFRVRUJ
112 Unit II Gene Expression

2 3 4 5

6 8 9 10 11 12

I
13 14 15 16 17 18

..
19 20 21 22 x y

Figure 6-1 A karyotype showing a Robertsonian balanced translocation: 45,XX,<ler,t(14;21 )(q10;q10).

Chromosome 13

Figure 6-2 Comparison of normal chromo- Normal Normal Robertsonian

somes 13 and 21 along with a Robertsonian chromosome 13 chromosome 21 translocation
translocation. t(13;21)

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 Chapter 6 Autosomal Inheritance and Disorders 113

2 3 Translocation 4 5

6 7 8 12

13 14 15 16 17 18

19 20 21 22 x y

Figure 6-3 A karyotype showing a reciprocal translocation between segments of 1 and 17:
46, XX,t(1 ;17)(p36;q11.2).

precursors to the germ cells were once diploid, having the balanced translocation in all the early germ cells.
Formation of the germ cells and progression to gametes (gametogenesis) requires cell divisions known as meiosis,
in which chromosomal reduction occurs to ensure that resulting gametes are haploid.
Figure 6-4 demonstrates these possibilities for the ova of a woman who has a t( 14;21). In the precursor
cells, she has one completely normal chromosome 14, one completely normal chromosome 21, and a whole
chromosome 21 linked to a whole chromosome 14. This precursor egg is balanced with two normal 14s and
two normal 21s. However, when her precursor eggs undergo meiosis, several different results can happen.
She may produce a mature ovum that has one separate chromosome 14 and one separate chromosome 21.
When this ovum is fertilized with a sperm that also contains one separate chromosome 14 and one separate
chromosome 21, the resulting individual has the normal number of chromosomes 14 and 21 and is not even
a translocation carrier. For this person, no developmental, functional, or eventual reproductive consequences
result from being the offspring of a person who is a balanced translocation carrier.
The translocation carrier may also produce a mature ovum with a balanced translocation of one normal
chromosome 21 attached ro a normal chromosome 14. When this ovum is fertilized with a sperm that contains
one separate chromosome 14 and one separate chromosome 21, the resulting individual has the normal number
of chromosomes 14 and 21 bur is also a balanced translocation carrier. For this individual, no developmental

ERRNVPHGLFRVRUJ
114 Unit II Gene Expression

The 145 and 21s of a woman's

precursor egg cells with a
Robertsonian translocation t(14;21)
before meiosis

1
Possible outcomes of meiosis

Ovum with one Ovum having a balanced Ovum having an excess of Ovum having an excess of
separate chromosome translocation with one chromosome 14 (two) chromosome 21 (two)
14 and one separate chromosome 14 and one along with one along with one
chromosome 21 chromosome 21 chromosome 21 chromosome 14
Possible outcomes ollertilization with a sperm having one normal 14 and one normal 21

1
Totally normal
1
Balanced translocation
1
Trisomy 14, two
1
Trisomy 21, two
with two 14s carrier like the mother with chromosome 21 chromosome 14
and two 21s two 14s and two 21s

Figure 6-4 Reproductivepossibilities with a balanced translocation carrier and a person with a
normal karyotype.

or functional consequences result from being the offspring of a person who is a balanced translocation carrier,
but the reproductive issues will be the same for this individual as they were for his or her mother.
The translocation carrier may produce a mature ovum containing a separate chromosome 14 and the addi-
tional one that has the chromosome 21 attached. When this ovum is fertilized with a sperm that contains one
separate chromosome 14 and one separate chromosome 21, the resulting individual has the normal number
of chromosomes 21 but also has trisomy 14, which is not compatible with life.
Lastly, the translocation carrier may produce a mature ovum that contains a separate chromosome 21 and
one that is attached to chromosome 14. When this ovum is fertilized with a sperm that contains one separate
chromosome 14 and one separate chromosome 21, the resulting individual has the normal number of chro-
mosomes 14 but also has trisomy 21. For this person, significant developmental, functional, and reproductive
consequences result from being the offspring of a person who is a balanced translocation carrier. (Trisomy 21
is discussed later in this chapter in the "Trisomy 21" section.)
For individuals who have reciprocal translocations, the reproductive issues are similar. If the germ cells created
from meiosis have the normal chromosomes rather than the ones containing the translocations, the resulting
individual has no chromosomal problems regarding development, function, or reproductive issues related to
the translocation. When the germ cells contain only the chromosomes with the reciprocal translocations and

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 Chapter 6 Autosomal Inheritance and Disorders 115

not the normal nonhomologous chromosomes, the resulting individual also is a balanced translocation carrier
who has no developmental or functional consequences related to being the offspring of a balanced transloca-
tion carrier. However, the reproductive issues will be the same for this individual as for the parent who is the
reciprocal translocation carrier.
When germ cells created during meiosis have only one of the reciprocal translocations along with the normal
nonhomologous chromosome, the resulting zygote will be missing specific gene alleles. This can result in
failure of the zygote to progress into an embryo, or, if pregnancy progression does occur, it will result in an
individual with developmental and functional problems as well as reproductive issues.
When germ cells created during meiosis have both reciprocal translocations along with the normal non-
homologous chromosome, the resulting zygote will have three copies of some specific gene alleles. This can
result in failure of the zygote to progress, or progression will result in an individual with developmental and
functional problems as well as reproductive issues.

Unbalanced Translocations
An unbalanced translocation results when a child inherits more than or less than two copies of a chromo-
some or part of a chromosome from a parent. Such inheritance represents a disproportionate or unbalanced
inheritance of the gene alleles on that chromosome and results in abnormal anatomic development and physi-
ologic function. These unbalanced translocations can lead to trisomy, monosomy, and other chromosomal
disorders.

COMMON CHROMOSOMAL DISORDERS

Trisomy
Overview
Inheritance of an extra copy of one chromosome results in a condition called trisomy. For example, Down
syndrome, or trisomy 21, results from the inheritance of three copies of chromosome 21 instead of JUSttwO
copies. Most commonly, trisomies occur when one pair of chromosomes fails to separate properly during
meiosis, a problem termed nondisjunction. Any chromosome pair can undergo nondisjunction, which results
in a trisomy. However, trisomy 21 is the most common trisomic problem that results in a live birth. Trisomy
of most other chromosomes is presumably incompatible with life.

Examples of Common Trisomic Disorders

The most common disorders of trisomy are trisomy 21, 18, and 13. Theoretically, these chromosomes are
involved in trisomic conditions that can result in a term pregnancy instead of an early miscarriage because
they contain relatively few gene alleles. Trisomy of chromosomes containing more alleles is more likely to
be embryo lethal, and the pregnancy does not progress beyond the first trimester. The presence of extra sex
chromosomes, especially the X chromosome, also is relatively common (see Chapter 7).
Most incidences of trisomy occur from nondisjunction during the meiosis of ova, although this can occur
during spermatogenesis as well. This condition is most often associated with advanced maternal age at the
time of conception (age greater than 35 years is considered "advanced" for pregnancy). Trisomy can also occur
because of a Roberrsonian translocation (see earlier) or as the result of an unbalanced translocation of material
from one chromosome to another. This condition is rarer and requires more careful or precise chromosome
analysis or other genetic testing techniques to identify. The developmental and functional consequences of
trisomy are the same regardless of the origin of the extra chromosome material.

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116 Unit II Gene Expression

Trisomy 21
Trisomy 21, also known as Down syndrome, involves an extra number 21 chromosome in all or most of a
person's cells. In the United States, it occurs as frequently as I in every 800 births, although the rate of Down
syndrome births is decreasing because of prenatal diagnosis and pregnancy termination. The disorder is found
among all races and ethnicities (National Institutes of Health [NIH], 2017b).
Developmental and functional abnormalities result from having three copies of all or most alleles on chro-
mosome 21. Table 6-1 lists the common problems or abnormalities associated with trisomy 21. Importantly,
not all problems or abnormalities are present in anyone person who has trisomy 21. In addition, anyone (or
more) of these problems may be present in a person who has no chromosomal disorder (e.g., having a single
palmar crease [simian crease] on one or both palms does not classify a person as having Down syndrome).
Individuals with Down syndrome do share many phenotypic features, such as hair color, eye color, skin tone,
blood type, and other inherited characteristics, with their family members. However, the classic facial features
associated with Down syndrome are unique enough to allow Down syndrome individuals to resemble each
other (Fig. 6-5). Although the life expectancy of individuals with Down syndrome has increased significantly
as the result of better diagnosis and management of associated health problems, on average, it is still lower
than for the general population.
At one time, individuals with Down syndrome were all considered to have severely reduced cognitive ability.
However, having such individuals remain part of a Familyand participate in all aspects of social interaction has
demonstrated that the ultimate level of intellectual function appears relatively high. Cognition and learning
may require more intense interactions and a greater number of practice times, but many skills and cogni-
tive abilities, and psychosocial perception, in people with Down syndrome approach nearly "normal" levels
(Milojevich & Lukowski, 2015; Zampini er al., 2016). Some people who have Down syndrome hold jobs
(even as actors who must memorize lines and assume the persona of another individual), drive cars, and have
successfully completed college courses. Such individuals are termed highfunctioning; however, the actual intel-
lectual potential for any person with Down syndrome is uniquely dependent on environmental stimulation
(Khatri & Burrrram-Carlisle, 2016). As with many disorders that impact cognitive development, the ultimate
potential of any affected person to attain completely normal physical and psychosocial development or for less
than fully normal development cannot be predicted (Bagger & Bagger, 2016; NIH, 2017b).
Reproductive issues are also a concern. Males with trisomy 21 are sterile and do not produce offspring.
Females with trisomy 21 have an approximate 50% chance of producing a zygote with trisomy 21 as the
result of any conception. However, many of these conceptions do not progress to term pregnancies. So, the
actual percentage of children with trisomy 21 born to mothers who have trisomy 21 is considerably less
than 50%.
Trisomy 18
Trisomy 18, also known as Edward syndrome, involves an extra number 18 chromosome in ill or most of
a person's cells. It is the second most common trisomic condition, occurring in about lout of 3,000 to
5,000 births, affecting many more females than males.
Severe developmental and functional abnormalities result from having three copies of ill or most alleles on
chromosome 18, and most affected children are stillborn. Of those born alive, more than 90% die within the
first year of life (Rasmussen, Wong, Yang, May, & Friedman, 2003). Table 6-1 lists the common problems
or abnormalities associated with trisomy 18, such as "rocker-bottom" feet (Fig. 6-6). JUSt as for trisomy 21,
not all problems or abnormalities are presenr in anyone person who has trisomy 18.
Although very few children with trisomy 18 survive childhood, and they have greatly reduced intellectual
capacity, some are able to interact with family members. Skills such as social smiling, rolling over, and limited
self-feeding have been reported (Trisomy 18 Foundation, 2017).

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 Chapter 6 Autosomal Inheritance and Disorders 117

.'!':jlll=-01:IIIl,
Abnormalities Associated With Common Trisomic Conditions
Trisomy Common Abnormalities

Trisomy 21 Slower intellectual development

(Down syndrome) Congenital heart defects (especially cardiac cushion defects)
Simian crease across palms
Epicanthal folds with upslanting palpebral fissures
Flat facies
Widely spaced eyes
Slightly low-set ears
Small, short, nose
Brushfield spots (speckling) on iris
Short neck with limited motion and extra skin folds
Short little finger that curves inward
Wide gap between first and second toes
Intestinal obstruction
Shorter stature than siblings
Thicker lips, with slightly protruding tongue
Poor muscle tone and reflexes (at birth)
More likely to have hearing and vision losses at earlier ages
Cataract formation
Hypothyroidism
Premature aging
Increased risk for leukemia
Trisomy 18
Edward syndrome Small, strawberry-shaped head with receding chin, small jaw, and elongated occiput
Low-set, abnormal ears
Clenched fist with overlapping fingers
Single palmar creases, arch-patterned fingerprints
Rocker-bottom feet with a prominent heel (toes may appear large and be fused); see
Figure 6-6
Severely reduced intellectual development
Heart malformations (atrial septal defects, ventricular septal defects, coarctation of
the aorta)
Kidney malformations
Esophageal atresia
Omphalocele
Inguinal and umbilical hernias
Brain cysts
Trisomy 13
Patau syndrome Small head (microcephaly)
Small lower jaw (micrognathia)
Cleft lip (with or without cleft palate)
Clenched fist with overlapping fingers
Single palmar crease
Extra digits on hands or feet (polydactyly)
Comilltled

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118 Unit II Gene Expression

• f.!.':t I =-:!!!II

Abnormalities Associated With Common Trisomic Conditions-cont'd

Trisomy Common Abnormalities

Fusion of digits on hands or feet (syndactyly)

Rocker-bottom feet (see Fig. 6--6)
Severe reduction of intellectual capacity
Low-set ears
Abnormal iris (split, off-center, key-hole shaped)
Small, close-set eyes (may even have eye fusion)
Umbilical and inguinal hernias
Heart malformations (heart on right side of body [dextrocardial. atrial septal defects,
ventricular septal defects, patent ductus arteriosus)
Abnormal rotation of internal organs
Fusion of brain hemispheres (holoprosencephaly)
Deafness
Vision problems
Seizures
Apnea

Figure 6-5 Trisomy 21.Typical facial features include flat nasal

bridge and epicanthal folds, distinct shortening of the fingers,
and broad hands with a single transverse palmar crease on both
hands. (Used with permission from Schaaf. CP; Zschocl<e, J; Potocki,
L. Basiswissen Humangenetik. Berlin Heidelberg: SpflngeF-Verlag, 2008,
2013.)

Trisomy 13
Trisomy 13, also known as Palau syndrome, involves an extra number 13 chromosome in all or most of a
person's cells. It occurs in about lout of every 10,000 [0 16,000 births (NIH, 2017 d).
Severe developmental and functional abnormalities result from having three copies of all or most alleles
on chromosome 13, and both stillbirths and early neonatal deaths are common. Of those who are born alive,

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 Chapter 6 Autosomal Inheritance and Disorders 119

Figure 6--6 "Rocker-bottom" feet in a newborn with trisomy 18.

(Courtesy of Universitat-Kinderklinik Heidelberg.)

more than 90% die within the first year of life (Rasmussen er al., 2003). Some of the phenotypic features
of trisomy 13 resemble those of trisomy 18, although others are unique to the disorder. Table 6-1 lists the
com rnon problems or abnormalities associated with trisomy 13.
Although most children with trisomy 13 die before their first birthday, some survive into adulthood, but
they are not independent in activities of daily living. In addition to greatly reduced intellectual capacity, physical
growth is poor. These individuals usually have shorr stature. Depending on which skeletal malformations also
occur, some are able to sit, stand, and walk. Those individuals who remain in loving and stimulating home
environments tend to interact socially, although speech is extremely limited.

Monosomy
Overview
Inheriting only one chromosome of a pair is a condition calJed monosomy. The most common cause of
this condition is thought to be nondisjunction during meiosis, in which one sex cell with 46 chromosomes
should undergo a reduction division that results in two cells, each with half of each chromosome pair. When
nondisjunction occurs, one cell will retain a full pair of chromosomes, whereas the other cell does not have
that chromosome at all. When this sex cell unites with the opposite sex cell. the resulring individual wilJ have
only 45 chromosomes instead of 46. Although, in theory, monosomy can occur among any pair of chromo-
somes, the only common incidence of monosomy is Turner syndrome, in which a female is missing one of
the X chromosomes and has a karyotype of 45,X (see Chapter 7). In addition, a few cases of monosomy 21
have been reported.

Triploidy
Very rarely, uiploidy occurs in human development. Teiploidy is the inheritance of an extra copy of each
chromosome, resulring in a person who has 69 chromosomes per cell instead of 46. Although the extra genetic
material is balanced in aU celJs, this condition is usually lethal. Most triploidy conceptions are lost as spon-
taneous miscarriages, and only a few progress ro term. Infants are usually stillborn or die within the first few
days after birth. Although an extremely small number of infants with rriploidy have survived a few months,
none has reached the first birthday. The condition is considered incompatible with life.
The most common cause of triploidy conceptions is the ferrilizarion of one ovum by two sperm. The result
is one copy of all maternal chromosomes and two copies of all paternal chromosomes. Less commonly, an
ovum may fail ro complete meiosis and have 46 chromosomes. When fertilization of this ovum occurs, the
zygote and embryo have two copies of all maternal chromosomes and one copy of all paternal chromosomes.
Triploidy is associated with numerous malformations and health problems. The specific problems vary somewhat

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120 Unit II Gene Expression

based on whether the extra set of chromosomes is maternal or paternal in origin. For parents whose infant had
rriploidy, the risk for conception with another triploidy on future pregnancies does not appear to be increased.

Partial Chromosome Duplications and Deletions

Overview
In addition to having additional or missing whole chromosomes, having extra pieces of and deletions of chro-
mosome material is also possible. This is essentially having a triple dose of some gene alleles or a single dose
of some alleles. Both types of conditions are relatively uncommon in gene-coding regions. When the dupli-
cated or deleted chromosome material of a gene-coding region is present in most or all of an affected person's
tissues, it typically leads to many anatomic and functional problems. Chromosomal analysis of duplications
and deletions is usually not sufficient to determine how many copies of genes are affected, and other genetic
testing methods are needed to precisely determine which chromosome pieces are involved. Remember that a
duplication or deletion large enough to be visualized on chromosomal analysis usually contains a minimum
of 200,000 bases.
Duplications represent amplified gene presence and expression. They are more likely to cause a change in
phenotype and symptoms if the duplication is large. For example, a duplication of several genes on chromo-
some 21 provides a triple dose of those genes to the affected individual, and he or she expresses some degree
of the Down syndrome phenotype.
Deletions represent a loss of alleles and reduced expression. JUStlike duplications, deletions are more likely
to cause a change in phenotype and symptoms if the deleted area is large. Some children with congenital
problems that include reduced intellectual capacity may have small deletions of specific gene alleles that have
not yet been identified. For children who have syndromes associated with specific deletions, their functional
potential may not truly be known for several reasons. First, because many of these children were predicted co
have profound intellectual disabilities, most were placed in institutional care, where stimulation was limited
and life spans were short. The syndromes were rare, and the need to determine possible functional potential
was not considered important or likely to be fruitful. With a more modern approach coward keeping affected
children at home in contact with other children and providing more than JUStcustodial care, expectations of
function and social interaction are increasing. JUStas for many types of chromosome disorders, the variation in
function of individuals who have duplications or deletions is great, and ultimate potential cannot be predicted.
Unlike trisomy and monosomy, most partial chromosome duplications and deletions are random events that
result from chromosomal breakage and structural rearrangement, usually during gametogenesis. They are not
related to parental age, and because many individuals who have the duplication or deletion are not capable of
reproduction, little risk exists for passing on the aberration. The exception is when the source of the ovum or
sperm involved is the unbalanced haploid gamete of a balanced translocation carrier.

Examples of Syndromes of Deletion

Widely varying deletions in autosomes and sex chromosomes have been found among tissues obtained from
sponraneous and induced abortions. The examples presented here, although rare, represenr autosome deletions
found among live-born children.
WAGR Syndrome
WAGR syndrome stands for Wums tumor, aniridia, genitourinary malformations, and intellectual disability
(formerly referred to as retardation). Children born without an iris (aniridia) were noted to share other con-
sistent clinical features, including severely reduced cognitive function (intellectual disability) and a variety of
genitourinary (GU) tract malformations. The GU malformations can be as mild as first-degree hypospadias,

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 Chapter 6 Autosomal Inheritance and Disorders 121

in which the urethral opening on the penis is located off to one side rather than centered, or as severe as
complete exstrophy of the bladder. About 40% of children expressing these symptoms at birth went on to
develop a specific type of kidney cancer caUed Wilms tumor (nephroblasrorna), usually before age 5 years. The
consistent expression of this phenotype suggested a chromosome problem; however, the specific deletion was
not identified until the late 1970s. The deletion is a relatively small one located in the interstitial band region
of 11p(l3) on chromosome II. This deletion can be seen on chromosomal analysis only when the metaphase
chromosomes viewed are long and well banded.
Interestingly, the cancer occurs in only 40% of affected individuals, even though the other manifestations
are always present. This suggests that the deletion increases the risk for the specific cancer, but actual cancer
development requires additional factors. Chapter 14 discusses the genetic basis of cancer development in
more detail.
Retinoblastoma
Retinoblastoma is a rare malignant tumor of the retina that generally occurs in early childhood. Most often
it is a sporadic cancer, and no history of any other family members who have the same type of cancer
exists. However, in the inherited type of retinoblastoma, incidence follows an autosomal-dominant pattern
of expression. Individuals at greatest risk for this type of rerinoblasrorna are missing the RB gene on at least
one chromosome 13. The role of the RB gene product is to prevent transcription factors from enhancing ceU
division. In this sense, the RB gene is a cancer-suppressor gene. When one allele of the pair for this gene is
missing, the risk for retinoblastoma greatly increases. (Chapter 14 discusses the roles of transcription factors
and cancer-suppressor genes in more derail.)
Although retinoblastoma in general is a childhood cancer, individuals with the deletion in chromosome 13
develop the tumor at earlier ages. The tumor has been found in children during the first week after birth and
has even been identified by ultrasound during the third trimester of pregnancy. Of note, other phenotypic
features are not associated with this deletion, although the development of other cancers is more common.
Cri Du Chat
Cri du chat translates from the French as "cry of the cat." It is a syndrome in which affected infants and
children have a distinctive cry that sounds Like that of a cat. The chromosomal deletion is a small part of
5p in either the terminal or interstitial region of chromosome 5. The manifestations of this disorder include
microcephaly, cleft lip and palate, widely spaced eyes (hypertelarism), epicanrhal folds, low-set ears with few
folds, a small chin, a variety of heart defects, and moderately to severely reduced cognition. In general, the
larger the deletion, the greater the degree of reduced cognition.
Angelman Syndrome
Angelman syndrome occurs because of a deletion in the maternally derived chromosome 15 from q 11 to q13.
The condition is estimated to occur in lout of 10,000 to 15,000 births. Children with this deletion com-
monly have a normal appearance at birth, with no obvious birth defects, and some feeding difficulties. As the
infant ages, head circumference increases abnormally slowly (the head is microcephalic compared with body
size), and developmental delay appears. Over time, the developmental delay and reduced cognition become
more apparent. The child learns to walk but usually has an unsteady or clumsy gait, with jerky motions.
The child smiles and laughs frequently, regardless of circumstances (Fig. ~7). (Very old textbooks describe
this syndrome as the "happy puppet" syndrome because of the continual smiling and the jerky gait.) This is
accompanied by an easily excited personality and hand-waving or flapping motions. Speech is usually greatly
impaired, although the child can communicate using nonverbal cues and signals.
Most children develop seizure disorders that become less severe with aging but persist to some degree
throughout adulthood. Other features that mayor may not accompany the syndrome include the presence

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122 Unit II Gene Expression

Figure 6-7 Angelman syndrome. With increas-

ing age. the face enlarges. the mouth broad-
ens. and marked prognathiabecomes apparent.
!Used with permission from Schaaf. CP; Zschocke, J;
Potocki, L. Basiswissen Humangenetik. Berlm HeIdel-
berg: Springer-Verlag, 2008. 2013.)

of an occipital groove; a tongue that protrudes; a large mouth with widely spaced teeth; drooling; strabis-
mus; and skin, hair, and eye color that is lighter than those of other family members (Angelman Syndrome
Foundation, 2015).
Prader-Willi Syndrome
Prader-Willi syndrome (PWS) occurs because of a deletion in the paternally derived chromosome 15 from
q 11 to q 13. It is estimated to occur in lout of every 10,000 to 30,000 live births worldwide and affects all
races and erhniciries, The loss of alleles from chromosome 15 affeCts many parts of the body. At birth, infants
with PWS have a normal appearance, with no obvious birth defects. The face may be narrow, and the infant
may have skin, hair, and eye coloring that is lighter than those of other family members. The most notable
problems in infancy are hypotonia, poor sucking reflex, and failure to thrive (Thomson, 2010).
As the child ages, other characteristic changes are
How Can the Same Chromosomal Deletion observed. Most children have a short stature with dis-
Result in Two Very Different Phenotypes?
proportionately small hands and feet (Fig. 6-8). Devel-
If you are not asking yourself this question. go back opmental delay and a mild-to-moderate reduction in
and reread the Angelman syndrome and Prader-Willi cognition are present. In both males and females, the
syndrome sections. Then read the next section,
gonads are small. Often, skeletal changes lead to scoliosis.
which discusses genomic imprinting.
The most outstanding feature is an insatiable appetite that

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 Chapter 6 Autosomal Inheritance and Disorders 123

Figure 6-8 Prader-Willisyndrome in a 3-year-

old male. Note truncal obesity and micrope-
nis. The hands are relatively small (acromicria).
(Used with permission from Schaaf. CP; Zschocke, J;
Potocki, L. Basiswissen Humangenetik. Berlin Heidel-
berg: Springer-Verlag, 2008, 2013.)

usually manifesrs by age 3 years. The food craving and overeating lead co obesity and all the health problems
associated wirh it. Behavioral problems, especially remper tantrums and poor impulse control, are common.
For affecred individuals of both genders, puberty is delayed or incomplete, and most are infertile. Without
treatment with gender-specific hormones, secondary sex characteristics do nor develop. When obesiry and its
associated health problems are controlled, people with PWS have life expectancies that are the same as those
of the general population.

Genomic Imprinting
As presented in Chapter 5, epigenetic events can affect gene expression. Genomic imprinting is an epigenetic
event in which a gene (or gene allele) is inactivated by means other than mutation, so the DNA sequence of
the gene remains normal, but irs expression is inhibited. This is an abnormal stare, and we are unsure of how
often it occurs. When it does, it usually happens during gametogenesis, which can allow identification of
whether the allele is maternally inherited or paternally inherited. When a gene or genes have been imprinted
during gametogenesis, the imprint remains in the cells of the conceived child throughout life. The effect of

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124 Unit II Gene Expression

an imprinted gene allele from one parent means that only the nonimprinted allele from the other parent is
expressed. For the most part, when the nonimprinred gene allele is normal, its sole expression is not a problem.
Problems arise with sole expression of mutated nonirnprinted gene alleles.
For example, suppose a couple has decided to have a baby, and they are concerned about the possibility of
having a child with sickle cell disease (abnormality in the beta chain of hemoglobin). This disease is autosomal
recessive and is expressed only in individuals who are homozygous for a mutation in the HBB gene (loci on
chromosome 11). Testing of this couple finds that the husband is heterozygous for an HBB mutation, and
the wife is homozygous for normal alleles of the HBB gene. The possible outcome of a pregnancy for this
couple is a child who is either homozygous for normal HBB gene alleles or is heterozygous with one mutated
and one normal HBB allele (and would be a carrier of sickle cell disease). So, the couple goes ahead, gets
pregnant, and has a daughter.
Shortly after birth, testing shows the daughter to have only one mutated HBB allele, and she is expressing
only hemoglobin S. Further testing shows that the maternal normal HBB allele is not being expressed in this
child from the result of imprinting.
Another cause for such a scenario is the loss of the mother's HBB allele and a duplication of the father's
mutated HBB allele, so the child is homozygous for the sickle cell gene. This strange occurrence can be the
result of uniparental disomy (UPD) in which both chromosomes of a pair (in this case, chromosome 11)
come from JUStone parent. The gamete of the father contained rwo of his number 11 chromosomes instead
of JUStone. For this to work out, the mother's ovum had to be completely missing chromosome 11. So, in
this case, two mistakes are still mistakes!
Now let's get back to how the same deletion of 15q can result in either Angelman syndrome or Prader- Willi
syndrome, depending on which parent contributed the chromosomal deletion. For decades, the assumption
was that one chromosome of a pair that had all normal gene alleles was the same as a homologous chromo-
some with all normal gene alleles from another person, even one of the opposite gender. The Angelman and
Prader-Willi issue tells us that something is different for at least chromosome 15 between men a.nd women.
When no maternal material from 15q(11-13) is present, and only paternal material is expressed, Angelman
syndrome results. When no paternal material from 15q(l1-13) is present, and only maternal material is
expressed, Prader- Willi syndrome results.
When a child has UPD of chromosome IS with both chromosomes being derived from the father, a.nd no
material has been deleted on either chromosome, Angelman syndrome results. Even though no deletion exists,
without maternal input, the result is the same as if one chromosome IS had a deletion. The same situation
occurs when both copies of chromosome IS are inherited from the mother so that there is no paternal input,
resulting in Prader- Willi syndrome.
Only a few other disorders have been found to be associated with UPD of other chromosomes, although
instances ofUPD have been documented for nearly all human chromosomes. These include Beckwith-Wiedemann
syndrome (chromosome II) and cystic fibrosis (chromosome 7). Although rare, the possibility ofUPD needs
to be considered when a person expresses an autosomal-recessive disorder, but only one parent is a carrier or
is affected. This phenomenon can relieve the pressure placed on a mother when an infant demonstrates an
autosomal-recessive (fait for which she is a carrier, but the father is not, Obviously, this complicates genetic
counseling and demonstrates that the "gray area" of genetics/genomics is getting larger rather than smaller as
more is known.

Mosaicism
Mosaicism is a condition in which twO (or more) different karyotypes are consistently present in one individual.
This means that some cells have an abnormal karyotype, and others have a normal karyotype. Misconceptions

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 Chapter 6 Autosomal Inheritance and Disorders 125

and "reconceptions" about mosaicism abound. For example, when parents are told that their baby boy has
Down syndrome with mosaicism, and the proportion of cells with 47 chromosomes (47,)(Y,+21) is 70% and
those with 46 chromosomes (46,XY) is 30%, they sometimes assume that this child is "only 70% a Down
syndrome individual" and will be at least 30% "smarter" than the average person who has "pure" Down syn-
drome. Yearsago, such parental hopes would have been dashed by being informed that the degree of dysfunction
or problems associated with Down syndrome was not related to the percentage of abnormal cells-"Down
syndrome is Down syndrome." Now such beliefs and issues are less clear.
First of all, mosaicism can be tissue specific, meaning that some tissues can express a mixture of normal and
abnormal karyotypes, and other tissues may express all or nearly all of JUStone type. Because most cytogenetic
studies are performed on blood cells or skin cells (which are rapidly dividing cells that are not tremendously
difficult to retrieve), when mosaicism is found in these tissues, the percentage of cells with abnormal karyo-
types may not represent the actual proportion of cells with the abnormality in other tissues. So, it is possible
for a person to have 70% 47,XY+21 blood cells, yet with the proportion of 47 chromosome cells being very
small in the brain. Geneticists suggest that tissue-specific differences in mosaicism may be responsible for the
extreme variation seen in behavior and cognition among people with the same chromosome disorder. After
all, we do not biopsy brain cells to check the ratio of chromosomally normal to chromosomally abnormal
neurons in living people.
One example of mosaicism is the birth of monozygoric twins diagnosed with trisomy 13 mosaicism by
amniocentesis at 16 weeks' gestation. The parents chose not to terminate the pregnancy, and the twin girls were
born at 37 weeks' gestation. Twin A had the classic phenotype of trisomy 13 and died within 12 hours after
birth. Twin B had no observable features of trisomy 13, although her blood cells demonstrated 500/0 mosaicism.
Twin B is now 21 years old and still maintains 50% trisomy 13 mosaicism in her blood cells. She does
not have the characteristic facial features of trisomy 13, is doing well at college, and is an active participant in
athletic and intellectual pursuits. She has been counseled that her risk to conceive a child with trisomy 13 is
likely to be greater than that of the general population based on statistical probability alone. (Her eggs have
not been karyoryped to know what the mosaicism percentage is in that tissue, if any.)
What is the explanation for this huge difference between twO identical twins? The most likely process is
that the nondisjunction causing the trisomy 13 did not occur in one of the parental gametes before conception
but rather in one of the dividing embryonic cells after conception (Fig. 6-9). This had to occur before the
original embryo split into two embryos. So, suppose at the 32-cell stage of the embryo, cell division resulted
in 64 new cells: 1 cell contained 47 chromosomes with 3 number 13 chromosomes, and 1 contained only
45 chromosomes with just 1 chromosome 13. The remaining 62 cells had 46 chromosomes with 2 number
13 chromosomes. As this 64-cell-stage embryo underwent another round of cell division, 127 cells resulted
(124 with 46 chromosomes; 2 with trisomy 13; and the I monosomy 13 cell, which did not divide). By the
time the embryo split to form rwo separate embryos, it contained perhaps 1,008 cells, and only 16 of them
had trisomy 13 (the cell with monosomy 13 died off). So, 504 cel1s go to each of the two new embryos,
but the trisomic cells are not equally divided between these embryos. One embryo receives 15 trisomic cells
and 489 normal cel1s, and the other receives I trisomic cell along with 504 normal cells. So, embryo A has
15 times the dose of trisomic cells at this stage than does embryo B. As development progresses and com-
mitment occurs, it is possible that few, if any, trisomic cel1sare the precursor cells for any of embryo B's vital
organs (and those trisomic cel1smay not continue to divide at the same rate as the normal cells). As a result,
embryo B (eventually, twin B) has a very low percentage (if any) of trisomy 13 cel1sin her brain, heart, liver,
and other vital organs, whereas embryo A (twin A) has a much higher percentage of trisomy 13 cel1s in all
her tissues, leading to abnormal development.
The situation JUStpresented is a rare but actual case. However, its existence complicates counseling issues and
predictability for mosaicism. Many geneticists believe that low-level mosaicism for chromosome abnormalities

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126 Unit II Gene Expression

Early embryoblast with all cells

having 46 chromosomes

Error in cell division occurring

1 here resultingin the formation of a

47 chromosomecell that continues
to divide.

Largerembryoblastwith mostlycells
that have 46 chromosomesand some
that have 47 chromosomes

Twin A Twin B

o Cell with 46 chromosomes

Cell with 47 chromosomes
• (first as a result of nondisjunction)

Figure 6-9 Possible mechanism for unequal mosaicism in monozygotic twins.

is higher among the general population than first thought, but because such individuals have no functional
problems, they are not diagnosed. Additionally, based on the very high rate of spontaneous pregnancy loss
for embryos with a missing or extra whole chromosome, some geneticists purport that all people living with
a trisomy (and the deletion of one X chromosome discussed in Chapter 7) are all mosaic in most tissues but
not in the blood or skin tissues that are used for chromosome analysis.

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 Chapter 6 Autosomal Inheritance and Disorders 127

SUMMARY
Most individuals are genetically "normal," although very few humans are genetically perfect. Rearrangements
of genetic material occur frequently during the process of gametogenesis. Fertilization and conception occur
more frequently than does a live birth or even a detectable pregnancy. Some conceptions fail to develop beyond
the earliest stages, and still others fail to implant in the uterus. Even when implantation occurs, pregnancy
loss during the first trimester is significant. Both random chromosome changes and heritable chromosome
changes account for many of these losses.

GENE GEMS

• Although chromosome structure is temporary, the double-Stranded DNA that makes up the chromo-
some is a permanent section of the roral DNA within one cell's nucleus.
• Individuals who have balanced chromosomal rranslocarions do not have abnormal development or phe-
notypes because of the translocation; however, the translocation does pose reproductive consequences.
• Individuals who have unbalanced chromosomal translocations do have abnormal development and
phenotypes because of the translocation.
• Robertsonian translocarions occur only between acrocentric chromosomes.
• The most common chromosomal abnormality among live-born infants is trisomy 21 (Down syndrome).
• Many specific features are associated with various trisomies; however, few affected individuals express
every feature.
• Monosorny of autosomal chromosomes appears to be lethal .
• Individuals with Angelman syndrome and individuals who have Prader-Willi syndrome have the same
chromosomal deletion, but the parental origin of the chromosome with the deletion differs.

,..
Self-Assessment Questions. '
1. Why do balanced translocation carriers have normal development and function?
a. The extra chromosomal material is present only in germ cells and not in somatic cells.
b. The extra chromosomal material is presenr only in somatic cells and not in germ cells.
c. They have the correct amount of chromosomal material, and only its location is abnormal.
d. Their rranslocations involve only DNA noncoding regions, with no involvement of actual gene-
coding regions.
2. Which chromosomes are most likely to be involved in a Roberrsonian translocation?
a. An X chromosome and a Y chromosome
b. Chromosome 21 and chromosome 11
c. Chromosome 21 and the X chromosome
d. Chromosome 13 and chromosome 14
Continued

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128 Unit II Gene Expression

3. What is the difference between triploidy and trisomy?

a. Triploidy involves an extra copy of every chromosome, and trisomy involves an extra copy of only
one chromosome.
b. Trisomy involves an extra copy of every chromosome, and rriploidy involves an extra copy of only
one chromosome.
c. Triploidies are maternally derived, and trisomies are paternally derived.
d. Trisomies are fatal more frequently than are rriploidies.
4. Which clinical feature is a common finding for infants with trisomy 21, trisomy 18, and trisomy 13?
a. Rocker-bottom feet
b. Single palmar crease
c. Small, close-set eyes
d. Cleft lip (with or without cleft palate)
5. What is the risk for a woman with Down syndrome to produce a child with Down syndrome when
impregnated by a man who has normal chromosome numbers?
a. No chance
b. Less than 50%
c. Greater than 50%
d. Approachi ng 100%
6. A friend of yours is concerned that he may be a "carrier" for Down syndrome because both he and
his sister have a "simian" crease on one hand. What is your best action or response?
a. Ask him how many people in his family have been diagnosed with Down syndrome.
b. Tell him the simian crease is only diagnostic if it is present on both hands.
c. Remind him that Down syndrome "carriers" must be homologous to transmit the disorder.
d. Explain that chromosomally normal people often have one or more features associated with Down
syndrome.

CASE STUDY

A couple in their early 30s give birth to an infant who dies within an hour of delivery. Pathologic analysis
of the infant indicates trisomy 13. The couple undergoes chromosomal analysis. and the father is found to
have a balanced translocation of chromosomes 13 and 21. The couple asks whether this problem is related
to their ages and what risk they might have for having another child with trisomy 13.
1. Is this problem age-related?
2. Does this couple have an increased risk for having another child with trisomy 13?
3. What other pregnancy outcomes are possible for this couple?

References
Angelman Syndrome Foundation. (2015). WIlat is AS? Retrieved from hnps:llwww.angelman.org
Baggot. P.• & Baggot. R. (2016). Doubling the rate of neurologic development in Down syndrome: A pilot study. Issues in Law
and Medicine. 31(2). 125-137.

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 Chapter 6 Autosomal Inheritance and Disorders 129

Carey.]. (2012). Perspectives on the care and management of inf.Ultswith trisomy 18 and trisomy 13: Striving for balance.
Currens Opinion ill Pediatrics. 24(6). 672-678.
Khatri. S .• & Burrrram-Carlisle, ]. (2016). Down syndrome: Primary physicians and parents parcner in care. Contempomry
Pediatrics. 33(8). 3~6.
Milojevich, H .• & Lukowski. A. (2015). Recallmemory in children with Down syndrome and typically developing peets matched
on developmental age.journal of Intellecrua] Disnbi!iry Researcl). 60( 1). 89-100.
National Institutes of Health. (2017a). NIH gmetics 110mereftrmt:t!:O)rOmo<omNand mfDNA. Retrieved Ifom hnps:llghr.nlm.nih.govl
chromosome
National Institutes of Health. (2017b). Doum syndrome. Retrieved from hrrps:llghr.nlm.nih.gov/condicion/down-syndrome
National Institutes of Health. (2017c). Gmetic home reftrmu: Prnd"r-\Ylilli <y"drom". Retrieved from hrrp:llghr.nlm.nih.govl
con di rionl prade r-willi-syndro me
National Institutes of Health. (2017d). NIH genetics home reference: Yourguide to understanding genetics conditions. Retrieved
from Imps:llghr.nlm.nih.gov/condirion/trisomy-13
Rasmussen. S .• Wong. L.. Yang. Q. May. K.• & Friedman.]. (2003). Population-based analysis of morraliry in trisomy 13 and
trisomy 18. Pediatrics. 111(4. Parr 1). 777-784.
Thomson. A. (2010). The transition berween the phenotypes of Prader-Willi syndrome during infancy and early childhood.
Deoelopmenm! Medicine and Child Nmrology. 52(6). 506-507.
Trisomy 18 Foundation. (2017). W'],aris trisomy 18) Retrieved from hrrp:llwww.trisomyI8.org/site/PageServer
Zampini, L.. Fasolo, M.• Spinelli. M.• Zanchi. P.. Surrora, c.. & Salemi. N. (2016). Prosodic skills in children with Down
syndrome and in typically developing children. InumarionaljolimalofLanguage and Communication Disorders, 51(1),74-83.

Self-Assessment Answers
I. c 2. d 3. a 4. b 5. b 6. d

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 pier
Sex Chromosome
and Mitochondrial
Inheritance and Disorders
Learning Outcomes
1. Idemify the common features of and possible health issues for people who have Turner syndrome,
Klinefelter syndrome, and other syndromes with extra sex chromosomes.
2. Explain how it is possible for genotypic gender to not match phenotypic gender without artificial intervention.
3. Describe the probable mechanisms for expression of fragile X syndrome.
4. Identify the common features of and possible health issues for people who have fragile X syndrome.
5. Explain the inheritance pattern for mitochondria and mitochondrial mutations and disorders.
6. Identify the common features of and possible health issues for people who have mitochondrial disorders,

Key Terms
Adenosine triphosphate (ATP) Heteroplasmy Oxidative phosphorylation
Androgen insensitivity Homoplasmy Premutation
syndrome (AIS) Klinefelter syndrome Replication segregation
Anticipation Mitochondria Sex chromosome abnormality
Bipotential gonad Mitochondrial DNA (mtDNA) (SeA)
Expansion Monosomy Sex reversal
Fragile X syndrome (FXS) Nondisjunction Turner syndrome

130

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 Chapter 7 Sex Chromosome and Mitochondrial Inheritance and Disorders 131

INTRODUCTION
As first introduced in Chapter 1, sex chromosomes normally determine sexual phenotype. Most males have
an X and a Y as their pair of sex chromosomes. Most females usually have rwo Xs as their pair of sex chromo-
somes. Unlike many autosomal chromosome excesses and deletions, phenotypic changes with more than or less
than the correct number of sex chromosomes may be less obvious or even go unnoticed by the individual or
family. Any change from the normal number of sex chromosomes is a sex chromosome abnormality (SCA)
regardless of whether the phenotype is affected.
JUSt as for aurosornes, remember that the sex chromosomes are large chunks of DNA that are temporarily
formed during the metaphase of mitosis in the cell cycle. Also like aurosornes, you normally inherit one sex
chromosome from your mother (always an X) and one sex chromosome from your father (either an X or
a Y). This inheritance occurs when each sperm and each ovum has only half of the sex chromosome pair
so that the fertilization of an ovum by a sperm results in one new cell with 23 pairs of chromosomes that
can develop into a new person. The cells that become the germ cells (sperm and ova) Start out diploid with
23 pairs of chromosomes. During the formation of germ cells through the process of meiosis, the cells become
haploid. containing half of each chromosome pair. For ova, most of meiosis occurs in the fetal female ovary,
so a girl is born with all the ova she is ever going to have. For sperm, spermatogenesis (the forming of mature
sperm) and meiosis begin at puberty and continue throughout life. For both ova and sperm, the diploid cells
become haploid. When conception occurs, the rwo haploid cells fuse, forming a single diploid cell called a
zygote that contains the entire human genome. (Review Chapter 3 to familiarize yourself with these conceprs.)

EXTRA X CHROMOSOMES
Unlike with autosomal chromosomes, having extra copies of the X chromosome is relatively common. This
can result in trisomy X, tetrasomy X, penrasomy X, and Klinefelter syndrome.

Trisomy X
Some women have three X chromosomes (trisomy X) and a karyotype of 47,XXX. This condition is estimated
to occur as frequently as 1 in 300 to 400 births; however, because the physical phenotype is normal and the
individual is fertile, few are ever diagnosed (Milunsky & Milunsky, 2010). Inactivation of tWOof the three Xs
is most likely the reason for the normal phenotype. The most outstanding and consistent feature is that these
women are taller than average and are taller than most family members. Additional associated features may
include slight delays in language development and motor skills. An intelligence quotient (IQ) slightly lower
than that of siblings has also been reponed, as has a higher incidence of shyness and social anxiety (van Rijn
er al., 2014). However, because these features are not unique to people who have an extra X chromosome and
are influenced by both environmental and social factors, variation in the expression of these features is great.
Most important, the ultimate potential of any affected person for completely normal physical and psychosocial
development or for less than fully normal developmenr cannot be predicted.

Tetrasomy X
Terrasomy X (48,XXXX) and penrasomy X (49,)0000() are much rarer conditions than trisomy X, and both
are consistently associated with phenotypic abnormalities. Females who are 48,XXXX are usually tall and have
significant reductions in cognitive function and intellectual capacity (IQs range berween 35 and 70). The

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132 Unit II Gene Expression

head is small and has minor changes in facial features, such as epicanrhal folds and a depressed nasal bridge.
The incidence of skeletal abnormalities and unstable behavior is increased (Milunsky & Milunsky, 2010).

Pentasomy X
Fewer than 40 females who have five X chromosomes have been reported (49,XXXXX). Among these indi-
viduals, consistent phenotypic features include severely reduced intellectual function, short stature, cleft palate,
hypotonia, coarse facial features, microcephaly, hyperrelorism, and congenital heart defects.

Klinefelter Syndrome
Men can have an extra X chromosome, resulting in a 47,XXY karyotype, also known as Klinefelter syndrome.
This SeA is seen among live-born children and is estimated to occur in lout of every 660 male births, making
it the most commonly diagnosed SeA among males (Groth, Skakkebaek, Host, Gravholt, & Bojesen, 2013).
Fetal survival for this SCA is about 97%, and most individuals are not identified at birth. The cause is both
maternal and paternal nondisjunction and is associated with both maternal and paternal aging.
No specific morphologic features are present at birth or through childhood except that the boy is taller
than average, with long legs. This lack of phenotypic differences is responsible for the common late diagnosis
or misdiagnosis of the disorder (Groth er al., 2013). Puberty usually begins at the expected time, with normal
levels of testosterone and the presence of secondary sex characteristics. As the teen ages and becomes a young
adult, testosterone levelsdecline and gonadotrophin hormone (luteinizing hormone [LH] and follicle-stimulating
hormone (FSH]) levels become very high. Genitalia fail to grow, resulting in smaller testes and a smaller penis
compared to those of normal peers. Gynecomastia (breast development in males) occurs in about 50% of
individuals. Ferriliry problems include lack of sperm production {azoospermia) or greatly reduced sperm pro-
duction (oligospermia) and decreased libido. Sperm are commonly present within the testes and absent in the
ejaculated seminal fluid. Health problems that are more likely to develop during adulthood among men with
Klinefelter syndrome include osteoporosis, systemic lupus erythematosus, thyroid disease, breast cancer, non-
Hodgkin lymphoma, germ cell tumors, metabolic syndrome, and type 2 diabetes mellitus (Groth et al., 2013).
Other features associated with Klinefelter syndrome include a slightly reduced IQ (lower than that of sib-
lings), delayed or slower language skills and reading, delayed walking, decreased moror skills, and an increase in
attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASDs). Again, because these
features are not unique [0 people who have a 47,XXY karyotype and are influenced by both environmenral
and social factors, variation in the expression of these features is great. Importantly, the ultimate potential of
any affected person for completely normal physical and psychosocial development or for less than fully normal
development cannot be predicted.
Early diagnosis is desirable, Some of the phenotypic changes can be managed with testosterone replacement
therapy. More important, however, is the implementation of strategies to prevent or manage the associated
health problems, especially diabetes, that can lead [0 premature death.
Although men with Klinefelter syndrome are not able to father children normally, pregnancy is possible for
the couple through the process of aspirating sperm from the epididymis and then performing either in vitro
fertilization (IVF) or intracytoplasmic sperm injection (leSI). Because the spermarowa of Klinefelter men
may have an extra X chromosome, their offspring have a greater risk for an SeA.

EXTRA Y CHROMOSOMES
Another sex chromosome abnormality is the presence of an extra Y chromosome, resulting in a 47,XYY karyo-
type. This karyotype is estimated to occur in 1 our of 1,000 male births; however, because it is not associated

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 Chapter 7 Sex Chromosome and Mitochondrial Inheritance and Disorders 133

with phenotypic abnormalities, the actual incidence is nor known. The origin of the extra Y chromosome
is always paternal (your mother cannot give you a Y chromosome) and occurs as an error in meiosis II of
spermatogenesis. This is not an age-related problem.
Most men with 47,XYY are never diagnosed. The only physical association is tall stature, with these men
typically being taller than their parents and siblings. Widely varying psychosocial issues have been erroneously
associated with this karyotype because of biased data collection. Decades ago, prison populations and those
in institutions for the criminally insane were often the source of much testing (without personal consent),
and the 47,XYY karyotype was first discovered in these environments. Thus, early genetic papers warned of
an excess of psychopathology and socially deviant behavior among people with this karyotype. More recent
studies have shown the incidence of psychopathology among 47,XYY individuals to parallel that of the general
population.
Other features reported with a 47,XYY karyotype include severe teenage acne and slower motor and lan-
guage development. These individuals are reported to have a higher incidence of learning disabili ties; are more
easily distracted; are hyperactive; are more easily frustrated; and have behavior that is impulsive, disorganized,
and aggressive. However, these personal traits may only be present consistently in those individuals whose
behavior warranted further study.
Men with a 47,XYY karyotype are fertile. Because the extra Y chromosome is likely to be present in
approximately 50% of mature spermatozoa, the incidence of this karyotype in the male offspring of affected
men is increased.

MONOSOMY

Overview
As discussed in Chapter 6, inheriting only one chromosome of a pair is a condition called monosomy, which
most likely occurs because of nondisjunction during meiosis for gamete formation. (Recall that with nondis-
junction of a chromosome pair, the pair fails to separate during meiosis. Thus, segregation does not occur;
both chromosomes of the pair move into one gamete, and the other gamete does not receive a chromosome
from this pair.) This results in an ovum having two X chromosomes and an ovum with no X chromosome.
Nondisjunction appears to occur more often with the sex chromosome, particularly the X. The only common
incidence of monosomy among Living people is Turner syndrome, in which a female is missing one of the
X chromosomes and has a karyotype of 45,X.

Turner Syndrome
The loss or partial loss of an X chromosome results in Turner syndrome and a 45,X karyotype. (Older refer-
ences may term this karyotype 45,x0; however, "0" chromosomes do not exist.) Studies of early pregnancy
losses indicate that this is by far the most common chromosomal abnormality conceived, but that 99%
do nor survive the first trimester. In the United States, the frequency of Turner syndrome is 1 in 1,500 to
2,500 female live births (Milunsky & Milunsky, 2010).
Girls with Turner syndrome are often, but not always, identified at birth (or even during pregnancy by
ultrasound) because of the presence of "classic" phenotypic features. These include a smaller-than-expected size
at full-term pregnancy, neck webbing, pedal edema, and cardiac abnormalities (Table 7-1 and Fig. 7-1). On
ulrrasound, many fetuses have a nuchal hygroma, which is a Huid-filled cyst that forms like a collar around the
neck. In addition, the prenatal alpha (0.) feroprorein levels are not appropriate for gestational age. Although
lower-than-normal levels are most common, higher-than-normal levels have also been reported.

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134 Unit II Gene Expression

.f!.':JIII:wal
Common Features Associated With Turner Syndrome (45.X)
Body Area or System Feature

Skeletal features Hypermobile joints

Lymphedema Pedal edema
Hygroma
Facial features High, arched, narrow palate
Widely spaced eyes
Poor dentition (short dental roots, thin enamel)
Wide mandible with small chin
Low posterior hairline
Cardiovascular Coarctation of the aorta
Bicuspid aortic valve
Aortic dissection
Hypertension
Coronary artery disease
Long Q-T syndrome
Partial anomalous pulmonary connection
Endocrine Diabetes mellitus type 1
Diabetes mellitus type 2
Renal/urinary Collecting-system malformations
Horseshoe-shaped kidney
Malrotation of one or both kidneys
Eye and vision Epicanthal folds
Drooping eyelids
Uptilted palpebral fissures
Red-green color blindness
Strabismus
Hyperopia
Cognitive function Normal intelligence
Good verbal skills
Some difficulty with math, spatial perception
Ear and hearing Malformed ears
Unusual relationship between position of Eustachian tube and middle ear
Excessively high incidence of otitis media
Conductive hearing loss
Progressive sensorineural hearing loss (adults)
Cholesteatoma formation
Secondary sexual features Absent or delayed menses
(without hormone Poor breast development
supplementation) Infertility
Ovarian dysgenesis with loss of ova and fibrotic changes
Small, undeveloped uterus

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 Chapter 7 Sex Chromosome and Mitochondrial Inheritance and Disorders 135

Figure 7-1 Turner syndrome. Edematous swelling of the back

of the foot in a newborn girl. (Courtesy of Hj MOiler. Department
of Medical Genetics. University Children's Hospital Basel, Switzerland.)

The consistent features of this syndrome include short stature and a decreased childhood growth rate with
no adolescent growth Spurt. The average final adult height for girls with Turner syndrome who do nor receive
growth hormone supplementation is 57 inches (Milunsky & Milunsky, 2010). Most people with 45,X have
some degree of gonadal dysgenesis, although 5% to 10% do menstruate, and a few have even become pregnant.
The Turner syndrome phenotype is much more variable among females who are mosaic for this chromosome
disorder, which contributes to a later diagnosis (Radtke, Sauder, Rehm, & McKenna, 2014).
Health problems are common and can be significant for the person who has Turner syndrome (see
Table 7-1). Many require careful management to prevent or reduce complications. Life expectancy is slighdy
less than average, generally because of the cardiovascular complications of the syndrome, especially long-term
hypertension and hyperlipidemia, which may be present even in early chiJdhood (Bondy, 2007). Dental prob-
lems appear at an early age and may be the first indication of the disorder when it is not diagnosed at birth
(Walker, 2014). Progressive hearing loss with aging is very common among women with Turner syndrome
(Oliveira et al., 2013)
Older references describe girls and women who have Turner syndrome to have less-than-average inrelli-
gence and poor social skills. Lower intelligence is nor a consistent characteristic of this syndrome, and social
interactions are more influenced by famiJy and socioenvironmenral factors. The results of a recent large study
comparing education levels and employment status of women with Turner syndrome with those of women
in the general U.S. population dispel many of these misconceptions. Among the 261 women with Turner
syndrome in this study, the percentage completing a college education and holding professional employment
was higher than that of the general population (Gould, Balalov, Tenkersley, & Bondy, 2013). JUStas for many
types of chromosome disorders, the variation in ability among girls and women with Turner syndrome is
enormous, and ultimate potential cannot be predicted

GENOTYPE-PHENOTYPE GENDER MISMATCH

Overview
After karyoryping became possible, some people were discovered to have the genotype of one gender and the
phenotype of the opposite gender without undergoing surgery, hormonal manipulation, or any other form
of artificial or intentional phenotype adjustment. These are not very common problems, but they do occur.
So, both phenotypic women with a 46,)CY karyotype and phenotypic men with a 46,XX karyotype exist,
conditions known as sex reversal.
When we are conceived, our genetic gender is determined by chromosome constitution. Usually, zygOteswith
a 46,XY genotype develop into phenotypic males, and those with a 46,XX genotype develop into phenotypic

ERRNVPHGLFRVRUJ
136 Unit II Gene Expression

females. In addition to the genes on the sex chromosomes, many autosomal genes are needed to ensure the
expected gender match between genotype and phenotype.
When the hollow ball of the early ernbryoblasr cells begins to organize after commitment (see Chapter 3)
into various early tissues that will become specific organs, a structure known as a biporenrial gonad forms in
both males and females. This development begins during the fifth week after conception in the urogenital
ridge area of the embryo. The bipotential gonad, at one time known as the indifferent gonad, has the potential
to develop into a testis or an ovary, depending on which hormones and other factors influence it. Usually, in
a 46,XY embryo, this tissue forms a testis, and in an embryo with a 46,XX karyotype, it forms an ovary. In
addition to this biporenrial gonad, other tissues develop into male or female sex organs, depending on the
presence of genetic, hormonal, and some unidentified factors. The important concept to remember here is
that these tissues are present in both XX and XY embryos.
Early embryonic tissue capable of developing into male sex organs, including the penis, scrotum, prostate,
and the tubular system connecting the testis to the urinary system, is the mesonephric ductal tissue (Wolffian
glands). The tissue capable of developing into female sex organs is the pararnesonephric ductal tissue (Mulle-
rian ducts). The mesonephric tissues have androgen (testosterone is one androgen) receptors on them, and the
paramesonephric tissues do not. Interestingly, the gene coding for the androgen receptor (AR gene) is located
on the X chromosome, which is nor where you would expect to find a gene for a male hormone receptOr.

Normal Gender Development

Initial Male Development
The Y chromosome has several genes that work in coordination to cause the biporential gonad to organize early
into a testis and begin secreting the androgen testosterone. One of these genes is the SRY gene, which produces
testis-determining factor (TDF). Other gene products with loci on the Y chromosome are anti-Milllerian factor
([AMFJ also known as Miiflerian-inhibiting substance) and H-Y antigen. The H-Y antigen and TDF together
organize the biporential gonad into a testis, which then begins secreting testosterone as early as 6 to 7 weeks after
conception. The testosterone binds to androgen receptor sites on the mesonephric ductal tissue and causes it to
undergo mitosis and differentiation into anatomic male sex structures. At the same time, AMF causes regression
and degeneration of the pararnesonephric ductal tissues so that anatomic female sex structures do not develop.

Initial Female Development

At one time, geneticists believed that complete female development associated with the 46,XX genotype
occurred purely as a result of the absence of a Y chromosome, a theory called default sex. However, this is no
longer the simple answer. Complete female development requires the input of maternal hormones, the absence
ofY chromosome-associated gene products, the input of both X chromosomes, and the input of factors from
autosomal gene products.
Without the presence ofTDF, testosterone, and AMF, the mesonephric ducts regress and degenerate. Under
the influence of maternal hormones, the bipotential gonad develops into an active ovary around 6 weeks after
conception that almost immediately begins generating cells that will become future ova. The lack of AMF
together wi th the genetic influence of autosomal gene products causes the development of the paramesonephric
ductal tissues into complete anatomic female sex structures.

Sex Reversal
Multiple genetic mutations or rearrangements can be involved in sex reversal. The mechanisms presen ted here
describe only the most common ones that have been identified as actual physiologic phenomena and are not
merely theoretical.

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 Chapter 7 Sex Chromosome and Mitochondrial Inheritance and Disorders 137

XY Females
An identified genetic problem resulting in an XY genotype with a female phenotype is complete androgen
insensitivity or androgen insensitivity syndrome (AIS), which appears to occur at a rate of 1 in about
50,000 live births (Online Mendelian Inheritance in Man [OMIM], 20 16a). (This condition was originally
known as testicularfeminization [TFM) before the actual mechanism had been elucidared.) In this condition,
all tissues, including the masculine tissues (mesonephric ductal tissues), are missing androgen receptors. Again,
remember that the androgen receptor gene (AR) is located on the X chromosome, not the Y (normal women
do have some androgen receptors and can respond to both imernal and external androgens).
In individuals who have complete androgen insensitivity, the presence of the Y chromosome starts the
organization of the bipotenrial gonad into a testis at the appropriate time in embryonic life. This testis then
begins secreting testosterone; however, the resrosrerone has no developmental influence on the mesonephric
ductal tissues because they lack the receptors for binding and allowing the testosterone to change the gene
activity of these cells. Thus, the mesonephric ducts regress, and the paramesonephric ducts undergo partial
growth. At birth, the child has recognizable female external genitalia.
Commonly, not until puberty do the individual and her parents begin to suspect something is not quite
right. This girl does go through her adolescent growth spurt, commonly becoming taller than her parents
and siblings, and Starts to develop hip curves and breasts, but she does not begin menstruation. On physical
examination, the girl is found to have a vagina that ends as a blind pouch, with no accompanying uterus
and fallopian tubes. Although scalp hair is plentiful, all body hair, including axillary and pubic hair, is sparse.
The once organized testicular tissue, often located within the abdomen or inguinal canals rather than in the
usual ovarian position, mayor may not continue to produce androgens that essentially have no target tissue.
However, this gonad is at higher risk of developing testicular cancer. It is often seen as a possible inguinal
hernia and may be the initial reason why the individual seeks health-care advice (OM 1M, 2016a).
A girl with complete AlS cannot become pregnant but is female in every other sense. The genitalia at birth
appears clearly female, and this phenotype continues throughout life (Wisniewski et al., 2000). Modifying
the vagina with surgical reconstruction is usually necessary for full participation in sexual activity. The non-
functional testis is commonly removed. The person may have an enviably female figure. In fact, a well-known
Hollywood actress has complete AlS. She does not doubt her femininity and, now in her 60s, is a Strikingly
beautiful woman with a 46,XY karyotype.
When androgen insensitivity is partial, greater variation occurs in phenotype, sexual identification, and
sexual function (OMIM, 2016a). This problem is beyond the scope of this text.

XX Males
The most common cause of this phenomenon is translo- So, Without a Y Chromosome and Its Genes,
cation of the SRY gene OntOone of the X chromosomes Which Are Important to Male Development,
(46,XX+SRY), which occurs in lout of every 20,000 to How Can a Person With an XX Genotype
25,000 live births. As a result, men with this genotype Naturally Develop an XY Phenotype?
share many characteristics with men who have Klinefelter Remember that the Y chromosome contains rela-
syndrome. Phenotype exceptions are that XX men tend tively few genes. When the SRY gene is present,
to have a shorter-than-average final height, normal intel- even if a complete Y chromosome is not, male
ligence, and normal penile length. Just like men with sex structures can develop and result in a male
Klinefelter, these men have no sperm in the seminal Auid phenotype.
and are infertile. Some sexual development problems are
more common in XX men, including some degree of hypospadiLls(abnormal location of the urethral opening)
and cryptorchidism (undescended testicles).

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138 Unit II Gene Expression

Just like for AlS, degrees of expression of XX+SRY vary. Discussion of these variations is not within the
scope of this text.

FRAGILE X SYNDROME
Overview
Fragile X syndrome (FXS) is one of three variations of problems resulting from reduced or absent expression
of the FMRJ (fragileX mental retardation 1) gene (Lieb-Lundell, 2016). The protein coded by FMRJ is critical
in brain development and maintenance of neural synapses. In classic FXS, the FMR1 gene-coding regions are
normal, but the gene's expression is silenced by large numbers of the trinucleotide sequence of CGG being
repeated within the noncoding regions of the gene (National Institutes of Health [NIH], 2017).
This syndrome has had other names, including Martin-Bell syndrome, X-linked mental retardation, and
macroorcbidism, The term "fragile X" comes from the tendency of the X chromosome to exhibit a small break
or gap at the end of the long arm when chromosomal analysis is performed under certain laboratory condi-
tions. Classic FXS occurs in about lout of every 4,000 male births and lout of every 8,000 female births
and is the mosr common chromosome problem leading to reduced cognitive function and intellectual capacity
in males (NIH, 2017).

Expression
FXS is somewhat unusual in that it is a demonstration of anticipation and expansion. Anticipation is the term
used to describe that the phenotype of a genetic condition is expressed with greater severity and at earlier ages
with successive generations. Expansion is an increase, usually of trinucleotide repeat sequences, within a gene.
For FXS, expansion of the CGG trinucleotide repeat sequences occurs with successive generations, leading
to anticipation. The greatly expanded CGG regions increase the methylation of the FMR1 gene, silencing its
expression and leading to the manifestations of classic FXS (Saul & Tarleton, 2012). These characteristics are
shown in Table 7-2.
At one time, FXS was thought to be clearly expressed in an X-Linked recessive pattern, with mothers trans-
mitting the disorder to their sons. However, females do express the disorder to varying degrees when only one
X chromosome has the expanded trinucleotide repeat sequences. Therefore, the problem is instead X-linked
dominant with differences in severity related to differences in the number of repeat sequences, differences in
penetrance, and random X-inactivation in different tissues.

Transmission
The disorder is initially transmitted by a man with 40 or so trinucleotide repeat sequences, who is not affected,
to his daughters, who also are unaffected. The disorder usually is first recognizable in the male offspring of
the daughters. The unaffected grandfather is known as a normal transmitting male, rather than a carrier. This
man usually has what is considered a normal number of trinucleotide CGG repeat sequences in the FMRJ
gene on his X chromosome, usually ranging from 5 [0 44. All his daughters inherit his X chromosome and
will be obligate carriers of the gene. Some expansion of the repeat sequences can occur in the ova of these
daughters (NIH, 2017). When the expansion results in 50 to 200 trinucleotide repeat sequences, the daughter
has a premutation. The larger the number of expansions in a woman who has a premutation in her gametes,
the more likely the expansions will continue within some gametes to progress to a full mutation (more than
200 trinucleotide repeat sequences) that, with fertilization, can result in offspring who do express FXS. All
mothers of affected sons are carriers who have a 50% risk of transmitting the mutation with each pregnancy

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 Chapter 7 Sex Chromosome and Mitochondrial Inheritance and Disorders 139

.'!':j
Common Features Associated With Fragile X Syndrome
Body Area or System Feature

Skeletal features Flat feet

Muscle aches and pains of unknown origin
Reduced muscle tone (in infants)
Scoliosis
Delayed walking
Hip instability
Caved-in appearance of the chest (pectus excavatum)
Neurologic Poor balance and coordination
Tremor (with aging)
Autism spectrum disorders (high incidence)
Seizures (in about 15% of affected males)
Facial features Large ears
Long, narrow face
Prominent jaw
High, arched palate
Macrocephaly (especially forehead)
Cardiovascular Mitral valve prolapse
Miscellaneous Soft, smooth skin
Strabismus
Recurrent middle ear infections
Gastroesophageal reflux disease
Cognitive function Reduced intelligence
Poor verbal skills
Behavioral function Social anxiety
Attention deficit
Distractibility
Poor tolerance of change
Secondary sexual features Large testicles with increased volume

(NIH, 2017). The expansion of trinucleotide repeat sequences is related to allele instability in the FMRI gene.
Some individuals have more than 1,000 repeat sequences. Higher numbers of repeats and greater methylation
increase the severity of the disorder.
Of interest is the role of interruption of the large areas of CGG trinucleotide repeat sequences with a differ-
ent trinucleotide, AGG. When these additional trinucleotides are interspersed within the CGG repeat sequence
segments, they appear [Q add stability [Q the allele and reduce the expansion process (Yrigollen et al., 2012).
Thus, premutarion carriers who have these interrupting sequences may have a lower risk for transmitting a
full mutation to their offspring.
The difference in expression of this disorder in females who inherit the expansions is most likely the result
of random X-inactivation (see Chapter 4). However, any woman who has the expansion has a 50% chance
of transmitting the full mutation to her offipring with each pregnancy.

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140 Unit II Gene Expression

Figure 7-2 Fragile X syndrome at school age: mild facial symp-

toms with large ears and prognathism. (Used with permission from
Schaaf. CP; Zschocke. J; Potocki, L. Basiswissen Humangenetik. Berlin
Heidelberg: Springer-Verlag. 2008. 2013.)

Classic Fragile X Syndrome

The typical picture of FXS is an infant to toddler boy who shows a significant delay in sitting, standing,
walking, and verbal skills. The child usually does not have facial or head features ofFXS at this stage. Physical
delay is more prominent as the child grows, and cognitive developmental delay becomes more obvious. Verbal
skills are poor, and the child often has social anxiety. The incidence of autism spectrum problems appears
relatively high in these children (McCary & Roberts, 2013; Smith, Hong, Greenberg, & Mallick, 2016). The
physical features are outlined in Table 7-2, and some are shown in Fig. 7-2. Other behavioral problems include
difficulty accepting change of any rype, heightened stress, hyperactivity, tantrums, and short attention span
(Lieb-Lundell, 2016). The severity of the behavioral problems tends to decrease over time, especially among
children and adolescents who are active participants in loving families using many behavioral interventions
(Smith et aI., 2016).

Associated Fragile X Syndromes

In addition to classic FXS, two other associated syndromes are noted to occur with the FMRI mutation. These
are fragiLeX-associated primary ovarian insufficiency syndrome (FXPOf) and [ragile X-associated tremor/ataxia
syndrome (FXTAS). FXPOI is an early onser of ovarian failure causing the onser of menopause in women who
are prernutation carriers at ages under 40 years. About 20% of women who are prernutation carriers have
FXPOI (Saul and Tarleton, 2012). FXTAS occurs in people who have 50 to 200 repeat sequences (prernuta-
rions) and do not express FXS bur do develop progressive ataxia and tremors after age 50 years.

MITOCHONDRIAL GENE INHERITANCE

Overview
Mitochondria are organelles (lirrle organs) within a cell's cytoplasm that are responsible for generating most
of a high-energy chemical substance used to power cellular work (Fig. 7-3). In this sense, mitochondria are

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 Chapter 7 Sex Chromosome and Mitochondrial Inheritance and Disorders 141

Centrosome

Nuclear envelope
Nucleus Nuclear pore
{ Nucleoplasm
Nucleolus

Exocytosis

Rough endoplasmic
reticulum

Figure 7-3 Typical human cell with mitochondria. {Modified from Jones, SA Pocket Anatomy
and Physiology, 2e. Philadelphia: FA. DaVIs, 2012.}

considered the "power plants" of cellular energy production. These organelles contain the very small amount
of cellular DNA (extranuclear DNA) that is not located in the nucleus, which is known as mitochondrial
DNA (mtDNA). Each mitochondrion contains many copies or sets of mtDNA.
Mitochondrial DNA differs from nuclear DNA in several ways. The shape of mtDNA is circular, and this
circle is sometimes referred to as the mitochondrial chromosome. In addition, mrDNA replicates separately
from nuclear DNA during cell division. A critical difference is that both mtDNA replication and subsequent
distribution are not as well-regulated as that of nuclear DNA. Thus, no mechanism is in place to ensure that
each new daughter cell receives equal amounts of mirochondria and mtDNA. Because mtDNA has few, if
any, DNA repair mechanisms, it is more prone to permanent mutations than is nuclear DNA. In addition,
mtDNA appears ro have only coding regions (exons) for 37 genes and no noncoding regions (introns). As a
result, any mutation is much more likely to affect the expression of one or more mrDNA genes.

Function
Recall that all normal body cells perform at least one differentiated function that always requires energy.
A common energy source used in cellular actions and reactions is that derived from the breakdown of the
high-energy compound adenosine triphosphate (ATP). This compound contains two high-energy "squiggle"
bonds that, when broken (hydrolyzed), release a large amount of energy within the cell to perform important
functions. Although ATP and a few other high-energy substances can be generated outside of the mitochon-
dria, the reaction that most efficiently generates large amounts of ATP without the buildup of toxic wastes is
oxidative phosphorylation. This reaction occurs within the mitochondria and requires sufficient amounts of
oxygen and hydrogen molecules that have been stripped from our foodstuffs, especially sugar.

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142 Unit II Gene Expression

The process of oxidative phosphorylation is driven by several gene products, many of which are present only
in the mitochondria. Each mtDNA chromosome contains the coding genes for 37 products that, together with
an additional 74 small products from nuclear DNA genes, ensure proper activiry of oxidative phosphorylation
and the generation of ATP.The mtDNA gene products include 13 small proteins that are parts (subunits) of
the enzymes needed for oxidative phosphorylation, along with tWOrypes of ribosomes and the 20 different
types of transfer RNAs (tRNAs) needed for translation during the synthesis of enzymes used to drive the
oxidative phosphorylation process.
The number of mitochondria present in the cytoplasm varies among cells. Those cells that are least active,
such as mature red blood cells, have few, if any, mitochondria. Cells that continually work or perform multiple
functions, such as liver cells, skeletal muscle cells, and cardiac cells, each contain thousands of mitochondria.
When a mutation results in specific mtDNA product nor being made, the cell's energy supply may be insuf-
ficient to perform its functions properly. Problems related to disorders of mtDNA appear first in cells that
require a continuous supply of large amounts of ATP.

Parental Origin
An interesting feature of mtDNA is that it is all maternally derived. Maternal inheritance of mtDNA occurs
because of the basic Structures of mature gametes, the ovum and sperm. The mature ovum is the largest
single cell in the human body and has a relatively small nucleus because it is haploid. Thus, the cell contains
a large volume of cytoplasm and mitochondria that will be distributed to the new cells after fertilization for
many rounds of cell division. New cytoplasm and new mitochondria are not generated for several days after
fertilization. The actual size of the egg does not increase with many rounds of cell division because with
each division, the cells within the egg become smaller. Because the work of the ovum after fertilization is
rapid cell division (a process that requires high energy), the cytoplasm of the mature ovum contains at least
100,000 mitochondria, each containing abundant mtDNA. This amount represents close to one-third of the
total DNA content of the mature ovum.
Mature sperm, on the other hand, are the smallest cells in the body and contain practically no cytoplasm.
(The mature ovum is about 1,000 times larger than a mature sperm.) In addition, the scant cytoplasm with
mirochondria that a sperm does contain is located in the middle tailpiece, which drops off the sperm when it
penetrates the ovum during fertilization. Thus, these mirochondria never become parr of the zygote. Essentially,
the mature sperm is a swimming haploid nucleus (Fig. 7-4). Its mitochondria are located outside the cell at
the connection between the sperm head and the principal tailpiece. The purpose of these mitochondria is to
generate the energy needed to move the tail for sperm propulsion.
At fertilization, the sperm head with its nucleus and no mitochondria enters the mature ovum to form a
zygote. This zygote is now the large diploid mature ovum, complete with all its cytoplasm and approximately
100,000 maternal mitochondria, each containing thousands of copies of mtDMA. Figure 7-5 shows the
first five rounds of cell division for this zygote in which nuclear DNA is replicated and the number of cells
increased, but the initial size of the ball of cells does not enlarge.

Replication
Replication of mtDNA occurs only within the mitochondria, even in cells that will become mature ova.
Within the ovum, mitochondrial and mtDNA replication does not occur concurrently with meiosis of
the nuclear DNA. Most mitochondrial and mtDNA replication in ova occurs rapidly, so replicated seg-
ments of mtDNA do not remain in close contact with each other, thereby preventing the "crossing over" or

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 Chapter 7 Sex Chromosome and Mitochondrial Inheritance and Disorders 143

End tailpiece
Principal tailpiece
(flagellum)

Figure 7-4 Anatomy of a mature sperm.

First round of Second round of Figure 7-5 Five rounds of cell division after the
cell division cell division conception of a zygote.

Zygote, single cell, Two cells, each with Four celiS, each with
46 chromosomes 46 chromosomes 46 chromosomes
and about half the and about 1/4th
initial cytoplasm the initial cytoplasm
and mitochondria and mitochondria

Third round of
ceU division

Thirty-two cells, Sixteen cells, each Eight cells, each with

each with 46 with 46 chromosomes 46 chromosomes
chromosomes and and about 1/16th and about 1/8th
about 1/32nd the initial cytoplasm the initial cytoplasm
the initial cytoplasm and mitochondria and mitochondria
and mitochondria

ERRNVPHGLFRVRUJ
144 Unit II Gene Expression

swapping of chromosome material between segments. In addition, after replication, mtDNA is randomly
sorted and distributed into the newly produced mitochondria. When mitochondrial reproduction is occur-
ring during typical mitosis of somatic cells, the newly produced mitochondria are distributed randomly
into the two new daughter cells. When the mtDNA remains unmutated, this random assortment and
distribution have no significance. However, when a mutation occurs within mtDNA, random assortment
and distribution are responsible for variance in the extent of impairment and which tissues are involved or
impaired.

Mitochondrial Disorders
Overview
More than 100 different point mutations in mtDNA have been observed to cause human disorders, some of
which are apparent in childhood and some that do nor manifest until adulthood. Mitochondrial disorders
occur at a rate of about lout of every 10,000 live births (Scaglia er al., 2004). Some people with mutations
of mtDNA have observable clinical and functional impairments, whereas others may have no manifestations
of disease but do have either a specific mutation in mtDNA, reduced enzyme activity, changes in the appear-
ance of some cells, or indicators of impairment in metabolism.
Most problems associated with mtDNA mutations and mitochondrial disease are present in the musculo-
skeletal, cardiovascular, and neurological systems. Why are the results of mtDNA mutations more apparent in
these systems and tissues? Because these cells are highly dependent on the mitochondrial production of ATP
and contain many thousands of mitochondria per cell. The significant reduction or loss of mitochondrial ATP
production in these cells results in an observable reduction of function. The mechanisms for mtDNA muta-
tions that cause mitochondrial disorders can include problems in transcription, translation, or posrrranslational
modification of proteins and polypeptides coded for by mtDNA (Smits, Smeirink, & van den Heuvel, 20 I0).
Table 7-3 lists examples of human diseases caused by mutations in mtDNA.
Some mitochondrial diseases affect only one tissue or organ and may become obvious only in adulthood,
such as Leber hereditary optic neuropathy (LHON), in which the person develops bilateral, painless, blurred
vision followed by progressive vision loss during young adult life. Occasionally, LHON is not recognized until
later in life (Malouf et al., 2016). Other mitochondrial diseases affect many tissues and organs and manifest
in relatively early childhood (Codier & Codier, 2014). One such disorder is myoclonic epilepsy with ragged
redfibers (MERRF) (OM 1M, 2014). The first sympmm is myoclonus and usually occurs in early childhood
sometime after the toddler stage. This is usually followed by generalized epilepsy, ataxia, muscle weakness, and
dementia. Other associated findings include hearing loss, short stature, optic atrophy, and cardiomyopathy.
Another multisystem mitochondrial disease is mitochondrial encephalomyopnthy; lactic acidosis, and stroke/ike
episodes(MELAS), which usually begins in childhood (OMIM, 2016c). Early childhood development is usually
normal, and the onset of initial sympmms (generalized tonic-clonic seizures, recurrent headaches, anorexia,
weakness in arm and leg muscles, and recurrent vomiting) occurs before 10 years of age. After seizures, the
person often has strokelike problems with brief periods of one-sided paralysis and blindness. By adolescence
or young adulthood, most patients have impaired motor abilities, vision, hearing, and cognition. The eventual
development of diabetes mellitus is common. For those mtDNA diseases that affect multiple organs and tissues,
fatigue is the most prevalent early symptom (Dassler & Allen, 2014; Wrigley, Wilkinson, & Appleby, 2015).

Mechanisms of Variation in mtDNA Mutation Expression

Most mitochondrial diseases that result from point mutations usually are inherited from the maternal line as
mutations in the germ cell mtDNA. Those that result from deletions or duplications may not be inherited
but occur from somatic cell mtDNA mutations during the early embryo blast stage of development.

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 Chapter 7 Sex Chromosome and Mitochondrial Inheritance and Disorders 145

.'!':jlll:w~lL'
Examples of Mitochondrial Diseases
Disorder/Disease Specific Mutat.ion (When Known)

Chronic progressive external ophthalmoplegia (CPEO) tRNAAsn

Kearns-Sayre syndrome (KSS) Large deletions of mtDNA
Leber hereditary optic neuropathy (LHON) MT-ND1
MT-ND2
MT-ND4
MT-ND4L
MT-ND5
MT-ATP6
MT-CYB
MT-C03
Leigh syndrome T8993G and T8993C mutations of MT-ATP6;
sequence variance in all mitochondrial genes
Mitochondrial encephalomyopathy, lactic acidosis, 3243A>G in MT-TL 1
and stroke-like episodes (MELAS)
Mitochondrial neurogastrointestinal encephalopathy TYMP (on chromosome 22)
(MNGIE)
Myoclonic epilepsy with ragged red muscle fibers 8344A>G in MT-TK;
(MERRF) 83561>C in MT-TK;
8363G>A in MT-TK;
8361 G>A in MT-TK;
sequence variance in all mitochondrial genes
Neuropathy, ataxia, retinitis pigmentosa (NARP) 8993C> T in MT-ATP6

Replication Segregation
Replication segregation is the random sorting of newly
So, What Accounts for So Much Variation in
synthesized mirochondria to new daughter cells. When Expression Among the Tissues Involved and
a mutation first occurs in mtDNA, it is present in only the Degree of Impairment?
one mtDNA molecule of a single mitochondrion within
Three mechanisms are largely responsible for varia-
one cell. As mtDNA within that single mitochondrion tion in expression of mltodiondrel disease, whether
replicates, that mirochondrion eventually has multiple the disease is maternally inherited or results from
copies of mtDNA with the mutation along with mul- mtDNA deletions that occur after conception, These
tiple copies of normal mtDNA. The racio of mutated mechanisms are replication segregation, homo-
mtDNA to normal mtDNA is relatively low. However, plasmy, and heteroplasmy.
this is all still in one cell. If that cell is not capable of
cell division, the mcDNA mutation does not affect the energy produccion of the tissue or organ because the
loss of one cell's function within a cissue of billions of cells is at too Iowa level to be problematic.
When this cell that contains a particular mixture of mitochondria with mutated mtDNA and mirochondria
with normal mtDNA undergoes cell division, each mitochondrion replicates, and the total number of mito-
chondria is divided between the rwo new daughter cells. However, because the mitochondria are randomly

ERRNVPHGLFRVRUJ
146 Unit II Gene Expression

segregated (distributed) into the two new daughter cells, these twO new cells each only contain approximately
equal numbers (amounts) of mitochondria, but the ratio of mutated mtDNA to normal mtDNA is unlikely
to be equal. When one daughter cell's cytoplasm contains mitochondria with either all normal mtDNA or all
mutated mtDNA, the condition is termed homoplasmy. When one daughter cell's cytoplasm contains a mixture
of mitochondria that have normal mtONA and mutated mtDNA, the condition is termed heteroplasmy.
(The unequal distribution of mutated mitochondria during cell division occurs in a manner similar to the
unequal distribution of the extra chromosome in Fig. 6-5 within the discussion of mosaicism in Chapter 6.)

Homoplasmy
When a daughter cell with homoplasmy of the mitochondria divides, all resulting new daughter cells will have
the same mitochondrial population as this cell. If the original daughter cell is homoplasmic for mitochondria
with normal mtDNA, the immediate new daughter cells will also be hornoplasmic for mitochondria with
normal mtDNA (providing no further mutational event occurs in these cells). On the other hand, if the
original daughter cell is homoplastic for mitochondria with mutated mtDNA, the immediate new daughter
cells also will be homoplasmic for mitochondria with mutated mtDNA. As this cell reproduces, more cells
that are hornoplasrnic for mitochondria with mutated mtONA are produced, eventually resulting in a tissue
or organ that has a high concentration of cells with impaired energy generation and reduced function.

Heteroplasmy
When a daughter cell with heteroplasmy of mitochondria divides, the resulting new daughter cells are likely
to have hereroplasrny with a mixture of mitochondria with normal and mutated mtDNA. However, because
of random segregation, the ratio of hereroplasmy will be different from the original daughter cell and will be
different between the two new daughter cells. The progeny of the cell with a lower ratio of mutated mtDNA
may continue to dilute this ratio through many rounds of cell division over time, resulting in a tissue or organ
that has such a low concentration of cells with poor energy generation that overall function is minimally
affected. On the other hand, the progeny of the cell with a higher ratio of mutated mtDNA could amplify
the ratio of mutated mtDNA through random segregation so that, over time, homoplasmy of mitochondria
with mutated mtDNA occurs. When the concentration of cells that are hornoplasrnic for mitochondria with
mutated DNA increases within a tissue or organ, the function of that tissue or organ is reduced proportion-
ately. Just as with mosaicism for nuclear chromosomal aberrations, tissues or organs that have more cells with
high percentages of mitochondria that contain mutated mtDNA are more likely to express the phenotype.
Early in embryonic development, the randomness of the distribution of mitochondria that contain mtDNA
with mutations during mitosis is largely responsible for variation in the expression of any mitochondrial disease.
Furthermore, some 74 nuclear DNA gene products are also involved in mitochondrial function. Products of
these genes interact with and can modify the expression of mtDNA genes. A mutation in any of these nuclear
genes involved in mitochondrial function can also affect energy generation and tissue or organ expression of
mitochondrial disease.

Mitochondrial Replacement
Mitochondrial disorders represent problems of function more than of structure. Therefore, the concept of
adding to or "replacing" mitochondria has been considered as a possible means of treating or ameliorating
the effects of mitochondrial diseases within families known to have the problem. Two procedures have been
developed in animal models and are beginning to be tried in humans in the United Kingdom. Both techniques
could result in what are sometimes referred ro as "three-parent babies."
The maternal-spindle transfer (MST) technique involves manipulation of an ovum before conception. In
this technique, the maternal spindle (which contains the nuclear DNA of an ovum) is taken from a woman

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 Chapter 7 Sex Chromosome and Mitochondrial Inheritance and Disorders 147

desiring pregnancy but at high risk for having a child with a mirochondrial disorder and implanted in a donor
egg that has had its nucleus removed {has been enucleated). This new egg, containing the nuclear DNA of the
prospective mother and the mtDNA of another woman (who does not have a risk for mitochondrial disease)
is then fertilized with the sperm of the prospective mother's male parmer. When conception occurs, the zygote
has the nuclear DNA of both parents and the healthy mitochondria (with the mtDNA) of the egg donor.
The pronuclear transfer (PNT) technique is similar but involves manipulation of the zygote after concep-
tion. In this approach, the nucleus from a zygote is removed from the conceptual cytoplasm and transferred
to the enucleated egg of a donor. The zygote was formed from the egg of a woman at risk for passing on a
mitochondrial disorder after it was fertilized by her male partner.
Both techniques have been successful with nonhuman primates. At least one human pregnancy has occurred
from the procedure in the United Kingdom. The controversy surrounding these techniques largely centers on
the fact that although the resulting human will have characteristics inherited from his or her parents, he or
she will have the mitochondrial identity of the person who donated the egg with the healthy mitochondria.

SUMMARY
Sex chromosome abnormalities (SCAs) of number occur much more frequently among live-born humans
than do autosomal chromosome abnormalities, particularly of the X chromosome. Females who have an extra
X chromosome and males who have an extra Y chromosome usually are undiagnosed because they do not have
one or more obvious phenotypical differences compared with individuals whose sex chromosome numbers
are completely normal. In addition, such individuals have normal fertility. Some of the earlier observations
of individuals with SCA resulted in erroneous assumptions regarding intellectual ability, social behavior, and
physical function.

GENE GEMS

• The most common sex chromosomal abnormality conceived is monosomy X (Turner syndrome, 45,X).
• Individuals with an extra X chromosome or an exrra Y chromosome are usually taller than other family
members.
• Unlike with autosornes, monosomy of a sex chromosome is compatible with life.
• With any sex chromosome disorder, the variation in expression is great, and the limitations or ultimate
potential of anyone affected person cannot be generalized or predicted.
• Early tissues that are capable of developing inro anatomical male sex structures (mesonephric ducts)
and those that are capable of developing into anaromical female sex structures (paramesonephric ducts)
are present in both XX and XY embryos.
• The most common mechanism for XY females is complete androgen insensitivity.
• The most common mechanism for XX males is translocation of the SRY gene to an X chromosome
during crossover in gametogenesis.
• Fragile X syndrome is the most common chromosomal disorder leading to reduced cognitive function
and decreased intellectual capacity in males.
• Fragile X prernurations can be expanded to full mutations in the ova of female carriers.
• Males do not inherit fragile X from their affected fathers.
Continued

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148 Unit II Gene Expression

• Heritable mitochondrial disorders that result from point mutations are usually transmitted by maternal
inheritance only.
• Mitochondrial DNA deletions occur after conception and usually are random events that are not heritable.
• The most common symptom associated with mitochondrial diseases is fatigue.
• The mature ovum is the largest single cell in the human body, and the mature sperm is the smallest
single cell in the human body.
• Mitochondrial replacement techniques can result in "three-parent babies," although the characteristics
of the "third parent" are limited to those controlled by mitochondrial DNA

Self-Assessment Questions . ...lo."l .....

1. Which chromosomal trisomy is most often conceived?

a. Trisomy 13
b. Trisomy 18
c. Trisomy 21
d. Trisomy X
2. Which genetic disorder is associated with older parental age at conception?
a. 47,)0tY
b. Turner syndrome
c. Klinefelter syndrome
d. All mitochondrial disorders
3. What mechanism is the most probable reason that females with a 47,XXX karyotype usually have a
normal phenotype?
a. 50% mosaicism for the extra X chromosome
b. Consistent inacrivarion of rwo of the three X chromosomes
c. Failure of chromosome segregation during meiosis II of gametogenesis
d. Excessive methylation of genes on the paternally derived X chromosome
4. Which health problems are common to both Turner and Klinefelter syndromes? Select all that apply.
a. Sociopathic behavior
b. Male-pattern baldness
c. Germ cell tumors
d. Color blindness
e. Osteoporosis
f. Infertility
5. Why does injection of testosterone fail to induce male secondary sex characteristics in females who
are 46,XY with complete androgen insensitivity?
a. Their target tissues for testosterone lack testosterone receptors.
b. The injected testosterone is destroyed JUStas rapidly as their own naturally produced testosterone.
c. Their production of esuogen far exceeds the amount of testosterone that can be administered safely.
d. The injected testosterone inhibits the gonadouophin hormone feedback loops, decreasing the
production of testosterone by the remaining testicular tissue.

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 Chapter 7 Sex Chromosome and Mitochondrial Inheritance and Disorders 149

6. Which situation or condition best exemplifies anticipation?

a. Expression of the disorder is the same for dizygotic twins as it is for monozygotic twins.
b. A mother of a child with a mitochondrial disorder elects to have surgical sterilization.
c. Clinical manifestations of a disorder become less severe or noticeable as the person ages.
d. A son with a genetic problem expresses symptoms 20 years earlier than his mother did.
7. A 39-year-old man with mitochondrial disease is in profound heart failure. What is the source of the
heart failure?
a. Structural malformation of the heart muscle from mitochondrial mutations.
b. Structural malformation of the major heart valves from mitochondrial mutations.
c. Failure of the heart muscle cells to contract effectively because of decreased cellular energy production.
d. Failure of the aortic and pulmonic valves to close effectively because of decreased cellular energy
production.
S. A 21-year-old soldier disappeared in Vietnam. Forry years later, bones are discovered that may include
his remains. Which available living relative's mitochondrial DNA would provide the most accurate
comparison sample to determine whether the bones belong to this soldier?
a. Father
b. Daughter
c. Sister's son
d. Brother's daughter
9. Which molecular mechanism is responsible for the phenotype of fragile X syndrome?
a. Failure of the X chromosome to undergo correct segregation during meiosis II of gametogenesis.
b. Presence of excessive trinucleotide repeat sequences in the noncoding regions of the FMRI gene.
c. Premature "splicing out" of the AGG47 I inrron during early translation of the FMRI gene.
d. Whole body absence of receptors for the FMRI gene product.

CASE STUDY

Adam had one daughter (Beverly) when he was 25 years old, another (Bonnie) when he was 27 years old,
and a son (Brian) when he was 30. Bonnie has two sons and a daughter. Her first son (Charlie) has many
developmental delays, and the pediatrician has done enzyme studies for specific biochemical disorders. All
were negative. When Charlie is 6 years old, his maternal aunt (Adam's first daughter, Beverly) is 40 years
old and pregnant. As part of prenatal diagnostic work, she has blood drawn for genetic disorders, and an
amniocentesis is performed. The amniocentesis indicates she is pregnant with a normal girl. However,
Beverly's blood work reveals that she is a fragile X syndrome premutation carrier. When Beverly tells Bonnie
about this, Bonnie informs her pediatrician about Beverly's premutation carrier status. The pediatrician sends
Charlie for testing, and he is found to have more than 1,000 CGG trinucleotide repeat sequences in his
FMR1 gene alleles with 90% methylation, giving him a diagnosis of fragile X syndrome.
1. What risks do Bonnie's children have for premutation carrier status?
2. What risks do Beverly's children have for premutation carrier status or for FXS?
3. What risks do Brian's children have for premutation carrier status or for FXS?
4. Why is Adam unaffected?
5. What are the risks for Adam's mutation status to change to a full mutation? Explain your response.

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150 Unit II Gene Expression

References

Bondy, C (2007). Clinical practice guideline: Care of girls and women with Turner syndrome: A guideline of the Turner syn-
drome study group. fournal of Clinical Endocrinology and Mnabolism, 92(1), 10-25.
Codier, E., & Codier, D. (2014). Understanding mitochondrial disease and goals for its treatment. British journal of Ntlrsil1g,
23(5). 254-258.
Dassler, A., & Allen, P. (2014). Mitochondrial diseases in children and adolescents. Pediatric Nursing, 40(3),
150-154.
Gould, H., Balalov, v., Tenkersley, C, & Bondy, C. (2013). High levels of education and employment among women with
Turner syndrome. journal of\'(!omm's Health; 22(3), 230-235.
Groth, K., Skakkebaek, A., Host, C, Gravholr, C, & Bojesen, A. (2013). Klinefelter syndrome: A clinical update. [ournnl of
Clinical Endocrinology and Membolum, 98(1), 20-30.
Lieb-Lundell, C (2016). Three faces offragile X. Physical Tlurapy, 96(11), 1782-1790.
Malouf, M., Levin, M., & Mathews, M. (201G). Leber's hereditary optic neuropathy-Not just a young men's disease.joumal
of the American Geriatric Society, 64(1), 237-239.
McCary, L.. & Roberes.}. (2013). Early identification of autism in fragile X syndrome: A review.journal of Inrellectua] Disability
R~search. 17(9),803-814.
Milunsky. A.• & Milunsky, ]. (2010). Generic disorder: in tht' j;'l/s: Diagl/osis, prruention, and treatment (Gth ed.). Oxford. UK:
Wiley-Blackwell.
National Institutes of Health. (2017). Genetia IJOmt' 1'I'.forrnc~:Fmgilt' X syndram«. Retrieved from Imps:lIghr.nlm.nih.govl
con di rionl fragile-x-syndro me
Oliveira. C. Ribeiro. E. Lago, R.• & Alves. C (2013). Audiological abnormalities in patients with Turner syndrome. American
journal of Audiology. 22(2). 226-232.
Online Mendelian Inheritance in Man. (2014). Myoclonic ~pi/~psy associaud with raggt'd-rt'd ./ibm; MERRF. Retrieved from
http://w,,/w.omim .org/entry/545000
Online Mendelian Inheritance in Man. (201Ga). Androgm inst'llsiriviry syndrom~; A IS. Retrieved from Imp:llwww.omim.org/
entry/3000G8
Online Mendelian Inheritance in Man. (201Gb). Fmgilt' X mental retardation. Retrieved from hcrp:llwww.omim.org/entryl
300G24
Online Mendelian Inheritance in Man. (201Gc). Mitochondrial myopathy. t'I1ct'phalopalby, lactic acidosis, and strok~-likt' episodes;
MELAS. Retrieved from http://www.omim.org/entry/540000
Radtke. A.• Sauder, C. Rehrn, ) .• & McKenna, P. (2014). Complexity in the diagnosis and management of 45,x Turner syn-
drome mosaicism. journal of Urology. 84(4). 919-921.
Saul. R., & Tarleton. ). (2012). FMR1-relared disorders. Gmt' I'I'vit'/us. Retrieved from https:llwww.ncbi.nlm.gov/books/
NBK13841
Scaglia, E, Towbin, ) .• Craigen, W. Belmont.). W. Smith. E. O. B.• Neish, S. R.•... Vogel. H. (2004). Clinical spectrum.
morbidity, and mortality in 113 pediatric patients with mitochondrial disease. Pediatrics, 114(4).925-931.
Smith. L., Hong, I- Greenberg, ]., & Mailick, M. (20 1G). Change in the behavioral phenotype of adolescents and adults with
FXS: Role of the family environment. journal of Autism and Deoelopmental Disorders, 46(5), 1824-1833.
Smits. P.• Smeitink, J.. & van den Heuvel, L. (2010). Mitochondrial translation and beyond: Processes implicated in com-
bined oxidative phosphorylarion deficiencies. [oumal of Biomedicine and Biotechnology, 2010, 1-24. doi:IO. I 155/20101
737385
van Rijn, S., Srockrnann, L, Borghgraef, M., Bruining, H., van Ravenswaaij-Arts, C, Govaerts, ... Swaab, H. (2014). The social
behavioral phenotype in boys and girls with an extra X chromosome (Klinefelter syndrome and trisomy X): A comparison
with autism spectrum disorder. [ournal of Autum 6- Deoelopmental Disorders, 44(2), 310-320.
Walker, K. (2014). Oral manifestacions of Turner syndrome. kem, 28(5), 32-34.
Wisniewski, A.• Migeon, C., Meyer-Bahlburd, H., Ge3Iharr, J., Berkovitz. G., Brown, T.• & Money. J. (2000). Complete
androgen insensiriviry syndrome: Long-term medical, surgical, and psychosexual outcome. journal of Clinical Endocrinology
and Metabolism, 85(8), 2664-26G9.

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 Chapter 7 Sex Chromosome and Mitochondrial Inheritance and Disorders 151

Wrigley, A., Willcinson, S., & Appleby, J. (20IS). Mitochondrial replacement: Ethics and identity. Bioethics, 29(9),
631-638.
Yrigollen, C, Durbin-Johnson, B., Gane, L., Nelson, D., Hagerman, R., Hargerman, P., & Tassone, F. (2012). AGG inter-
ruptions within the maternal FMRI gene reduce the risk of oflSpring with fragile X syndrome. emetics in Medicine, 14(8),
729-736.

Self-Assessment Answers
I. d 2. c 3. b 4. c, e, f 5. a 6. d 7. c 8. c 9. b

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 Family History and
Pedigree Construction
Learning Outcomes
1. Complete an accurate three-generation pedigree using standard symbols.
2. Explain the "red flags" for genetics referral.
3. Determine the most likely transmission pattern depicted in a simple pedigree.
4. Construct an accurate Punnett square for both an autosomal-dominant and autosomal-recessive disorder.
5. Discuss the importance of collecting and updating family histories.

Key Terms
Pedigree Punnett squares
Proband Risk stratification

INTRODUCTION
Nurses in any patient care setting must be able to collect data for an accurate depiction of patient and family
history for inclusion in a pedigree. A pedigree is a pictorial or graphic illustration of family members' places
within a family and their medical history. Using the data to construct a pedigree visually organizes family
information to identify individual risks for family-specific disorders. This picture allows efficient cornmmu-
nication to others on the health-care team. Having the abiliey ro organize a family history into a pedigree is
an important skill for all health professionals and is an expectation for registered nurses with a bachelor of
science in nursing (BSN) degree. In 2008, the Essentials of Baccalaureate Education for ProfessionalNursing
Practice were published by the American Association of Colleges of Nursing, requiring that all BSN gradu-
ates be able to "generate a pedigree from a three-generation family history using standardized symbols and
terminology." This paradigm-shifting inclusion continued the movement to enforce the need for genetics in
the clinical practice of nursing.
Completing a family history is an easy and affordable way to begin genetic screening; however, family
history is not stable over time. On the day you take your patient's family history, no one may have cancer.

152

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 Chapter 8 Family History and Pedigree Construction 153

The next day, your patient's 35-year-old brother or sister could be diagnosed with colorecral cancer, changing
your patient's genetic risk for cancer from low to high. Family history can also change depending on who
provides the information. For example. your patient's Aunt Grace may remember more about the family's
health problems than your patient does, and sometimes other family members will remember things differ-
ently. Perhaps one relative says that a grandmother died because of a heart problem, but a different relative
remembers that she died from cancer. Teasing out what conditions actually occurred within a family lineage
can be difficult for the health-care worker.

FAMILY HISTORY
The best way for a family history to be as complete and as accurate as possible is for several family members
to construct it tOgether. A study has found that about 96% of Americans believe that knowing their family
history is important, yet only about one-third of those reported having made any effort to collect their fam-
ily's health history. The U.S. Department of Health and Human Services (2017) provides a Surgeon General's
Family Health History Initiative with all the tools needed for a family to complete and update the family
health history (http://www.hhs.gov/familyhistory/). Easy-to-follow directions are provided at the My Family
Health Tool website in English, Spanish, Italian, and Portuguese. Families can develop their family histories
alone or under the guidance of a health care professional. Instructions include what questions to ask as well as
what documents could help provide important information and should be on hand when the information is
gathered and recorded. A family gathering during the holidays is a great time for people to collect their fam-
ily's health history because, for many, this is a time when most of their relatives are together, Having family
members know about the plan for purring the history together and bringing any documents or pictures to
the gathering that can enhance memory are helpful to the process. Once the history is generated, each family
member should have a copy. Encourage your patienrs to collect and frequently update their fa.mily health
histories and to bring them along for each visit to any health-care provider. A recent study by Cheung. Blue,
and Wijsman (2014) found that pedigrees. especially the second and third generations, continue to remain
useful when identifying persons with a high risk of carrying a mutation.

Genetics Referral
How Do You Know When to Refer a Family
Risk stratification is the process of identifying whether
for Genetics Counseling?
a person is at a high. moderate. or low risk of developing
Although specific guidelines for when a patient anctl
a genetic disorder. It is an important step in deciding
or family should be referred have not been estab-
whether or not a patient or family would benefit from
lished, the Association of Clinical Medical Genet-
genetics referral. Importantly, nurses and allied health ics (Pletcher et al., 2007) published guidelines for
professionals in traditional roles should nor attempt to conditions that are "red flags" for genetic referral,
provide genetic counseling because this is beyond the meaning that an individual or family with one or
scope of practice; however, they should have a good more of these conditions should be referred to a
sense of when referral should be considered. genetics specialist (Table 8-1). Referral to a genet-
Table 8-2 provides a list of questions for the health- ics specialist (as defined in Chapter 18) should be
care provider to use with a patient to ensure important considered by the health-care team if the patient has
points are included when obtaining a family history. a group of problems or malformations present since
These are easy to remember by using the acronym birth (congenital anomalies), extreme or exceptional
presentation of common conditions, neurodevelop-
SCREEN, which stands for Some Concern about diseases
mental delay or degeneration, extreme or excep-
that might run in the family, especially problems with
tional pathology. or surprising laboratory values.
Reproduction, Early disease or death in family members,

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154 Unit II Gene Expression

F-Genes Mnemonic for Red Flags of Genetic Disease

Family history. Multiple affected siblings or individuals in multiple generations. Remember that lack of a
family history does not rule out genetic causes.
G: group of congenital anomalies. Common anatomic variations are, well, common, but two or more
anomalies are much more likely to indicate the presence of a syndrome with genetic implications.
E: extreme or exceptional presentation of common conditions. Early-onset cardiovascular disease,
cancer, or renal failure. Unusually severe reaction to infectious or metabolic stress. Recurrent
miscarriage. Bilateral primary cancers in paired organs, multiple primary cancers of different tissues.
N: neurodevelopmental delay or degeneration. Developmental delay in the pediatric age group carries
a very high risk for genetic disorders. Developmental regression in children or early-onset dementia in
adults should similarly raise suspicion for genetic etiologies.
E: extreme or exceptional pathology. Unusual tissue histology, such as pheochromocytoma, acoustic
neuroma, medullary thyroid cancer, multiple colon polyps, plexiform neurofibromas, multiple exostoses,
most pediatric malignancies.
S: surprising laboratory values. Transferrin saturation of 65%, potassium of 5.5 mmollL, and sodium of
128 mmol/L in an infant; cholesterol greater than 500 mg/dL and unconjugated bilirubin of 2.2 mg/dL in
an otherwise healthy 25-year-old: phosphate of 2 mg/dL and glucose of 35 mg/dL in a 6-month-old child.

Developed by the Red Flags Worki"9 Group of the Genetics in Primary Care (GPC) project (Alison Whelan MD, Chair). Reproduced with
permission.
Whelan, A. J.. Ball, S.. Best, L., et al. (2004). Genetic red flags. Clues to thinking genetically in primary care practice. Primary Care, 37,
497-508.

Abbreviated Family History: SCREEN Questions for Familial Disease

I- -
SC Some Concern Do you have any concern about diseases that run in the family? Have any
members had more than one type of cancer diagnosis? Are there traits
that run in your family (e.g., large head or freckles on lips and/or tongue)?
R Reproduction Have there been complicated pregnancies, infertility, or birth defects?
E Early disease/death Has anyone in your family become sick or died at an early age?
E Ethnicity How would you describe your ethnicity?
N Nongenetic Are there risk factors that run in your family?

Adapted from Hinton, R. B., Jr. (2008). The family history: Reemergence of an established tool. Critical Care Nursing Clinics of Nonh
America, 2m2), 149-158; Carts, Z., & Hampel, H. (2015). Certified genetic counselors: A crucial clinical resource in the management of
patients with suspected hereditary syndromes. Surgical Oncology Clirics of North America. 24, 653...,66.

Ethnicity (some generic diseases are more common in people who are from certain ethnic groups), and Non-
genetic risk facrors for disease. The quesrions are simple and can be added ro a general health assessmenr to
increase the likelihood of derecring any generic risk (Generics in Primary Care Institute, 2016). Another
approach is the "rule of two/roo," which uses quesrions that may indicate a generic condirion. These include
the following: roo tall, roo short, roo early, roo many, roo young, roo differenr, two rumors, two generations,
two in the family, and rwo birth defecrs (Generics in Primary Care Institute, 2016).

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 Chapter 8 Family History and Pedigree Construction 155

PEDIGREE CONSTRUCTION

Pedigree Symbols and Conventions

As described earlier, a pedigree is a pictorial or graphic illustration of members' positions within a family and
their medical history. It allows health-care providers to view the health history of multiple generations and
makes identitying persons who are at risk easier for genetics professionals. Once you become familiar with
the symbols and conventions used to construct pedigrees, they are simple to read. A well-constructed pedigree
makes communicating the medical issues of extended family to health-care team members quick and efficient.
By using the standard pedigree symbols presented here, the family's history can be sketched out a..~ it is
provided, and whether a disease "runs in the family" may become clear. You may even be able to identify
possible modes of transmission, such as autosomal dominant or autosomal recessive.
The symbols have been standardized so that all clinicians use the same symbols for the same things. In this
way, the information is communicated from one clinician or facility to another without confusion. Circles are
used to represent women, and squares represent men. Lines depict relationships, with horizontal connecting
lines indicating mating, not necessarily marriage. In a mating relationship, males are drawn on the left and
women on the right (Fig. 8-1).
Vertical lines are called lines of descent and are drawn between biological parents and children. The symbols
for all children born to a couple are drawn from the same line. So, a mating couple with a son and twO
daughters would look like the depiction in Figure 8-2. If a parent has children from a previous relationship,
those children have a vertical line drawn from the mother or the father.
A horizontal slash through a symbol indicates that the person is deceased, and the age of death is indicated
beside the symbol. If the mother in the family in Figures 8-1 and 8-2 had been married before and had one
son with her previous husband before he died, the pedigree would look like the depiction in Figure 8-3.
When a pedigree is being used to record the history of one particular trait, such as hypertension, the circle
or square representing every affected person is depicted using the same shading, pattern, and so on (Fig. 8-4).
When multiple traits are being recorded, the list of health problems is commonly written next to each
person's symbol. ln some pedigrees, the symbols have color-coded segments that correspond to different traits.
When these are present, they must be explained in a legend because these symbols are not standardized. In

2 Figure 8-1 Mating between a man and a woman.

D-O
2 Figure 8-2 Lines of descent and sibship.

2 3
II

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156 Unit II Gene Expression

2 3

2 3 4
Figure 8-3 Deceased mate and second mating, with
II
both matings producing offspring.

Figure 8-4 Person affected with the trait of interest.

Hypertension
Coronary artery
disease

2 3
II

Diabetes mellitus type I Asthma

Asthma

.:J Diabetes type I ~ Hypertension

~ Coronary artery
~Asthma CJdisease
Figure 8-5 Recording multiple traits.

Figure 8-5, a green upper-left quadrant indicates coronary artery disease, and a blue upper-right quadrant
indicates hypertension, so the father, who has both hypertension and coronary artery disease, has green in
the upper left and blue in the upper right. On the pedigree depicted in Figure 8-5, an arrow in the lower
left corner indicates the proband. (The proband is usually defined as the person in a family who brought the
potential genetic issue to the attention of a health-care professional.) The proband has both diabetes mellitus
type 1 and asthma, whereas his brother has only asthma.

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 Chapter 8 Family History and Pedigree Construction 157

Although having the ability to construct and analyze pedigrees is useful for nurses and other health-
care professionals, communicating the information about transmission patterns is best left to genetic profes-
sionals. These professionals may be physicians with specialty work in genetics, certified genetics counselors,
PhD-educated geneticists, or advanced-practice nurses with a specialization in genetics. These roles are discussed
in detail in Chapter 18. As part of their scope of practice, bedside nurses and other nongenetics professionals
are expected to identify patients and families who may be at an increased risk for genetic problems; however,
quantifying and communicating that risk fall within the scope of practice for genetic professionals.
For a pedigree to provide useful information regarding the potential of a genetic disorder within a family,
it must contain at least three generations. The generations are identified by Roman numerals, so in the
three-generation pedigree, the grandparents would be generation I, the parents would be generation II, and
the children would be generation III. If a pedigree shows more than three generations, the oldest generation
is designated as generation I, with each succeeding generation numbered in order after the first generation.
Within each generation, individuals are designated by Arabic numerals, and all persons in the pedigree are
numbered from left to right. The goal is for each family member co have a distinct identifying number.
Figure 8-6 shows the correct numbering of a three-generation pedigree.
Additional information should be included on the actual pedigree to increase its usefulness in identifying a
heritable genetic problem. One type of especially important information is family erhnicity, Noting the ethnic-
iry (or erhniciries) of each side of the family is helpful because genetic risk varies with the geographic origin
of ancestors. For example, knowing if a patient's grandparents were Ashkenazi Jews (from Eastern Europe) is
very important because that particular ethnic group is at higher risk for a number of recessive traits, such as
Gaucher disease, Tay-Sachs disease, some types of breast cancer, and cystic fibrosis.
Remember to sign and date the pedigrees you construct so that those who view them later will know when
the data were collected and whether the pedigree needs to be updated. Work in pencil so that you can make
adjustments as you collect the family history data. If you are constructing this pedigree as a family history, be
sure to identify the proband of the family. He or she is commonly the first person in the family who is affected
or identified. In other cases, the proband does not have the problem but is worried because the possibility
of a genetic issue exists. If you are generating a pedigree as parr of your patient assessment and no specific
problem is known, the proband is the patient whose family hisrory you are obtaining.

Figure 8-6 Three-generation pedigree with

appropriate Roman and Arabic numbering.

II

III

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158 Unit II Gene Expression

PUNNETT SQUARES
Punnett squares are diagrams used to determine the risk of offspring being affected when the mode of trans-
mission and the parents' carrier status are known. The maternal and paternal genotypes are represented by
uppercase letters to indicate dominant alleles, and lowercase letters represent recessive alleles. A homozygote
would be either BB or bb, and a heterozygote would be Bb. Remember that Punnen squares represent genotypes
and not phenotypes, and whether a person is ill may depend on other factors, such as incomplete penetrance
or whether the trait is likely to result in pregnancy loss if the embryo is a homozygote.
In Figure 8-7, the probability of each pregnancy resulting in a child with the genotype BB is 25%, Bb is
50%, and bb is 25% (Fig. 8-7 A). If this Punnett square represented a recessive trait such as cystic fibrosis, we
could estimate the risk of an unaffected child being a carrier. An unaffected child would not be bb (homozygous
recessive), which is covered in Figure 8-7B. She or he could be either BB (not affected and not a carrier-risk
25%) or Bb (not affected but a carrier-risk 50%). Therefore, the risk that an unaffected child in this family
is a carrier would be rwo out of three or 2/3.
The use of Punnert squares has limitations. For example, things get a bit more complicated when you
consider genotype for two different rraits {dihybrid cross}. For the Punnett square to work, the genes being
considered must be located on different chromosomes. Some alleles may affect the expression of other alleles,
and some genes can be imprinted such that when the allele was inherited from the mother or the father
(imprinting) makes a difference. What you figure out by doing a Punnen square may be unrelated to what
you see in the phenotype. When the genes of interest are located on the X or Y chromosomes also can com-
plicate matters because most men have only one X chromosome and most women have no Y. Variations in
dominance also exist, such as the codominance seen in the ABO sysrem of human blood type, which can make
the Punnett square more confusing. Remember that when the gene for a trait is found in the mitochondrial
DNA, virtually all transmission will be maternal. Doing a Punnerr square analysis can be helpful to deter-
mine the likelihood of having an affected or carrier child when transmission follows a standard Mendelian
pattern.

Mother Mother

B b B b

B BB Bb B BB Bb

Father b bB bb Father b bB
A B

Figure 8-7 (A) Punnett square of the possible offspring of two heterozygous parents. (8) The trait is expressed
in the offspring with two recessive alleles.

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 Chapter 8 Family History and Pedigree Construction 159

PEDIGREE ANALYSIS
This chapter provides some guidelines to follow when analyzing a pedigree to identify possible transmission.
When analyzing a pedigree, proceed in the following organiz.ed manner:
1. Make sure that you have collected all the relevant information from the family and that you construct
your pedigrees according to conventions presented in this chapter.
2. Look at the pedigree and test it against the possible inrerprerarions. Use the guidelines for each mode
of inheritance that were provided in Chapter 4. See what fitSand what does not. For example, if you
have male-to-male inheritance, you cannot have X-linked transmission.
3. Test against possible hypotheses:
a. Autosomal dominanr
b. Autosomal recessive
c. X-linked dominant
d. X-linked recessive
e. Y-linked
f. Maternal (mitochondrial)
4. Discard all hypotheses that do not fit the pedigree.
5. If only one remains, accept it as your working idea.
6. If two or more remain, which is the more likely? For example, which is the more likely explanation for
the pedigree in Figure 8-6?
a. Person ]]-2, who comes from a family with several affected members and has affected children, has
the genotype (but not the phenotype) for the trait (i.e., the trait is passed in an autosomal-dominant
fashion but has incomplete penerrance).
OR
b. Person 11-2 is a carrier for a rare trait and selected a mate (person II-I) from the general population
who is also a carrier for the same rare trait, and persons 1-1 and 11-3 are also carriers (i.e., the trait
is passed in an autosomal-recessive fashion).
Hint: Option A is much more likely!

Examples of Pedigree Analysis

In Figure 8-8A, the following conditions apply:
• Males are represented by squllres.
• Females are represented by circles.
• A person who has died has a diagonal line drawn through his or her symbol.
• A vertical line is called a line of descent and indicates the connection between parents and their
offspring.
• The proband is indicated by an arrow.
• A mating (not necessarily a marriage) is represented by a solid horizonral line, called the relationship line,
between the partners.
• If the relationship is casual not a formal marriage or a committed parmering, the relationship line can
be dashed (Fig. 8-8B).
• The horizontal line connecting siblings is called the sibship line. Each person in each generation is given
an Arabic numeral starting from the lefr (Fig. 8-8C).

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160 Unit II Gene Expression

• Person 4 in generation II was adopted into the family. The vertical dashed line indicates that there is no
biological relationship (Fig. 8-8D).
• This pedigree indicates that person 4 in generation II was adopted out of the family (Fig. 8-8E). She
no longer lives with them, but a biological relationship still exists with her siblings and birth parents.
• This pedigree indicates that person 4 and person 5 in generation II are dizygotic (fraternal) twins (Fig. 8-8F).

~1 1 2
A II B 0----0
2
1 2

~1 4:
C II ~~ o II [Q]
2
2

~1 ~1
Ell F II
2 2

Gil H II
2 2

1 2
O=D
1 2
J()-+-OK
Figure 8-8 (A-K) Standardized pedigree symbols.

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 Chapter 8 Family History and Pedigree Construction 161

• The addition of a horizontal line connecting the twins' lines of descent indicates that they are monozygotic
{identical} tunns (Fig. 8-8G).
• When a symbol is made small, it indicates a pregnancy loss. When the sex of the fetus or embryo is
unknown, a diamond (or sometimes a triangle) symbol is used (Fig. 8-8H).
• When the relationship line is double, it indicates consanguinity (these individuals are biologically related).
For example, a double line would be used if two cousins were in a mating relationship (Fig. 8-81).
• A double (or sometimes single) diagonal line through the relationship line indicates that the couple is
divorced (Fig. 8-8J).
• A short horizontal line at the end of a line of descent indicates that a couple has no children. They may
be infertile, or they may have chosen not to have children. The short horizontal line can be doubled to
indicate known infertility (Fig. 8-8K).

SUMMARY
Collecting an accurate and updated family history is an important first step in determining a family's genetic
risk. Constructing a pedigree with a minimum of three generations provides a convenient way to communicate
a family'S health history to other health-care providers. Standard symbols are used for pedigree construction,
and the use of standard conventions helps to make this communication easier. Conducting a step-by-step
analysis of a pedigree can reveal the most likely transmission pattern of a single-gene genetic disorder. Pedigree
analysis is more difficult for multifactorial (complex) disorders because multiple genes or combinations of
genes and the environment are involved. Some traits are considered important triggers or "red Rags" for referral
to genetics professionals, such as groups of congenital anomalies and neurodevelopmental delay. Identifying
a family history that should be evaluated by genetics professionals is an important role for all health-care
providers.

GENE GEMS

• Encourage your patients to complete an accurate family hisrory when their family members are gathered
together. When a deceased family member's disease is unknown, death certificates and pathology reporrs
are good sources of information when available .
• Teach your patients the importance of bringing an updated family history with them when they meet
with a health-care professional.
• Record a three-generation pedigree using Roman numerals to indicate vertical generations and Arabic
numerals to indicate individuals, horizontally.
• Include erhniciry for each side of the family.
• When analyzing a pedigree, test it against assumptions for each transmission parrern.

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162 Unit II Gene Expression

Self-Assessment uestions ....

1. March each of rhe following inherirance parrerns wirh the correcr pedigree illusrrarion.
a. Aurosomal dominanr 1. First Pedigree (Fig. 8-9A)
b. Aurosomal recessive 2. Second Pedigree (Fig. 8-98)
c. X-linked dominanr 3. Third Pedigree (Fig. 8-9C)
d. X-linked recessive 4. Fourrh Pedigree (Fig. 8-9D)
e. Y-linked dominanr 5. Fifth Pedigree (Fig. 8-9E)
f. Y-linked recessive
g. Mirochondrial

II

A III

II

Bill

C III

Figure 8-9 (A) First pedigree. (8) Second pedigree. (e) Third pedigree.

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 Chapter 8 Family History and Pedigree Construction 163

o III

II

E III

Figure 8-9 (D) Fourth pedigree. (E) Fifth pedigree.

CASE STUDIES

FAMILY HISTORIES

Family A
Doug and his maternal grandfather, Brad, have a diagnosis of hemophilia A. Neither Doug's brother (Dick)
nor his sister (Donna) have the disease. His father, Carl, the youngest of three sons (the other two are
Charles and Caleb) has no symptoms of hemophilia, but his oldest brother, Caleb, also has the disorder.
Caleb has two sons (David and Dennis) who are "normal" and one daughter, Darlene, who is also normal.
Carl's mother, Brenda, reports that one of her parents (Doug's paternal great-grandparents, Albert and
Adele) died from a bleeding problem but does not remember which one. Doug's partner is his paternal
uncle's daughter, Darlene. Doug and Darlene have two sons, Ethan and Elliot, and two daughters, Emma
and Elise. Ethan, Elliot, and Elise have hemophilia, whereas Emma is disease free.
Draw the pedigree, indicating affected individuals and probable carriers (see the correct pedigree in
Fig 8-10A).
Continued

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164 Unit II Gene Expression

II

Brenda Brad

III

Caleb Charles Carl

IV

David Dennis Darlene Doug Dick Donna

•
@
Affected

Obligatecarrier

V 0 Possiblecarrier

Ethan Elliot Emma Elise ? Possibleaffected

Figure 8-10A Pedigree for Family A.

1. What is the likely inheritance pattern of this family history?

2. Which of Brenda's parents is most likely to have had hemophilia?
3. What is the probability that Elise could have a son with hemophilia?
4. What is the probability that Elise could have a daughter with hemophilia?
5. Is it possible for Ethan or Elliot to have children with hemophilia? Explain why or why not.
6. Is it possible for Emma to have children with hemophilia? Explain why or why not.

Family 8
A couple, Jack and Jill, are both deaf, and each has one parent who also is deaf. Jack and Jill have eight
children: six boys and two girls, four of whom (one daughter and three sons) are also deaf.

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 Chapter 8 Family History and Pedigree Construction 165

III

Jack and Jill

Autosomaldominant If the deafness were autosomalrecessive,
Males and females about equally affected all of Jack and Jill's childrenwould be deal.
AffectedIndividualshave affected children If it was X-linked recessive,again, all of their
Transmitteddown to all generations children would be deal. II it was X-linked
dominant,all of their daughterswould
have it.

Figure 8-108 Pedigree for Family B.

Jill Dd Figure 8-10C Punnett square for Family B.

D d

D D D D d

Jack
Dd d d D d d

Autosomaldominant

Draw the pedigree for the family (see the correct pedigree in Fig. 8-10B; see the correct Punnett square
in Fig. 8-10C).
1. Identify the specific pattern of inheritance (if any) indicated for this family.
2. Indicate what criteria the pedigree presents that support the correct pattern of inheritance for this
health problem.

Family C
James is 52 years old and has just been diagnosed with a "recurrence" of colorectal carcinoma, previ-
ously treated by colon resection 8 years ago. His father is still living at age 80, and his mother died of
ovarian cancer at age 38 (diagnosed at age 36). His sister, Bonnie, was diagnosed with endometrial cancer
5 years ago at age 40. His brother, now age 43, was treated 3 years ago with surgery and chemotherapy
Continued

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166 Unit II Gene Expression

for colorectal cancer. James tells you that both of his parents' families are rather small. His mother had one
sister, Adele, who died of some kind of reproductive cancer when she was 34, and one brother, Arthur,
who died of liver cancer at age 40_ Her father's only sibling, a brother, died during World War II. James's
daughter, Caroline, is 30 and was recently diagnosed with ovarian cancer.
Draw the pedigree for the family (see the correct pedigree in Fig. 8-l0D).
1. Identify the specific pattern of inheritance (if any) indicated for this farnilv,
2. Indicate what factors in the pedigree support your choice for the correct pattern of inheritance for
this health problem.

Figure 8-100 Pedigree for Family C.

II

III

Autosomal dominant
Males and females affected
Affected individuals have affected offspring
Transmitted from one generation directly to the next

References
Cheung, C., Blue, E., & Wijsman, E. (2014). A statistical framework to guide sequencing choices in pedigrees. AjHG, 94(2),
257-267.
Genetics in Primary Care Institute. (20 16). GenesicT~dflags. Retrieved from hnps:llgeneticsinprimarycare.aap.orglYourPracticel
Family-Health-Hisrory/PagesiGenetic%20Red%20Flags.aspx
Pletcher, B., Toriello, H., Noblin,S., Seaver, L., Driscoll, D. A., Benerr, R., & Gross, S. (2007). Indications for genetic referral:
A guide for healthcare providers. Cenetics ill Medicine, 9(7), 385-389.
U.S. Deparrrnen r of Health and Human Services. (2017, March). The mrgeoll gmeml's family hMlth history initiative. Retrieved
from http://www.hhs.gov/fanlilyhisrory/

Self-Assessment Answers
1. a 2. b 3. b 4. d 5. a

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 C haptsr 9------'
Congenital Anomalies,
Basic Dysmorphology,
and Genetic Assessment
Learning Objectives
1. Compare the classifications of congenital anomalies, including dysmorphic features.
2. Differentiate among syndromes, sequences. and associations.
3. Distinguish between major and minor congenital anomalies.
4. Compare the processes that result in malformation, disruption, deformation, and dysplasia.
5. Identify common congenital anomalies.
6. Describe assessment strategies that are important in determining if a patient has dysmorphic features. ,
Key Terms
Association Frontal bossing Minor anomaly
Brachydactyly Gestalt Oligohydramnios
Canthus Hypertelorism Palpebral fissure
Cleft lip/palate Hypotelorism Philtrum
CIinodactyly Lip pits Plagiocephaly
Congenital anomalies Long fingers/toes Polydactyly
Craniofacial anomalies Low-set ears Ptosis
Craniosynostosis Macrocephaly Retrognathia
Deformation Major anomaly Sequence
Disruption Malformation Syndactyly
Dysmorphology Microcephaly Syndrome
Dysplasia Micrognathia Teratogen
Epicanthic folds Midface hypoplasia

167

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168 Unit II Gene Expression

INTRODUCTION
When a child is born with a visible alteration in anatomical features, such as a cleft lip and/or cleft palate,
parents can feel shocked and overwhelmed. Clinicians use the term dysmorphology to describe variations in the
shape of anatomical structures such as limb and/or craniofacial differences. Dysmorphology (dys = "painful";
morph = "shape") is defined as the study of congenital anomalies in the form or body parts of a person
or abnormal patterns of development. An anomaly is something that is different from what is common or
expected, and congenital means that it is present at birth. These are sometimes called birth defects or mal-
formations, even though the term malformation has a specific definition, which we will discuss later in this
chapter. The term dysmorphology was coined in the 1960s by Dr. David Smith, so it represents a relatively new
area of study. Smith's Recognizable Patterns 0/ Human Malformations remains the classic text on dysrnorphol-
ogy. This text, and others like it, helps clinicians match dysmorphic features with the disorders associated
with them.
Terminology has been inconsistent over time, so an international group of experts published a series of
articles in 2009 to standardize the definitions of terms used to describe dysrnorphic features. This chapter's
key terms are consistent with the definitions published by these experts: Allanson, Biesecker, Carey, and
Hennekam (2009); Biesecker er al. (2009); Carey er al. (2009); Hall, Graham, Cassidy, and Opitz (2009);
Hunter et al. (2009). We suggest that you review these articles if you are interested in learning about dysmor-
phic features in more detail.
Identifying the associated disorder or syndrome of a particular anomaly or pattern of anomalies is useful
for a variety of reasons. For one, a correct diagnosis can guide medical management. For example, if a child's
collection of dysmorphic features indicates that he has Noonan syndrome, the clinical geneticist will know
that the child must also be seen by a cardiologist because congenital heart defects (CHDs) and hypertro-
phic cardiomyopathy (HCM) are common features of that syndrome (Tartaglia, Zampino, & Gelb, 2010).
Some head and neck features that are characteristic of Noonan syndrome include a triangular-shaped face,
hypertelorism (widely spaced eyes), downward-slanting eyes, ptosis (drooping eyelids), low-set ears, a
high nasal bridge, and a short and webbed neck. Without knowing something about Noonan syndrome,
a clinician observing this collection of features might not look for heart involvement. Importantly, not
every person with a syndrome will have every symptom found in that syndrome. For example, about 80%
of people with Noonan syndrome have shorr stature, but that means that 20% of people with Noonan
syndrome are of average height. Although short stature is common in Noonan syndrome, not everyone
has it.
Identifying the syndrome can also help determine the probable progression of the disorder and can assist
genetic professionals in guiding parents with future reproductive decision making. In some cases, treatment
is available that will have an enormous impact on the future of an affected child. For example, knowing that
a child has Gaucher disease, which is a lysosomal storage disease like those discussed in Chapter 10, means
that enzyme-replacement therapy can be started immediately. Starting enzyme replacement early can prevent
the grossly enlarged liver and/or spleen that are characteristic of this disorder.
One concern with identifying dysmorphologies is that normal variations exist in some anatomical struc-
tures based on differences in geographical origin among our ancestors. This can make the diagnosis of genetic
syndromes more difficult, particularly with images included in textbooks that do not show normal variations
in phenotype. For examples, epicanthic folds are common in many people of Asian ancestry. Clinicians have
suggested that textbooks and atlases should include globally diverse populations in the photographs they
provide as examples, and some have considered the practical and ethical aspects of providing such a resource
(Korerzky et al., 2016).

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 Chapter 9 Congenital Anomalies. Basic Dvsrnorpholoqy and Genetic Assessment 169

MAJOR AND MINOR ANOMALIES

Congenital defects are often classified as either major or minor anomalies. Major anomalies are serious and
usually require medical or surgical attention. They can have life-threatening implications or have a serious
cosmetic effect. For example, although a cleft lip may not put a child's life at risk, the child's physical appear-
ance and self-esteem may be seriously affected; therefore, cleft lip is considered a major anomaly. Serious
concerns such as cognitive impairment, heart defects, and renal agenesis are also considered major anomalies.
A minor anomaly does not have serious functional or cosmetic consequences and mayor may not be
surgically corrected. Minor anomalies are found in less than 4% of the general population. Most dysmorphic
features are classified by clinicians as minor anomalies. However, when several minor anomalies appear in one
child, they can help lead the clinician to a correct diagnosis. An example of a minor anomaly is clinodac-
tyly, which is a laterally curved digit. This most commonly occurs as the fifth finger curving inward toward
the other fingers (Fig. 9-1). It probably happens because of an unusual shape or positioning of the growth
plate in the small bones of the fingers and can result in abnormal positioning of the finger joints. Although
clinodactyly can be found in approximately 10% of the general population, it is also common among people
who have Down syndrome.
One of the authors of this textbook has clinodacryly of her right fifth finger. She first noticed it in the third
grade when she was putting on gloves to march in a parade. She found that her right glove did not fit like
her left glove fit. The knuckle of her right fifth finger is positioned lower on that finger than on any of her
other fingers, making it appear to be a joint shorter than her left fifth finger. This is an example of a minor
anomaly with no clinical significance.
One important part of the definition of minor anomaly is that it has no serious significance to the person
who has it. However, clinicians must remember that a person may be very upset about a seemingly insignificant
abnormal feature. An old joke states that minor surgery is [he kind of surgery that is done on someone else!
Any surgery seems major when you are the person having it. When people are personally affected, a small
difference in appearance can be frightening. Even though new parents can be very distressed by something
they perceive as abnormal in their infant that seems minor [0 health-care providers, the family's concerns must
be taken seriously. For example, one of the author's sons had such severe metatarsus varus in both feet that
he could have played "parry cake" with his soles. This problem was related to uterine crowding and resolved
with exercise and special shoes.

Figure 9-1 Clinodactyly of the fifth finger.

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170 Unit II Gene Expression

In most cases, a single dysmorphic feature does not mean that a child has a disorder. Berween 13% and
39% of healthy newborns have one minor anomaly, but less than 1% of healthy newborns have two minor
anomalies. Some sources suggest that if a child has three minor anomalies or one major anomaly, chromosome
studies should be done to help determine the cause of the problem (jones, 2006). In practice, the situation is
more complicated. For example, genetic studies would be done on a child with a cleft lip only ifhe or she also
had developmental delay, growth delay, or a speech problem such as apraxia (difficulty coordinating mouth
movements or difficulty saying what is intended). Decisions about whether to order genetic studies are made
by genetic professionals who can consider all the elements of what is going on with a child.
Minor anomalies should be considered within the COntextof family history. Do any of the minor anomalies
seen in the child appear in other family members? Sometimes what seem to be minor anomalies may not be
caused by any disorder but may simply reflect an inherited group of unusual features. The familial contribu-
tion to a child's minor anomalies, along with other conditions (such as malformations) that might appear in
other family members, could provide clues [Q potential single-gene or submicroscopic chromosome imbalances.
The risk of a child having a major anomaly that is nor immediately obvious increases dramatically with the
number of minor anomalies identified, For example, if a child has three or more minor anomalies, the risk of
that child having a major Structural defect is about 20%. Although a single minor anomaly is usually of no
significance, finding an unusual feature should alert the clinician to look carefully to see if other abnormalities
are present that may have been missed.

CLASSIFICATION OF CONGENITAL ANOMALIES

Congenital anomalies can be classified in many ways. They might be classified according to the mechanism
that caused them or according to whether they affect a single body part or multiple body parts. Remem-
ber that many people have normal variations that are not associated with disease. These are defined as
variations that are found in more than 4% of the population. For example, Mongolian SpOts, the Rat blue or
blue-gray SpOtson the back, the buttocks, the base of the spine, or other body areas of people with dark skin,
are not found in everyone, but they are also not associated with disease. Thus, Mongolian SpOts represent a
normal skin pigment variation.
Specific terms are used to characterize anomalies by their type. The major categories are malformation,
deformation, disruption, and dysplasia.

Malformation
A malformation is caused by a primary problem in the growth or development of a particular tissue. For
example, cleft lip/palate, a feature caused by the failure of the Lipand/or palate tissues [Q fuse during devel-
opment, is considered a malformation because it is due to a developmental problem during facial formation.
The tissues making up the lip do not fuse properly, leaving a gap (or cleft). Although a cleft lip, with or
without cleft palate, is usually caused by a combination of genetic and environmental factors, it is the result
of an abnormal developmental process. Chromosome problems account for about 25% of malformations, but
others, such as achondroplasia, are inherited as single-gene disorders.

Deformation
A deformation is caused by the effect of a physical or mechanical force that prevents the proper growth of
a structure that would have developed normally. The embryo or fetus may be perfecdy fine, but something

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 Chapter 9 Congenital Anomalies. Basic Dvsrnorpholoqy and Genetic Assessment 171

is preventing it from growing properly. Constriction in the uterus is one possible cause. The correction of
deformations ofren occurs after the mechanical stressor is removed. If removing the stressor does not correct
the problem, clinicians start to consider the possibility that the structure was not properly formed.
Sometimes deformations are caused by a disease process that results in constriction, but the direct cause
of the problem is always mechanical. For example, anything that reduces the size of the uterus can cause a
deformation. With oligohydramnios, which is the state of nor having enough amniotic Auid, fetal growth
is restricted because the insufficient amount of amniotic Auid keeps the uterus from expanding enough ro
accommodate normal fetal growth. Also, having twins. triplets. or larger numbers of multiples can cause the
physical restriction of intrauterine space. Any of these conditions can lead to contractions in the joints or
other signs of deformation.

Disruption
A disruption is a bit more difficult to understand. In a disruption, a normal developmental process is "dis-
rupted" by some event that leads to the destruction of normal tissue. For example, exposure ro certain drugs
can cause a disruption, as can trauma or vascular insufficiency. It is different from a malformation because
everything started out normally. For example, the formation of amniotic bands, which are fibrous strands of
amniotic sac tissue, can restrict the proper growth of fetal body parts, including fingers, toes, arms, and legs
(Fig. 9-2). Amniotic band disruptions are rare. but the result can be mild to life-threatening, depending on
what part of the body is being constricted and how tightly it is entrapped. Some infections, such as rubeJla,
cytomegalovirus (CMV), and toxoplasmosis, can also cause disruptions.

Figure 9-2 Disruption of the right hand caused by amniotic bands. The distal third phalanx
is constricted. yet not completely amputated by an amniotic band. The distal pharynx of the
fourth digit is completely disrupted; no nail is present on this digit. Amniotic bands were
noted on the fetal surface of the placenta. (Courtesy of Lorraine Potocki. Department of Molecular
and Human Genetics. Baylor College of Medicine and Texas Chl7dren's Hospital. Houston.)

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172 Unit II Gene Expression

Although these classifications are useful clinically, they do sometimes overlap, which can be complicated,
if not confusing. Let us go back and look at oligohydramnios; remember that it can be a mechanical cause of
deformations, but the oligohydramnios may be caused by a primary genetic problem, such as Potter sequence.
In Potter sequence, the embryo does not develop functional kidneys (a malformation called renal agenesis).
Because the fetus has no kidneys, it cannot make urine. Because the fetus cannot make urine, less amniotic
fluid results. The low level of amniotic Auid is the direct mechanical cause of fetal growth restriction, which
makes it a deformation. In this case, we have an abnormality in fetal growth that can be looked at as both a
malformation and a deformation.

Dysplasia
Dysplasia is an alteration in the size, shape, and organization of ceLIs.Single-gene disorders are the most
common genetic cause. An example of a genetic disorder that is caused by dysplasia is ectodermal dysplasia,
which is abnormal cell growth in the skin, hair, nails, or sweat glands.

SYNDROME OR SEQUENCE
The difference between a syndrome and a sequence can also be confusing. Sometimes the words are used incor-
rectly, and many sequences are commonly referred to as syndromes. A syndrome is a collection of features that
occur together and have a consistent pattern. They are thought to have the same cause. The word syndrome
comes from the Greek words for "running together." Down syndrome is caused by an extra chromosome 21,
and it results in a collection of symptoms that are easily recognized by the clinician. (See Chapter 6 for more
information about Down syndrome.) Syndromes are more likely to be caused by chromosomal inheritance
than are single anomalies.
A sequence is a little different. In a sequence, one anomaly starts a chain reaction that causes another
problem that then causes another and then sometimes another. One example is Pierre-Robin (pronounced
"Roban") sequence. The anomaly that starts out Pierre-Robin is micrognathia (a small jaw, which is caused
by shortening and narrowing of the mandible) in the developing fetus (Fig. 9-3). Sometimes the word ret-
rognathia is used to indicate that the jaw is moved posteriorly (and may be accompanied by micrognathia).
This small jaw causes the tongue to be positioned backward into the pharynx (glossoptosis). The posteriorly
positioned tongue can cause a cleft palate and sometimes respiratory obstruction. It is a sequence of events that
started with the poorly formed jaw (Fig. 9-4). Although all of these features (small jaw, posteriorly displaced

Figure 9-3 Micrognathia (with retrognathia).

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 Chapter 9 Congenital Anomalies, Basic Dysmorphology, and Genetic Assessment 173

Small lower
jaw

Cleft palate
Figure 9-4 Pierre-Robin sequence.

tongue, respiratory obstruction, and cleft palate) occur together, they were all caused by the chain of events
that started with the jaw problem (Allanson, Cunniff, er al., 2009).
Potter sequence (mentioned earlier in the explanation of disruptions) is another example. The renal agen-
esis caused the low amniotic Auid level, which then led to growth restriction. The chain of events makes it
a sequence. To make this a bit more complicated, sometimes a sequence is part of a syndrome. For example,
Pierre-Robin sequence can be found in velo-cardio-facial syndrome, Stickler syndrome, and trisomy 18. The
primary malformation, which is micrognathia (with or without rerrognathia), leads to the cascade of anomalies
within these syndromes.
When a collection of features occurs together, but the relationship is not clear, the term association is
used. Sometimes disorders are called associations until more is learned about how they happened. Then the
name is changed to syndrome or sequence.

DYSMORPHOLOGY ASSESSMENT
When clinical geneticists or genetics nurse practitioners approach a new patient, they look for the overall
pattern of anomalies. Sometimes, particularly when looking at facial and developmental features, experts in
clinical genetics talk about getting a sense of the whole pattern or picture of the patient. The term gestalt
is used to convey this overall impression. Being able to appreciate the gestalt comes from much experience
working with patients who have anomalies and with their families.
Sometimes dysmorphic features are caused by prenatal exposure to drugs known as teratogens, which
are substances that can alter development and cause a birth defect. This word has an unfortunate derivation
(terata = "monstrosities"). This means mat assessment questions focusing on maternal use of prescription, over-
the-counter, and recreational drugs are very important. For example, a particular set of dysmorphic features is
associated with fetal alcohol spectrum disorder (FASD; Centers for Disease Control and prevention lCDCl,
2010). Although being exposed to alcohol as a fetus may not, at first, appear to be a genetic problem, some
people have a genetic predisposition to abuse alcohol and other drugs, so in some ways, this can be considered
a genetic problem. Furthermore, if FASD were completely environmental, you would expect a dose/exposure
response. That would mean that developing fetuses who were exposed to the most alcohol in utero would
be the sickest. However, this is not the case, and some babies born [Q mothers who are known alcoholics
have no detectable phenotype at all. Both maternal genes and fetal genes related to alcohol metabolism and
clearance probably contribute to how susceptible a fetus will be to me harmful effects of alcohol exposure.
FASD is a good example of a disorder with dysmorphic and developmental features in which an affected
child will benefit from an early and correct diagnosis (Figs. 9-5 and 9--6). FASD is also an example of a
disruption.
People often think that every set of abnormalities they see clinically must have a name. More than
3,500 nonchromosomal syndromes have been cataloged in the London Dysmorphology Database (Winter &

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174 Unit II Gene Expression

Low nasal
bridge

Small eye
openings

Short nose

Thin upper
lip

Figure 9-5 Dysmorphic features in fetal

alcohol spectrum disorder (FASD). Underdeveloped jaw

Figure 9-6 Child with fetal alcohol spectrum

disorder. (Used with permission from Schaaf. CP;
Zscbocke, J; Potocki, L. Basiswissen Humangenetik.
Berlin Heidelberg: Springer-Verlag, 2008, 2013.)

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 Chapter 9 Congenital Anomalies. Basic Dvsrnorpholoqy and Genetic Assessment 175

Barairser, 2005); however, only about 50% of rare parrerns of anomalies have been named (Jones, 2006). This
is sometimes difficult for families to understand because they want very much to know what is wrong with
their child. Having a name for the problem could make a difference to their sense of COntrol. Parents often
want to know if the same problem will happen to future children. Sometimes doing a chromosome study or
microarray will identify a chromosome imbalance that is not linked to a recognized, named disorder. In these
situations, further testing of parents may be necessary to determine if the chromosome imbalance is likely
ro be associated with the child's condition or if it is merely a benign inherited imbalance from an unaffected
parent. Once a cause is established, genetics professionals can often help parents understand the recurrence
risk; however, when no genetic abnormality can be found, even the best genetics professionals cannot provide
the parents with an accurate idea of the likelihood that the problem will reoccur in future children.

ASSESSMENT THROUGH A GENETIC LENS

The physical assessment skills you use for general assessment do not vary when you are considering whether
a child or adult has a genetic disorder. Following a head-to-toe pattern and using general assessment skills,
including inspection, palpation, and auscultation, are still important. What is different is the consideration of
findings that vary from what is normal. The presence of both major and minor anomalies must be carefully
considered and documented to inform decisions for referral to genetics professionals. Unfortunately, most
dysmorphic features are not specific for only one disorder. For example, low-set or malformed ears are features
of many genetic disorders, including Beckwith-Wiedemann syndrome, Potter syndrome, Rubinsrein-Taybi
syndrome, Srnirh-Lernli-Opi tz syndrome, Treacher Collins syndrome, trisomy 13, and trisomy 18. So, although
finding that a child has low-set ears is important, this finding must be combined with other observations
before it can be attributed to a specific genetic disorder. Finding low-set ears in a child does signal the need
for further careful evaluation. However, remembering that the presence of low-set ears also occurs in people
who have no other dysmorphology, major anomalies, or cognitive impairment is important. Be sure to take
note of the patient's posture and muscle tone during your assessment. Significant hypotonia (floppiness or
poor muscle tone) is associated with several disorders, such as Prader-Willi and Down syndromes (Read &
Donnai,2015).
Another important consideration is to always view an individual in the COntext of his or her family. Some-
times features that may appear dysmorphic are simply family traits. For example, a tall, thin person with long
fingers and toes (formerly called arachnodactyly) may have Marfan syndrome. However, she or he may also
JUStcome from a family that includes many healthy members who are rail and thin and have long fingers.
Being able ro meet or see photographs of other family members can help genetics specialists decide what is
and is not a cause for concern. Of course, remember that many traits are heritable, and if only a few family
members share a trait, the possibility that they each carry the genetic variation must be considered.

Cognitive Impairment
Cognitive impairment (CI) is one reason for evaluation by a genetics professional. Please note that the term
cognitive impairment is being used here to indicate a condition found in people who have limitations in their
mental abilities, with intelligence quotients (lQs) measured at 70 or less. They may have difficulty communi-
cating, developing social skills, and solving problems. They may need assistance with activities of daily living.
Some professionals prefer to use the term developmentally delLzyedwhen referring to people who have these
problems with thinking. The older term, mentally retarded, is considered derogatory by many people who
specialize in caring for those who are cognitively impaired. Specialists differ in what they believe is the most
appropriate terminology. Some believe that mental retardation is a diagnosis and that the term should still be

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176 Unit II Gene Expression

used when referring to this collection of cognitive symptoms, whereas others prefer intellectual disability. In
this text, we are using the term cognitive impairment to indicate the difficulty some people have in thinking
and processing information from the world around them.
CI can be attributed to genetics in a significant number of affected people. More than 500 genetic disorders
can cause CI, but most of these are very rare. Extra chromosome material, as in Down syndrome; microdele-
tions, as in cri du chat or Williams syndrome; and copy-number variants, as in some cases of Charcor-Marie-
Tooth disease (National Institute of Neurological Disorders and Stroke [NINDS], 20 10), can all result in CI.
Table 9-1 lists selected disorders in which cognitive impairment is a feature. Finding the specific cause of CI
is commonly difficult; some people are affected due to environmental issues during the pregnancy, such as
exposure to alcohol, infections, or malnutrition. Nevertheless, between 25% and 50% of severe CI is due to
a genetic problem (NINDS, 2010).
Of course, CI is not itself a dysrnorphic feature, but it does often coexist with dysmorphology and can
be considered a major anomaly. Therefore, it is an important finding that can contribute to a clear under-
standing of what is wrong with a person. CI is often classified as syndromic, meaning it occurs with other
clinical features, or nonsyndromic, meaning that the impairment is the only feature of the disorder. One of
the by-products of understanding more about the biological and chemical changes of disease is that the line
between syndromic and nonsyndrornic disorders is beginning to blur. Less obvious clinical features are being
identified along with CI for most cases that were once considered nonsyndromic (Chelly, Khelfaoui, Francis,
Cherif & Bienvenu, 2006).

Measurement
Not roo long ago, dysmorphic features were evaluated only qualitatively. Clinicians looked at patients and
described what they saw. Perhaps a child's eyes looked like they were tOOwide apart (hyperrelorism) or the
philtrum (the groove or depression that lies midline between the upper lip and the nose) looked tOOlong.
These qualitative descriptions made it difficult for other clinicians to judge the severity of the condition or
to compare one child's features to another child's. Comparing the features of one affected child to those of
another child with the same condition can help document how much variability exists among people with
the same genetic problem. Now a system of precise measurements has been developed so that features can be
compared against an age-related norm, and changes in a child's features can be recorded as the child grows
and develops. For example, we can clearly establish whether a child's head circumference, height, or weight
conforms to published normal growth curves and remains in the same percentile over time.
Figure 9-7 shows standard ways to measure various facial features. For example, the canthus is the angle
formed by the meeting of the upper and lower eyelids. The inner canthus is closer to the nose, and the outer
canthus is closer to the ear. The inner canthus distance is measured as the space berween the inside of each
eye, and the outer canthus distance is measured as the space between the outside of each eye. The philtrum
length is measured from the top of the lip to the nose.
When a primary clinician refers a patient to a medical genericisr, the structure and growth of the entire
body and specific body parts are documented. This is a complex process, and to do it well requires advanced
training. However, the nurse or allied health professional at the bedside can recognize basic dysmorphic features
and structural anomalies that should trigger referral.
When considering the possibility that the patient may have a genetic disorder, attention is focused on clinical
features that could indicate the need for further evaluation. This chapter includes a brief overview of selected
dysmorphic features that are of particular interest in determining whether a person has a genetic disorder.
There are many, many more! Targeted resources will provide a more comprehensive picture of dysmorphology,
and these are included in the reference list.

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 Chapter 9 Congenital Anomalies, Basic Dysmorphology, and Genetic Assessment 177

.'!':jll=-:.c::IIIl,
Selected Named Genetic Disorders That Can Cause Cognitive Impairment and Associated
Common Dysmorphic Features
Named Disorder Classification Locus Common Dysmorphic Features

Angelman syndrome Imprinting or 15q11 Distinctive" coarse" facial features,

deletion microcephaly, scoliosis
Down syndrome Large chromosome Trisomy 21 Distinctive facial features,
problem epicanthic folds, palmar creases,
upslanting palpebral fissures, flat
nasal bridge, open mouth with
tendency of tongue protrusion, and
small ears with overfolded helix
Cri du chat Microdeletion 5p15.2 Distinctive facial features,
microcephaly, widely set eyes
(hypertelorism), low-set ears, a
small jaw, and a rounded face
22 q deletion syndrome Deletion 22q11 Cleft palate and some mild variation
(includes DiGeorge syndrome) in facial features
Rubinstein- Taybi Single gene 16p13.3 Distinctive facial features, broad
thumbs and first toes, eye
abnormalities, dental problems,
obesity
Coffin-Lowry X-linked Xp22.2 Distinctive facial features and
skeletal syndrome anomalies.
Prominent forehead, widely spaced
and downslanting eyes, a short
nose with a wide tip, and a wide
mouth with full lips
Williams syndrome Single gene 7q11.23 Distinctive facial features, including
a broad forehead, a short nose
with a broad tip, full cheeks, and a
wide mouth with full lips and small,
widely spaced teeth that may be
crooked or missing
Fragile X syndrome Trinucleotide Xq27 Distinctive facial features with
repeat (expansion long and narrow face, large ears,
mutation) prominent jaw and forehead,
unusually flexible fingers,
macroorchidism

Data from Chelly, J., Khelfaoui. M .. Khelfaoui, M., Francis. F.. Cherif. B., & Biel1llenu. L (2006). Genetics and pathophysiology of mental
retardation. European Journal of Human Genetics, 14(6). 701-713; and Library of Medicine. (2010). Genetics home reference. Retrieved
from hnp://ghr.nlm.nih.gov/condition/d<MIr>-syndrome

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178 Unit II Gene Expression

.6.

...D

A· Outer canthal measurement

B • Inner canthal measurement
C • Interpupillarydistance
Figure 9-7 Standard facial measurements. D • Phinrumlength

Dysmorphic Features and General Appearance

Beginning the genetic assessment with observation of the general appearance of the patient is important.
Unusual features are often photographed for future reference. Having a photograph also allows review by
specialists, who may not be able to see the patient in person. The use of technologies such as telemedicine
can allow a genetics specialist located in another geographic area to complete a physical examination with the
assistance of local clinicians who are physically with the patient.
Some genetic disorders result in variations in normal height and/or weight, so whether the patient's height
and weight are in the range of normal for his or her age and are consistent with those of family members must
be determined. Growth curves are available to help with this determination. If a child's height or weight falls
outside of the normal range, possible causes can be considered, but this is only one piece of evidence and must
be considered along with what is typical within the child's family. (Hint, do not consider a child abnormally
short until you have seen both parents, any siblings, and know approximate grandparent height.) For example,
in Prader-Willi syndrome (PWS), failure to thrive is common during infancy due to hypotonia and feeding
difficulties, so babies with PWS may be underweight. However, children with PWS may have an increased
body weight or obesity due to hyperphagia (excessive eating). This is thought to be caused by an abnormality
in the hypothalamus, which limits the ability to feel satisfied after eating. However, not all obese children
have PWS. Other characteristics are associated with PWS, such as cognitive impairment and hypogonadism.
Another example is that people with achondroplasia have short stature with disproportionately short arms
and legs and a relatively large head because of a bone growth problem. However, their short stature does not
appear in isolation; characteristic facial features, including rnidface hypoplasia and frontal bossing, also occur.
In midface hypoplasia, the central parr of the face, including the upper jaw, cheeks, and eye region, is small
in proportion to the rest of the face. Frontal bossing describes a very large forehead with bilateral bulging
of the frontal bone prominences.
Tall stature is seen in people who have Marfan syndrome (MFS). This connective tissue disorder causes
patients to be tall and thin, bur the problem with connective tissue also causes a weakening of the blood
vessel walls, which can lead to an aneurysm. Young people with MFS must avoid strenuous physical activity

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 Chapter 9 Congenital Anomalies, Basic Dysmorphology, and Genetic Assessment 179

that might lead to rupture of an undiagnosed aneurysm and possible death. Identifying young people who
are at risk for serious or life-threatening injury during athletics and referring them for follow-up evaluation
are important reasons for a thorough physical examination before participating in SpOrts.

Dysmorphic Features of the Skull

Craniofacial anomalies are variations from the usual formation of the skull and face. The head is assessed
for its size, shape, and the symmetry of features. The head size should be compared to the size of the rest of
the body to determine whether it is in proportion. Plagiocephaly is significant asymmetry of the skull. It can
be caused by the way a newborn is positioned during sleep, which is called positional molding. This kind of
molding is benign and has become more common since the American Academy of Pediatrics recommended
that newborns sleep on their backs to reduce the incidence of sudden infant death syndrome (SIDS). Molding
is more likely to be the cause when the deformity is in the posterior skull. Plagiocephaly may also be caused by
an early fusion of one of the lambdoid cranial sutures. When the anterior skull is asymmetric, an underlying
problem is more often the cause. Craniosynostosis occurs when more than one of the cranial sutures fuse
together earlier than they should. If several sutures dose toO early, the brain may not have room to grow, and
intracranial pressure will increase (Reardon, 2008). This is a serious medical problem that requires urgent
surgical attention.
Scalp defects mayor may not involve the skull. However, most scalp defeces are not associated with a problem
within the brain, and they usually do not signify that a more complicated syndrome is involved. Sometimes
scalp defects do result in severe bleeding. For example, aplasia cutis congenita (ACC) is a scalp defect that
usually involves a single lesion on the scalp. For 86% of people with a single lesion, no other accompanying
features are present. Some people have several lesions that are circular, oval, or form a line or a star. The lesions
tend to be between 0.5 and [0 cm in size and often heal before birth, leaving behind a hairless area covered
by thin, parchment-like skin. Of course, having accompanying dysmorphic features increases the likelihood
that an affected person has a genetic syndrome. For example, when ACC is accompanied by limb anomalies,
the child may have Adams-Oliver syndrome, which can be either inherited (usually in an autosomal-dominant
manner) or sporadic and often includes heart involvement.
Head Size
Macrocephaly means "enlarged head," and, even though it is easy to define, exactly what makes a head seem
unusually large is much less clear. The technical definition is a cranium with an occipitofrontal circumference
greater than the 97th percentile compared with others of the same age and gender (Allanson, Cunniff, et al.,
2009). Head circumference is the largest measurement around the head. It is also called occipitofrontal circum-
ference because measuring from the frontal region, just above the eyebrow ridge, to an area near the top of
the occipital bone produces the largest head measurement. Measurements always must be considered in terms
of a child's age and general body size. Charts are available to help clinicians determine if a child is macro- or
microcephalic. The term macrocephaly is merely descriptive and does not imply a cause for the finding. Again,
some families have large heads as a familial trait, but many pathologic conditions also include macrocephaly
as a feature. Skull size variations are cause for concern about whether the brain is growing normally.
Microcephaly means that the head is smaller than expected. It is generally defined clinically as having a
head circumference that is more than two standard deviations below what is expected for the child's age and
gender (Ashwal, Michelson, Plawner, & Dobyns, 2010). Microcephaly is an important finding, suggesting that
the brain has grown abnormally. This may be caused by structural abnormalities or by a neurodegenerative
process in the brain, or the small head circumference could just run in the family and have no consequence.
Microcephaly can occur alone, with no other abnormal features, as an autosomal-recessive condition. Con-
sanguinity may be involved in these cases. A small head is also a feature of several rare genetic disorders, and

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180 Unit II Gene Expression

a thorough physical assessment is essential when this is seen. For example, in Smirh-Lernli-Opitz syndrome,
microcephaly is accompanied by narrowing of the head at both temples and syndactyly (partial fusing of the
digits) of the second and third toe (Fig. 9-8). Microcephaly can also occur in chromosomal disorders, such as
Down syndrome, or it may be due entirely to environmental factors, such as exposure to terarogens, maternal
malnutrition, or the Zika virus (Ashwal et al., 2010; CDC, 2016).

Dysmorphic Features of the Face

Coarse facial features are seen in several genetic problems, including mucopolysaccharide (MPS) disorders
such as MPS type IV (a lysosomal stOrage disease). You can read about biochemical diseases like MPS IV in
Chapter 10. Before deciding that someone has coarse facial features, her or his appearance should be compared
with that of other family members. If coarse features are a family trait, they may not be associated with disease.
What is meant by "coarse face" is somewhat difficult to explain, but the features are quite prominent and are
not refined, sharp, or finely sculpted. It is an example of a "bundled term" that conveys an overall impression
or gestalt. In MPS IV, patients have macrocephaly, enlarged tongues, prominent foreheads, and commonly a
coarse texture to the hair. These large and broad features give a coarse appearance to the face. Figure 9-9 shows
a man with a prominent nose, deep-set eyes, broad lips, and deep nasolabial folds. This man has a coarse face.
The length of the philtrum can vary with the size of the nose, leading to a wide range of normal. The
philtrum is smooth (no groove or depression) in many syndromes, including FASO, but by itself, a smooth
philtrum does not necessarily mean that a genetic problem exists. On the other hand, if additional signs of
dysmorphology have been documented, finding a smooth philtrum can help to suppOrt or refute a diagnosis.
Figures 9-5 and 9-6 show a smooth philtrum as one of the characteristic features in FASO.
Abnormal Nasal Bridge
Abnormal nasal bridge refers to an unusual appearance of the bony area between the eyes. What is considered
normal for this feature varies widely across age groups and populations, and this makes drawing conclusions
a bit tricky. As we have mentioned before, the presence of additional dysmorphic features can make finding a
raised or depressed nasal bridge more significant. A high nasal bridge is seen in Wolf-Hirschhorn syndrome,
which is a chromosome deletion problem that often involves seizure activity and general hypotonia. A depressed
nasal bridge can be seen in families with Stickler syndrome, which is transmitted in an autosomal-dominant
manner and often includes micrognathia and Pierre-Robin sequence. In addition, a depressed nasal bridge
with a "saddle nose" deformity is associated with WiUiams syndrome and with congenital syphilis infection.

Figure 9-8 Children with Smith-Lemli-Opitz syndrome usually

have syndactyly of the second and third toes (among other
characteristics). (Used with permission from Schaaf. CP; Zschocke, J;
Potocki. L. Basiswissen Humangenetik. Berlin Heidelberg: SpringerVerlag,
2008,2013)

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 Chapter 9 Congenital Anomalies, Basic Dysmorphology, and Genetic Assessment 181

Figure 9-9 Coarse features. (Used with permission from Schaaf, CP;
Zscbocke, J; Fbtocki. L BasiswissenHumangenetik.Berlin Heidelberg:
Spnnge"Verlag, 2008, 2013.)

Micrognathia
Micrognathia is the term used to describe the appearance of a recessed chin caused by an unusually small
mandible. If it is severe, micrognathia can result in feeding problems for affected infants and can also be the
cause of Pierre-Robin sequence (described earlier). If the small jaw is not roo severe, the child may outgrow
the unusual appearance. Always remember that a dysmorphic feature may simply be a common family trait.
But, then again, family members who share one or more dysmorphic features may have an unrecognized
genetic condition, such as Stickler syndrome or velo-cardio-facial syndrome. For this reason, the health-care
professional may best serve the family by having a low threshold for making a genetics referral based on dys-
morphology. In ocher words, if you are concerned that something might be wrong, it is always best to have
someone skilled in dysmorphic assessment evaluate the patient.

Dysmorphic Features of the Eyes

Hypertelorism is the term used to describe widely spaced eyes (Fig. 9-10). Several facial features can make the
eyes look like they are spaced widely apart, even when the distance between them is perfectly normal. This
can happen when a child has epicanthic folds or a depressed nasal bridge. Or, the distance between the inner
canthi might be abnormally wide, but the interpupillary and outer canthi distances are within normal range.
Although this situation resembles hypertelorism, it is instead called telecanthus. Because some families have
wide-spaced eyes as a benign family trait, yet hyperrelorism can be a feature in several genetic disorders, again,
a thorough physical assessment should follow chis observation. Hypertelorisrn is seen in Aarskog syndrome,
an X-linked disorder that has several other characteristic features, such as a wide philtrum; a fold in the rop
of the ears; and in males, a shawl scrotum (a condition in which the scrotum surrounds the penis and looks
very much like a shawl).
In hypotelorism, the eyes are much closer together than would be expected for the body size and age
of the child (see Fig. 9-10). Hyporelorism raises suspicion about central abnormalities in the brain, such as

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182 Unit II Gene Expression

Hypotelorism Normal spacing Hypertelorism

Figure 9-10 Hypotelorism. normal spacing. and hypertelorism. Left = hypotelorism;

middle = normal spacing; right = hypertelorism.

holoprosencephaly (a condition in which me brain does not grow properly, and me embryonic forebrain does
not divide as it should). For this reason, neuroimaging is commonly recommended when an infant or young
child with developmental delay has measured hyporelorisrn. It can also be a feature of several genetic disorders.
One example is Kallmann syndrome, which is a hypogonadorropic hypogonadism mat includes an impaired
or absent sense of smell (anosmia). It is transmitted as an X-linked recessive trait.
The palpebral fissure is me space between the eyelids of each eye. When me outer canthus of me eye lies
above an imaginary line mat connects the rwo inner canthi, the palpebral fissure is considered upward slant-
ing. An upward slant can be related to ethnic origin, or it may be simply a familial characteristic. However,
upslanting palpebral fissures are seen in many genetic disorders, particularly chromosome aneuploidies like
Down syndrome. When the outer canthus of the eye lies below me imaginary line, me palpebral fissure is
considered downward slanting. Downslanting palpebral fissures are common in Noonan syndrome, which also
affects the heart and can result in bleeding disorders. Therefore, when a child has downslan ring palpebral fis-
sures, doing a careful cardiac assessment and looking for other signs of dysmorphology is important (Fig. 9-11).
The epicanthus is a vertical fold of tissue that lies between me eye and the nose. It extends upward and
merges with the upper eyelid. Sometimes the fold is so deep that the inner canthus cannot be seen on inspec-
tion. As noted earlier, epicanthic folds can be a normal variation in people of Asian descent. They can also be
present in a young infant with a low nasal bridge, but this feature is typically gone by 2 years of age. Epicanthic
folds are seen in several genetic disorders, including Down syndrome, Stickler syndrome, Williams syndrome,
FASD, and connective tissue disorders such as Ehlers-Danlos syndrome. Figure 9-12 shows an eye with a
very prominent epicanthic fold, as might be seen in a child with Down syndrome.

Dysmorphic Features of the Ears

Low-set ears are a relatively common but highly nonspecific finding when assessing for dysmorphology. Many
genetic disorders include low-set ears as a feature. Using physical measuremen t to determine whether ears
are low-set is essential because simply looking at a face can lead to a wrong conclusion. Ears are considered
low-set when the root of the helix of me ear lies below an imaginary line drawn through me inner canthus
of the eye and back to the ear. Figure 9-13 shows where this line is drawn, although the ears depicted in the
figure are normally positioned.

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 Chapter 9 Congenital Anomalies. Basic Dvsrnorpholoqy and Genetic Assessment 183

Upslanting Normal Downslanting

Figure 9-11 Palpebral fissures. Left = upslanting; middle = normal; right = downslanting.

Figure 9-12 Prominent epicanthic fold. Figure 9-13 Measuring to determine if ears are low set.

Many dysmorphic variations are possible in the appearance or position of the ears. Ears can be rotated
forward or backward or have auricular pits, which are shallow indentations usually seen JUStin front of where
the helix inserts into the ear. Auricular pits can be seen in people who have Beckwith-Wiedemann syndrome
and in some people who have Treacher Collins syndrome. Variations in earlobe structure are also possible.
Some people with Ehlers-Danlos syndrome do not appear to have any earlobes at all, whereas earlobes can
be very prominent in people who have Kabuki syndrome. Of course, a wide range of normal variations in
earlobe configuration also exists.

Dysmorphic Features of the Mouth

Cleft lip (CL), with or without deft palate, is a relatively common anomaly that is associated with more than
400 different syndromes. (CL is the acronym mat designates deft lip without deft palate, and CLP is used
to indicate deft lip with deft palare.) These include Van der Woude syndrome, Stickler syndrome, and Patau
syndrome (trisomy 13). The process of forming the structure of the mouth during embryonic development

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184 Unit II Gene Expression

is very complex, with many opportunities for things to go wrong. For example, when the embryo is about
5 to 6 weeks old, the tissue that will become the upper lip is supposed to meet and fuse. At about 7 weeks,
the tissue that will become the palate should also meet and fuse. If growth is inhibited and the tissues of the
upper lip and/or palate do not meet, a gap (or cleft) results. In addition to genetic causes, CLlCLP can be
caused by many environmental factors related to the lifestyle of the pregnant woman. These include having
a diet that is low in vitamin B and folic acid, consuming alcohol, taking certain drugs (especially phenytoin
[Dilanrinj), and smoking cigarettes.
Lip pits are symmetrical depressions in the lip, usually in the part of the lower lip called the vermilion (the
area that is somewhat redder than the skin surrounding it). Lip pits are commonly associated with Van der
Woude syndrome (VWS); VWS is a common single-gene disorder associated with CL, CPoor CLP. VWS is an
autosomal-dominant trait with about 80% to 90% penetrttnce. Remember that 80% to 90% penetrance means
that out of 100 people who have the gene variant that causes the disease, between 10 and 20 of them will show
no clinical signs. About 70% of people who have VWS with lip pits also have CL or CP. Some family members
with the same gene variant can have only lip pits, whereas others have CUCr, and still others have JUStCP.
This is an example of the genetic phenomenon called variable expressiuity (Ziai, Benson, & Djalilian, 2005).

Dysmorphic Features of the Hands and Feet

Many variations in the development and formation of the hands and fingers are possible. The Greek word for
digits, meaning "fingers and toes," is dactylos, and you see this roor word used in most names of finger and toe
anomalies. Polydactyly refers to having an extra finger or toe. If the extra digit is on the thumb (radial side)
or big toe side, it is preaxial, and if it is near the fifth finger (ulnar side) or fifth toe, it is postaxial. Postaxial
polydactyly can rW1in families and can be transmitted in isolation as an autosomal-dominant trait; however, it
can also be a sign of a genetic disorder such as Ellis-van Creveld syndrome (see Fig. 6-6). Preaxial polydactyly
is uncommon but can also be transmitted as an autosomal-dominant trait in some families or can be part of
a genetic condition, such as Nager syndrome.
Long, slender fingers (also called ftrnchnodnctyLy) is a characteristic often seen in people who have Marfan
syndrome, but remember that long, slender fingers could just be a normal familial trait. It does make it much
easier to play the piano! When fingers or toes are short and are not in proportion ro the rest of the body, the
condition is called brachydactyly. Although brachydactyly may occur as part of a syndrome, another type
occurs in isolation, with no other anomalies present, and is transmitted in an autosomal-dominant manner.
We discussed clinodactyly earlier. It refers to the curving of one or more digits.
When fingers (or toes) are partially or completely fused together, the condition is called syndactyly (see
Fig. 9-8). It can affect only the skin and soft tissues (simple), or it can involve the bone as well (complex).
Syndactyly occurs when the fingers or toes do not separate into individual digits during embryonic development.
It is seen in at least 28 differenr syndromes, such as Smirh-Lernli-Opirz, Aperr, and Holt -Oram syndromes.
It can also be inherited as an autosomal-dominant trait with no other abnormalities or health problems.

Dysmorphology of the Joints

joints are considered hypermobile or hyperexrensible when they have a greater range of motion than what is
commonly seen at a given age. About 5% of the population is hyperexrensible. Women are twice as likely as
men to be hyperexrensible. However, hyperextensibiliry is also associated with disorders like Ehlers-Danlos
syndrome and is an important assessment finding. Ehiers-Danios syndrome refers to a group of connective
tissue disorders that can include fragile blood vessels;abnormal scar formation; hypermobiliry, and soft, velvety,
very elastic skin (see Fig. 10-3).
The extent of hypermobiliry can be quantified by using the Beighron and Wolf scale. On this scale, a person
would get 1 point if she or he can bend forward with the knees Straight and rest the palms of the hands on

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 Chapter 9 Congenital Anomalies. Basic Dvsrnorpholoqy and Genetic Assessment 185

the floor. Other scale components evaluate hyperextension of the elbows, knees, thumbs, and fingers. A score
of 5 out of the 9 items indicates that a person is hypermobile (Hall, Allenson, Gripp, & Slavotinek, 2007).

SUMMARY
Dysmorphology assessment is a key tool for syndrome/disorder identification by genetics professionals. Although
thoroughly and accurately assessing for dysmorphic features takes lots of practice and bedside experience,
nurses can use their assessment skills to screen and refer people who may have a genetic condition. This
chapter provides a brief overview of important concepts in dysmorphology and some of the more frequently
recognized dysmorphic features. The health-care professional nor speciaLizingin genetics must be objective and
accurate in describing anatomic variations and referring concerns to those professionals with the education
and experience to complete a comprehensive assessment and make an accurate diagnosis.

GENE GEMS

Dysmorphology focuses on the identification of abnormal features and their connection to genetic
conditions.
• Congenital anomalies can be classified as major anomalies, which usually require intervention, and
minor anomalies, which usually do not require intervention.
• Having one minor anomaly does not mean a person has a genetic problem.
• The four causes of congenital anomalies are as follows:
• Malformations, which are caused by an abnormal developmental process
• Deformations, which are caused by compression from mechanical forces
• Disruptions, which are caused by a disturbance in the normal developmental process
• Dysplasia, which is an alteration in the size and shape and organization of cells
• A syndrome is a collection of symptoms that all come from the same cause, whereas a sequence is a chain
of symptoms in which each one causes the next.
• Pierre-Robin is an example of a sequence that begins with micrognathia and ofren results in cleft palate
and airway obstruction.
• In addition to individual features, the clinician's overall impression of the patient's appearance (gestalt)
is important.
• Viewing the individual within the COntext of the family is important because some dysmorphic traits
could JUStbe benign family characteristics or could give further sUPpOrt for a possible genetic condition
that has gone unrecognized in the family.
• More than 300 genetic disorders can cause cognitive impairment,
• Standard ways of measuring features have allowed clinicians to compare suspected dysmorphology
against age-related norms.
• Some features, such as low-set ears, are seen in many different genetic disorders as well as in people
who do not have a genetic disorder. They are considered nonspecific.

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186 Unit II Gene Expression

Self-Assessment uestions ....

1. What term is used to describe the condition of a child who has several dysmorphic features that are
related to a single known genetic cause?
a. Sequence
h. Disruption
c. Syndrome
d. Malformation
2. Which characteristic or feature distinguishes a major anomaly from a minor anomaly?
a. Major anomalies affect tissue structure, and minor anomalies affect tissue function.
h. Minor anomalies affect tissue Structure, and major anomalies affect tissue function.
c. Minor anomalies occur in external tissues, and major anomalies occur in internal tissues.
d. Major anomalies require medical attention, whereas minor anomalies are considered a variation
in structure.
3. Which term is used to describe an anomaly caused by a physical or mechanical force that prevents
the proper growth of a Structure that would have developed normally if the force was nor present?
a. Dysplasia
h. Disruption
c. Deformation
d. Malformation
4. Which types of problems are more likely to be caused by a chromosomal abnormality?
a. Single structural anomalies
h. Deformations
c. Syndromes
d. Dysplasias
5. How is a sequence different from a syndrome?
a. A sequence is usually caused by a single gene mutation, and a syndrome is always caused by a
chromosomal abnormality.
h. A syndrome is usually caused by a single gene mutation, and a sequence is always caused by
a chromosomal abnormality.
c. In a syndrome, one structural problem leads to the development of other problems, whereas a
sequence is a collection of separate but consistent anomalies.
d. In a sequence, one structural problem leads to the development of other problems, whereas
a syndrome is a collection of separate but consisrenr anomalies.
6. Which statement regarding the phenotype of fetal alcohol spectrum disorder (FASD) is correct?
a. Generic and environrnental factors influence the FASD phenotype.
h. The malformarions in the phenotype of FASD represem a sequence.
c. The genotype of FASD accurately predicts the phenotype of FASD.
d. The phenotype of FASD accurately predicts the genotype of FASD.

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 Chapter 9 Congenital Anomalies. Basic Dysmorphology. and Genetic Assessment 187

CASE STUDY

Isaac is an 8-year-old boy who has been diagnosed with Treacher Collins syndrome (TCS). which can be
transmitted as either an autosomal-dominant or autosomal-recessive condition depending on the gene
involved. Isaac has micrognathia (small chin and jaw). and his cheekbones and other facial bones appear
underdeveloped. His eyes slant downward. and he has very small ears. His parents are most concerned
about his dentition. His teeth are very crooked. Issac is bright and is doing well in school. He has one
brother who shares similar facial features but has problems with snoring and significant hearing loss. The
boys have two sisters who do not appear to have any facial dysmorphology. The boys' mother has slightly
downslanted eyes and no other noticeable anomalies.
1. Provide an explanation for the differing phenotype among the family members described in this
study.
2. Are the sisters affected or unaffected? How would you know? Is their sex a factor in whether they
would be affected?
3. If TCS is being transmitted in an autosomal-dominant fashion in this family, what is the risk that
another sibling would be affected?
4. Explain whyTCS is considered a syndrome and not a sequence.

References
Allanson, J. E., Biesecker, L. G., Carey, J. c., & Hennekam, R. C. (2009). E1emenrs of morphology: Introduction. American
journal of Medical Genesic:Part A, 149A( 1).2-5.
Allanson, J. E., Cunniff, c., Hoyme, H. E., McGaughran, J .• Muenke, M., & Neri, G. (2009). Elements of morphology: Stan-
dard terminology for the head and face. American fournal of Medica! Gmerics Part A, 149A(I), 6-28.
Ashwal, S., Michelson, D., Plawner, L.. & Dobyns, W. B. (2010). Practice parameter: Evaluation of the child with microcephaly
(an evidence-based review): Report of the Quality Standards Subcommirree of the American Academy of Neurology and the
Practice Committee of the Child Neurology Society Reply. Neurology, 74(13), 1079.
Biesecker,L G., Aase, J. M., Clericuzio, C, Gurrieri, F., Temple, I. K., & Toriello, H. (2009). Elements of morphology Standard
terminology for the hands and feet. American journal of Medical Gmetics Part A, 149A(I), 93-127.
Carey, J. C, Cohen, Jr., M. M., Curry, C. J., Devriendr, K.. Holmes. L. B.• & Verloes, A. (2009). Elements of morphology:
Standard terminology for the lips, mouth, and oral region. American [ournal of Medical GeneticsPart A, 149A(I), 77-92.
Centers for Disease Control and Prevention. (2010, October 21). Feral alcohol spectrwll disorder. Retrieved from hrrp:1I
www.cdc.gov/ncbddd/fasd/index.htrlli
Centers for Disease Control and Prevention. (2016). CDC concludes Zika causes microcephaly and other birth defects. Retrieved
from Imp:llwww.cdc.gov/medialreleasesl2016Is0413-zika-microcephaly.html
Chelly, J., Khelfaoui, M .• Francis. F., Cherif, B., & Bienvenu. T. (2006). Genetics and pathophysiology of mental retardation.
European journal of Human Genetics, 14(6),701-713.
Hall, B. D., Graham, Jr., J. M., Cassidy, S. B., & Opitz, J. M. (2009). Elernents of morphology: Standard terminology for the
periorbital region. American journal of Medica! Genetics Pari A, 149A(I), 29-39.
Hall. J. G .• Allanson, J. E.• Gripp, K. W.• & Slavorinek, A. M. (2007). Handbook of piJ)"icai measurements. New York. NY:
Oxford University Press.
Hunter, A., Frias, J. L., Gillessen-Kaesbach, G., Hughes, H., Jones, K. L, & Wilson. L. (2009). Elements of morphology:
Standard terminology for the ear. American journal of Medicnl Gmetics Pari A, 149A(l}. 40-60.
Jones. K. (2006). Smith's recognizable patterns ofiJllmall malformation. Philadelphia. PA: Elsevier,

ERRNVPHGLFRVRUJ
188 Unit II Gene Expression

Korerzky, M., Bonham, V. L, Berkman, B. E., Kruszka, P., Adeyemo, A, Muenke, M., & Hull, S. C (2016). Towards a more
representative morphology: Clinical and ethical considerations for including diverse populations in diagnostic genetic atlases.
Genetics in Medicine, 18(11), 1069-1074. doi:10.10038/gim.2016.7
National Institute of Neurological Disorders and Stroke. (2010, May 12). Charcot-Marie-Tooth diseasefoct sheet. Retrieved from
hnp:llwww.ninds.nih.gov/disorderslcharcot_marie_tooth/detail_charcot_marie_toorh.hm1# 156213092
Read, A. & Donnai, D. (2015). New Clinical Genetics 3. Third edition. Banbury, UK: Scion Publishing.
Reardon, W. (2008). Till' bedside dysmorpJlologij!. New York, NY: Oxford University Press.
Tartaglia, M., Zampino, G., & Gelb, B. D. (2010). Noonan syndrome: Clinical aspects and molecular pathogenesis. Molecular
Syndromology, 1(1). 2-26.
Winter. R. M.• & Barairser, M. (2005). London dysmorphology Mraba.Jl'. London. England: Oxford University Press. 2005.
Ziai. M. N .. Benson. A. G., & Djalilian, H. R. (2005). Congenital lip pits and van der Woude syndrome. J CraniofociAI Surgery.
16(5). 930-932.

Self-Assessment Answers
1. c 2. d 3. c 4. c 5. d 6. a

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Genomic Health Problems
Across the Life Span

189

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 Enzyme and Collagen Disorders
Learning Outcomes
1. Discuss the role of enzymes in normal physiologic function.
2. Describe the genetic defect, pattern of inheritance, pathophysiology, and consequences of phenylketonuria.
3. Describe the genetic defects and patterns of inheritance for type 1 Gaucher disease, Hurler syndrome,
Hunter syndrome, and Fabry disease.
4. Explain the pathophysiology, signs and symptoms, and consequences of type 1 Gaucher disease, Hurler
syndrome, Hunter syndrome, and Fabry disease.
5. Explain the basis of enzyme-replacement therapy for specific lysosomal storage diseases.
6. Discuss the role of collagen in normal physiologic function.
7. Describe the genetic defects and patrerns of inheritance for osteogenesis imperfecta, Ehlers-Danlos syn-
drome, and Marfan syndrome.
8. Explain the pathophysiology, signs and symproms, and consequences of osteogenesis imperfecta, Ehlers-
Dan los syndrome, and Marfan syndrome.

Key Terms
Collagen Fibrillin Lysosomes
Ehlers-Danlos syndrome Gaucher disease Marfan syndrome (M FS)
Enzyme Hunter syndrome Osteogenesis imperfecta (01)
Enzyme-replacement therapy Hurler syndrome Phenylketonuria (PKU)
(ERT) Hyperaminoacidemia Pleiotropy
Executive functions Lysosomal storage disease Tay-Sachs disease
Fabry disease

190

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 Chapter 10 Enzyme and Collagen Disorders 191

INTRODUCTION
An enzyme is a protein that acts as a biological catalyst causing one or more biochemical reactions to occur
or increasing the rate of a biochemical reaction within a cell, body tissue, or organ (Fig. 10-1). Although the
function of all enzymes is important, some enzymes have critical roles in maintaining health. The many dif-
ferent types of collagen function to provide structural suppOrt to all organs and many body tissues.
Human body function is a dynamic and interactive process in which many enzymes and collagens are
produced, maintained, and often recycled daily. This huge "housekeeping" task requires the cooperation of
many tissues and organs working in concert and responding appropriately to changes in body conditions to
keep all body functions in balance. This balance can be disrupted by genetic mutations that interfere with
specific protein production, resulting in a change in the amount and/or activity of an enzyme or collagen.
Thus, inherited enzyme and collagen disorders have a negative impact on overall physiologic function.
Although the gene coding for any enzyme could have a mutation or variation that affects the function of its
product as a random occurrence, specific disease-causing mutations have been identified, and genetic testing is
available for prenatal diagnosis. In addition, disease management strategies can reduce the negative outcomes
for some of these genetic enzyme disorders. Genetic collagen disorders tend to have more pleiotropic effects
because collagen is a substance that is parr of almost all body tissues. A pleiotropic effect, or pleiotropy, is
one in which a single-gene disorder results in problems expressed in many tissues and functions.
Neither inherited enzyme disorders nor inherited collagen disorders are common. This chapter focuses on
those disorders that are more common or that can be managed to slow the rate of disease progression and
complications or to exemplify a specific disorder type.

ENZYME DISORDERS
Enzymes are common proteins used in many biochemical processes that change the composition of various
body substances and proteins. These reactions often combine substances and form a larger compound, break
compounds down into their individual componenrs, add or remove side chains to activate or deactivate a

Normal enzyme action Figure 10-1 Normal and deficient enzyme

actions on metabolism of precursor sub-
strates and final breakdown products.

Precursor substances Final products

Deficient enzyme action

c
Excessive buildup of Absent or low
precursor substances amounts of
final products

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192 Unit III Genomic Health Problems kross the Lite Span

compound, and prepare compounds for srorage or elimination. All enzymes are gene products. A mutation
in a gene coding for a specific enzyme usually reduces the enzyme's activity and results in a physiologic
problem. The results of an ineffective enzyme, or one that is deficient, is that the expected action does not
occur or occurs to only such a small degree that the final product is not present in sufficient quantities. On
the other hand, the substance the enzyme should act on can build up to excessive levels, which can be toxic.
Figure 10-1 shows the Outcomes of normal and deficient enzyme function on precursor substrates and final
breakdown products.
Most genetic enzyme disorders are inherited as autosomal-recessive conditions, and many have serious
adverse effects on a specific metabolic pathway or process. Some are hyperaminoacidemias in which one
particular amino acid accumulates in the blood to toxic levels. Usually, excess amino acids are also present
in the urine, which can be used to diagnose the disease. Table 10-1 lists some hyperaminoacidemias. Other
genetic enzyme disorders are lysosomal storage diseases in which an enzyme within lysosomes is defective
or deficient, causing the buildup of a precursor substance that becomes toxic to the cell. (Lysosomes are
intracellular vesicles that contain many enzymes to degrade the protein and lipid by-products of metabolism.)
Table 10-2 lists examples of the lysosomal storage diseases.
Usually in a genetic enzyme disorder, neither parent
What Is the Reason forThis? has an obvious problem, and the newborn does not have
The reason that symptoms are commonly not epoe« symptOms at birth.
ent in the newborn is that the maternal enzymes Interestingly, sometimes the tissues and organs that
cross the placenta and perform their specific func- are most affected are not those in which the enzyme is
tions in the cells of the fetus. When the child is born, usually synthesized. As with other recessive disorders, the
its access to effective maternal enzymes stops, and incidence of the problem is often higher in specific popu-
the enzyme deficiency begins to affect the child's lations that have been either geographically or socially
metabolism and eventually. appearance.
isolated, although the disorder can occur in anyone.

Phenylketonuria
Phenylketonuria (PKU) is a disorder in which a genetic mutation in the PAH gene causes the function of
the enzyme phenylalanine hydroxylase (PAH) ro be reduced, and the amino acid phenylalanine cannot be
enzymatically converted to the amino acid tyrosine. This results in an excess of phenylalanine and a deficiency
of tyrosine. PKU is an example of a problem that leads to hyperaminoacidemia.
As discussed in Chapter 2, a protein is synthesized by connecting individual amino acids in the order coded
for by the protein's gene. This process requires that the person has sufficient amounts of each of the individual
amino acids. Some amino acids are classified as essential amino acids, meaning that they must be included in

TABLE 10-.1~1
Examples of Hyperaminoacidemias
Disease Specific Amino Acid Involved Genets)
Alkaptonuria Phenylalanine, tyrosine HGO
Cystinuria Cystine SLC3AI, SLC7A9
Homocystinuria Homocysteine CBS, MTHFR, MTR, MTRR
Maple syrup urine disease Leucine, isoleucine, valine BCKOHA BCKOHB, OBT, OLD
Phenylketonuria Phenylalanine PAH

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 Chapter 10 Enzyme and Collagen Disorders 193

.'!~:JIII=- I~..ot

lysosomal Storage Diseases

Disease (% of Category) Deficient Enzyme Accumulated Product

Gaucher (14%) 13-Glucosidase (glucocerebroside) Glucosylceramide

Hurler (9%) a-l.=Iduronidase Mucopolysaccharides
(glycosaminoglycans)
Metachromatic leukodystrophy (8%) Arylsulfatase A Sulfatide sphingolipids
Sanfilippo A (7%) Sulfamidase Mucopolysaccharides
(glycosaminoglycans)
Fabry (7%) a-Glucosidase A (ceramide Globotriaosylceramide
trihexosidase) (GL-3)
Hunter (6%) Iduronate sulfatase Mucopolysaccharides
(glycosaminoglycans)
Krabbe (5%) Galactosylceramidase Galactolipids
Pompe (5%) Acid a-glucosidase Glycogen
Tay-Sachs (4%) 13-Hexosaminidase A Ganglioside GM2

the diet because the human body cannot generate them from other substances. Tyrosine is critical for protein
synthesis but is not an essential amino acid because it can normally be generated from phenylalanine even
when it is not ingested in the diet.
The PAH gene is located on chromosome 12q24.1. More than 400 different types of disease-causing mu ra-
tions have been identified in this gene, accounting for some differences in disease severity. Most of the muta-
tions do not interfere with the production of the enzyme, but the enzyme that is produced folds incorrectly
and is much less active. The incidence of PKU in the United States is about I in 10,000 live births (Online
Mendelian Inheritance in Man [OMIM], 2015b). It is more common among people whose ancestors came
from Northern Europe, particularly Ireland and Scotland, and is rare in those whose ancestors came from
Africa. Both genders are affected equally.

Pathophysiology
People who have phenylketonuria have a genetic mutation of the enzyme phenylalanine hydroxylase (PAH)
that reduces its activity. Some have greatly reduced PAH activity, and others have as much as 25% activity.
Greater PAH activity correlates with milder forms of the disorder (OMIM, 20 15b). With any significant PAH
deficiency, immediately after birth, the infant starts to build up excessive amounts of phenylalanine in the
blood and other body fluids. Some of this excess phenylalanine is metabolized by other el12ymes and pathways
into phenylpyruvare, a keto acid that lowers the pH of the blood Both phenylalanine and phenyl pyruvate are
found in the urine of patients with the disease.
The excessphenylalanine causes major problems in the developing nervous system, although the exact mecha-
nism or mechanisms of brain damage are not completely identified Problems also occur in skin pigmentation.

Signs and Symptoms

Tyrosine is an important amino acid in the production of thyroid hormones; melanin; and neurotransmitters,
such as dopamine and the catecholamines (epinephrine and norepinephrine). When the level of phenylalanine

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194 Unit III Genomic Health Problemskross the Life Span

is not managed, brain dysfunction results in severe cognitive deficiencies and diminished motor skills. Growth
is retarded, and the skin, eyes, and hair color are Lighterthan those of parents or unaffected siblings. Additional
symptoms usually include the following:
• Small head size
• Uncoordinated motor movement
• Seizure activity
• Tremors
• A musty or mousy odor, especially of the sweat, breath, and urine
PKU is now a part of newborn blood screening in every state. The disorder can be detected as early as
48 hours after birth.

Management Strategies
Once the disorder has been identified in an infant, most of the developmental issues can be avoided or become
less severe with strict dietary management of phenylalanine levels. Some phenylalanine must remain in the diet
because it is an essential amino acid; however, toO much phenylalanine leads to problems. Dietary restrictions
to slow or prevent neurologic issues have been successful to varying degrees for more than 60 years. The spe-
cific management involves first feeding the infant a "medical food" that is a low-phenylalanine infant formula.
Throughout childhood and adolescence, dietary control requires that phenylalanine is severely restricted
and tyrosine is increased. Usually, much of the diet is maintained with medical food that comes in a variety
of flavors and forms. However, this food is expensive and inconvenient (Singh er aI., 2014). The amount of
phenylalanine consumed must be carefully controlled and is usually less than 300 to 500 mg daily, although
adjustments are needed for body size and during growth periods. After brain development is complete, some
believe that less restriction of phenylalanine is needed, but this is controversial. Most experts agree that the
restriction should be lifelong. Even with good control over phenylalanine levels, many patients with low PAH
activity display somewhat lower cognitive abilities than siblings, hyperactive behavior, and below-normal
executive functions (DeRoche & Welsh, 2008). Executive functions are those behavioral functions associated
with prefrontal lobe brain activity and include solving problems, controlling impulses, planning, and making
goal-directed actions. Even when dietary managemenr is not started until a child is older or even an adolescent,
good phenylalanine control at that time results in some cognitive improvement (Singh et al., 2014).
People with PKU are monitored with blood levels of phenylalanine and tyrosine and with the phenylalanine-
to-tyrosine ratio. The goal is to keep the phenylalanine blood levels between 120 and 360 micromols/L.
Interestingly, some people tolerate higher amounts of phenylalanine in the diet and remain within this goal
level, although predicting this variation is not yet possible (Singh et al., 2014).
One drug approved for use in patients with PKU is saproprerin hydrochloride (Kuvan) (Singh et al., 2014).
This drug is not a replacement enzyme but is a synthetic form of a cofactor needed for PAH activity. The
mutated form of PAH possibly requires much more of the cofactor to be effective in converting phenylalanine
to tyrosine. Whatever the exact mechanism, for some people, this oral drug enhances PAH activity, increas-
ing the person's tolerance to dietary phenylalanine without exceeding blood level goals. Because the drug
has variable effectiveness, experts recommend that all people with PKU be started on the drug to determine
whether it is an appropriate therapy for them (Singh et al., 2014). When effective, the drug allows more use
of common foods in the diet along with prescribed medical foods.
With increasing life spans and cognition among people with PKU, the problem of an increased incidence
of a variety of health problems and birth defects among infants born to women with PKU emerges (National
Institutes of Health [NIH], 2017c). The infants do not have PKU; however, abnormal blood levels of amino
acids, especially during embryonic life, result in a wide variety of birch defects, most commonly of the

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 Chapter 10 Enzyme and Collagen Disorders 195

cardiovascular system. The best pregnancy outcomes for women with PKU are achieved when phenylalanine
levels are well controlled before and during pregnancy.

Gaucher Disease
Gaucher disease is a genetic lysosomal storage disease in which there is a deficiency of the GSA gene product,
the enzyme ~-glucocerebrosidase. It normally breaks down the metabolic glycolipid glucosylceramide (also
called glucocerebroside) into sugar and fat that can be recycled for other metabolic uses. Deficiency of this
enzyme results in the accumulation of glucosylceramide in macrophages and some other white blood cells
(National Gaucher Foundation, 2016). The GSA gene is located on chromosome Iq21, and the disease is
transmitted in an autosomal-recessive pattern (OMIM, 2016a). Gaucher disease is the most common of
the lysosomal stOrage diseases and occurs most often among the Ashkenazi Jewish population (incidence of
approximately I in 500-1,000 births) compared with non-Jewish populations (incidence of approximately I in
50,000-100,000 births). It is also more common among French Canadians in the Quebec area. About 20,000
individuals are living with Gaucher disease in the United States (NIH, 2017b).

Pathophysiology
Macrophages, which are mononuclear white blood cells, are present within most tissues and organs; however,
the three distinct forms of Gaucher disease affect organs differently. The most common form of the disease is
Gaucher type I, which is also known as nonneuronopathic Gaucher disease because central nervous system cells are
not affected. Cells and tissues that are affected include macrophages in the liver, spleen, bone marrow, and lungs.
Huge amOUJ1[Sof glucosylceramide collect in the macro phages of these tissues, resulting in organ enlargemen t.
Gaucher type 2 is also known as acute neuronopathic-injantile disease because neurons are severely affected, and
death usually occurs within the first 2 years oflife. Gaucher type 3, also known as chronic neuronopnthic disease,
is less common than type I and not as severe as type 2. This discussion of Gaucher disease focuses on type 1.
Although the glucosylceramide accumulates in tissue macrophages rather than in actual organ cells, the
excessively large macrophages exert pressure on nearby organ cells. In addition, as organs enlarge from the
continually increasing size of macrophages, perfusion and oxygenation to the organs decrease. Both the increased
pressure and poor organ perfusion greatly reduce organ function and shorten life.

Signs and Symptoms

The main signs and symptoms of Gaucher type 1 are related to the specific organs in which the macrophages
enlarge. These include the liver and spleen, which can increase to many times their normal sizes, resulting in
a large protruding abdomen and abdominal pain. The bone marrow is infiltrated with enlarged macrophages,
preventing the adequate production of red blood cells and platelets (thrombocytopenia). As a result, the person
bruises easily with minimal trauma and is anemic (causing fatigue). Bone marrow infilrrarion also causes bone
pain and osteoporosis. This condition can lead to pathologic bone fractures. Overall growth can be reduced
as well, possibly because of liver compression and poor production of various sornarornedins and other factors
that influence growth. Although more people are affected in childhood, some people do not show signs and
symptoms of the disease until adulthood.

Management Strategies
Some management strategies focus on the problems caused by the disease. For example, at one time, the
management of anemia and thrombocytopenia was based on iron and vitamin supplements coupled with
transfusions of blood and platelets. Growth facror therapy with epoetin alfa (Epogen, Procrir) can increase the
production of red blood cells. Therapy with oprelvekin (Neumega) can increase the production of platelets

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(Workman and Ls'Chariry, 2016). The effectiveness of these drugs on bone marrow decreases as active marrow
cells are replaced wi th glucosylceramide-filled macro phages.
An enlarged spleen can rupture and lead co death. A partial or total splenectomy can prevent this problem,
but it also reduces the antibody-generating responses of the person when infection, especially viral infection,
occurs.
Bone involvement can be managed with analgesics to help bone pain, calcium supplementation or drug
therapy with bisphosphonares to prevent bone density loss, and trauma precautions to prevent fractures.
Additional management involves removing cells from the marrow (core compression). Damaged joints can
be replaced with partial or tOtal joint prostheses.
Another management strategy is the replacement of the missing or malfunctioning enzyme with one that
has been generated artificially, a process known as enzyme-replacement therapy (ERT). Gaucher type 1 is a
disorder that responds well to this type of therapy. Three drugs are approved for treatment. These drugs are
imiglucerase (Cerezyme), taliglucerase (ELELYSO), and velaglucerase (VPRN), which are infused intravenously
every 2 weeks once a blood level has been achieved. Some patients have a dramatic reduction in liver size,
spleen size, and bone pain within a few weeks of beginning the therapy, although each patient's response is
variable. This therapy is very expensive and representS only a disease-management therapy, not a cure.
Another drug therapy approach to Gaucher type I management is known as substrate restrictive therapy
(SRT) (National Gaucher Foundation, 2016). Rather
So How Does a Stem Cell Transplant Help than replace the enzyme, this type of therapy reduces
Gaucher Disease When the Problem Is Not the amount of glucosylceramide (glucosylcerebroside)
in the Bone Marrow or Other Hematopoietic presem in macrophages. Drugs in this class are eliglustat
Tissue? (Cerdelga) and miglustat (Zavesca). These oral drugs are
This process is successful because the healthy taken daily to inhibit the enzyme that makes glucosylce-
stem cells transplanted into the patient take up ramide, resulting in less accumulation in macrophages.
residencein the patient'sbone marrow.Thesenew Currently, the drugs are approved only for use in adults.
cells produce a healthy version of the deficient
Currently, the only cure for Gaucher type 1 is a
enzyme, which then can be taken up and used
hematopoietic stem cell transplantation (HSCT) from
by many cells.
a donor who does not have the disease.
Not only is this procedure very expensive and often nor covered by insurance, but it is also dangerous
because the patient is completely immune deficient for weeks and is at great risk for overwhelming infection.
The main use of HSCT is in the treatment of some types of cancers. The mortality rate from complications
of the procedure is high. The cost of the treatment and rhe uncertainty of the outcome limit its utility as a
managemen t strategy for Gaucher or any other lysosomal storage disease.

Hurler Syndrome
Hurler syndrome, also known as mucopolysacchandosisI (MPS I), is a genetic lysosomal storage disease caused by
a mutation in the a-L-iduronidase gene (IDUA), which results in the deficiency of the enzyme a-L-idurorudase.
This deficiency results in the accumulation of mucopolysaccharides (MPSs) in the lysosomes of most cells. The
IDUA gene mutation is transmitted in an autosomal-recessive pattern and is located on chromosome 4pI6.3.
The disorder occurs in about lout of 100,000 births and affectS males and females equally (OMIM, 2016b).
More than 100 different mutations have been identified and are responsible for variation in disease severity.

Pathophysiology
Mucopolysaccharides (MPSs) are also known as gLycosaminogLycans(GAGs). These substances are large molecules
of sugar and protein that make up a major pan of tissue basement membranes. Many different types of MPSs

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exist, with each type having a slightly different chemical composition and requiring a different enzyme for
degradation. These aceUular substances are "recycled" almost daily to maintain basement membranes. Recy-
cling involves enzymatically breaking down a formed MPS into its constituent parts within cellular lysosomes.
When the enzyme responsible for degrading a specific type of MPS is either deficient or nonfunctional, the
large MPSs accumulate within the lysosomes. With MPS I, the lysosomes of almost aU ceUs are affected over
time by the progressive accumulation of MPSs.

Signs and Symptoms

Infants with Hurler syndrome appear normal at birth, although a higher incidence of umbilical hernia in
these children has been reported. The physical appearance begins to change within the first 6 months of life.
Facial features become coarser, with a large head, prominent forehead, Rat face, short and wide nose, thick
lips, heavy eyebrows, and a short neck. Physical growth is poor, resulting in a short stature. Skin is thicker
and less Rexible. Enlargement of the liver and spleen causes abdominal distention. The brain and surrounding
structures are involved, often progressing to hydrocephaly. Development is delayed, and intellectual functioning
is limited. Over time, intellectual functioning deteriorates to a profound degree. As MPSs increase in cardiac
tissue, this organ's function also deteriorates.
As the disease progresses, the respiratory structures are affected, and airway obstruction is common. Poor
cough and excessive nasal secretions increase the incidence of respiratory infections. Without treatment, death
commonly occurs from pneumonia or cardiac dysfunction berween the ages of 5 and 10 years.

Management Strategies
At one time, only supportive or comfort care was available for children with Hurler syndrome. Drug therapy
was used to prevent or treat respiratory infections and to improve cardiac function. Currently, two additional
management strategies are available, ERT and HSCT. The drug for ERT is laronidase (Aldurazyme), which is
administered as weekly infusions. Although it prevents disease progression in many tissues and reverses liver
and spleen enlargement, it does not prevent central nervous system deterioration because the drug does not
cross the blood-brain barrier. Therefore, this expensive drug is used to reduce disease progression until HSCT
can be performed (Bijarnia et al., 2009). Although HSCT is the standard of care for children with Hurler
syndrome and should be performed before 2 years of age, it remains a costly option with serious risks (see the
discussion in the "Management Strategies" section of "Gaucher Disease").

Hunter Syndrome
Hunter syndrome is a genetic lysosomal storage disease in which a mutation in the iduronate sulfatase gene
(IDS) results in a deficiency of the enzyme iduronare sulfatase. The enzyme deficiency results in the accumu-
lation of MPSs within the lysosomes of many tissues and organs. This disorder is also known as mucopolysac-
charidosisII (MPS II). Unlike Hurler syndrome, Hunter syndrome is an X-linked recessive disorder with the
gene located on Xq28. The disorder occurs in about lout of 100,000 to lout of 170,000 births and affects
males almost exclusively. Females are carriers. More than 300 different mutations have been identified and
are responsible for variation in disease severity (OMIM, 2016c).

Pathophysiology
The pathophysiology of Hunter syndrome regarding poor degradation of MPSs is identical to that of Hurler
syndrome. Major differences are that people with Hunter syndrome have a slower onset of symptoms, and the
effect on intellectual ability is more variable. In mild forms, loss of inrellecrual ability is minimal. In more severe
forms, the loss of intellectual ability is more severe bur occurs at a much later age than in Hurler syndrome.

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Signs and Symptoms

The clinical picture of a person with Hunter syndrome looks very similar to that of the person with Hurler
syndrome. In fact, the phenotype is so similar that except for the slower onset and less frequent reduction
of intellectual ability found in people with Hunter syndrome, at one time the rwo were considered the same
disorder; however, the deficient enzyme is different. Additional symptoms of Hunter syndrome include gradual
hearing loss and vision problems. People with the more severe form of the disease usually live for 10 to
20 years. People with the milder form of the disease usually live 20 to 60 years.

Management Strategies
Currently, two management strategies are available: ERT and HSCT The drug for enzyme replacement is
idursulfase (Elaprase), which is administered as weekly infusions (Little. Gould, & Hendriksz, 2009). This
drug is very expensive. costing families an average of $300.000 annually. HSCT is a costly and dangerous
option (see the discussion in the "Management Strategies" section of "Gaucher Disease"). For patients who
have a mild form of Hunter syndrome. the benefits of this therapy may not be worth the associated risks.

Fabry Disease
Fabry disease is a genetic lysosomal storage disease in which a mutation in the n-galacrosidase A gene (CLA)
results in a deficiency of the enzyme n-galacrcsidase A (also known as ceramide trihexosidnse). Without suf-
ficient amounts of the enzyme, globorriao-sylceramide (GL-3) accumulates in the lysosomes of many tissues
and organs. It is an X-linked recessive disorder. and CLA is located on chromosome Xq22. The disorder affects
about 1 in 40.000 to 60.000 males (NIH. 2017a). AJthough it is much more common among males. female
carriers may have significant symptOms of the disorder from skewed X chromosome inactivation in differem
tissues (see Chapter 4) (Schaefer. Tylki-Szymariska, & Hilz, 2009).

Pathophysiology
The enzyme normally degrades GL-3. which is composed of three sugar molecuJes attached to a lipid molecule.
Degradation of GL-3 is a part of the recycling of old red blood cells and other types of cells. When the enzyme
is deficient. large amounts of GL-3 and one of its toxic metabolites. globotriao-sphingosine, build up within
the blood and within the lysosomes of many tissues and organs (Schaefer et al., 2009). This lysosomal storage
of GL-3 causes changes and damage within the blood vessels. As blood vessels become less efficient. chronic
inflammatory responses Start. leading to poor tissue perfusion. ischemia. and eventual tissue or organ failure.

Signs and Symptoms

Although the biochemical changes can be identified in early childhood. the onset of signs and symptoms of
Fabry disease usually begin later in childhood. At first. symptoms are related to poor perfusion and include
cold intolerance, insufficient sweating in hot environments. and pain episodes of unknown origin. In ado-
lescence. the symptoms worsen, with opacities developing in the eye. Episodic numbness and tingling in the
fingers and toes also occurs. Angiokeratomas (small capillary lesions) of the skin are common. Blood vessels
are affected everywhere. but the more vascular organs, such as the heart, kidney, and brain. as well as those
that are very oxygen dependent, such as peripheral nerves, develop more damage earlier. In general. males
begin to have symptoms about 3 to 5 years earlier than females. By adulthood, the person usually has some
degree of renal insufficiency or failure. Strokes and hearing problems (deafness and tinnitus) are common.
Cardiac problems develop, including angina, myocardial infarction, and heart failure. Without treatment,
death usualJy occurs prematurely.

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Management Strategies
After identification of the disorder, symptomatic and preventive strategies for kidney, brain, and cardiovas-
cular health are employed. These have limited effect because they do not address the cause of the problems
associated with the disease.
ERT is now the standard of care for a person with Fabry disease. The ERT drugs are agalsidase alfa (Repla-
gal) and agalsidase beta (Fabrazyme). Several randomized controlled clinical trials indicate that these drugs are
able to normalize GL-3 levels in many tissues (Schaefer er at, 2009). A new drug, migalastat (Galafold), that
works by binding to and stabilizing any a-galactosidase the patient has, prolongs the enzyme's activity. This
drug is currently in phase III clinical trials.

Tay-Sachs Disease
Tay-Sachs disease is a genetic lysosomal storage disease in which the HEXA gene responsible for producing the
enzyme ~-hexosaminidase A is mutated. The enzyme deficiency results in the accumulation of GM2-ganglioside
in brain cells. The HEXA gene is located on chromosome 15q23 to q24, and the disorder is transmitted in
an autosomal-recessive pattern (OMIM, 2013). Although nearly 100 mutations have been identified, three
specific mutations are responsible for nearly all cases of the classic type ofTay-Sachs disease. The incidence of
Tay-Sachs disease is highest among people of Ashkenazi Jewish ethnicicy worldwide, about 1 in 3,900 births.
The incidence among non-Jewish populations is much less frequent, about 1 in 320,000 births (OMIM, 2013).

Pathophysiology
The precursor product or target of the enzyme ~-hexosaminidase A is a glycoprotein fat (lipid) substance
known as a ganglioside (GM2). Without adequate levels of the enzyme, GM2 builds up in many cells but
particularly in brain cells. The buildup increases neuronal size, causing them to have a ballooned and distorted
appearance. Over time, brain cells accumulate large amounts of GM2, and their function is destroyed. When
enough brain cells have been destroyed, death occurs. The most common cause of death is pneumonia related
to respiratory muscle weakness and the inability of the child to swallow effectively (leading to aspiration).

Signs and Symptoms

At birth, an infant with Tay-Sachs has a completely normal appearance and reflexes. He or she has normal
muscle tone and intellectual potential. During the first few months of life, the infant progresses normally,
usually learning to control the head, recognize parental faces, socially smile, and roll over. At this point, normal
development slows or stops. Over the next few months, physical development and cognitive development
regress. One hallmark of the disease is seen when the retina is examined with an ophthalmoscope. The retinal
cells have become filled with GM2 and are pale. This makes the fovea central is stand out as a cherry-red SpOt
against the pale retinal background.
Over time, the child's muscles become weaker, and most reflexes diminish. One reflex continues-the startle
response to sounds. All physical movement decreases, and paralysis eventually occurs. Other signs and symptoms
include blindness and seizure activity. Most children with Tay-Sachs disease die between 2 and 4 years of age.
Although the disorder is diagnosed based on history and manifestations, blood testing can confirm the
diagnosis by assaying blood enzyme levels. DNA analysis can determine which mutation is present. Carrier
status also can be identified from enzyme levels and gene sequence analysis.

Management Strategies
Currently, no therapy exists to cure Tay-Sachs disease or prevent its progressive brain degeneration. Manage-
ment strategies focus on delaying muscle weakness with passive exercise and preventing aspiration. Parents

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and siblings require much emotional support. Genetic counseling can be very beneficial in helping family
members assess risk and make decisions regarding reproduction.

Summary for Enzyme Disorders

Although the gene defect for enzyme disorders is present from conception, the manifestations of the disor-
ders usually are not present until sometime well after birth. Enzyme-replacement therapy is available to help
manage some, but not all, enzyme diseases. Hernaropoieric Stern cell transplantation can result in a cure for
many enzyme disorders, even though bone marrow cells are not usually the cells affected by the disorder.
The complications associated with this procedure and its COStmust be considered when assessing the benefits
versus the risks of pursuing this therapy.

COLLAGEN DISORDERS
Collagen is a group of glycoprotein fibers that forms the major component of the connective tissue
found in nearly all body tissues. It Starts Out as procollagen and is the most abundant protein in humans
and other mammals. Procollagen is processed or modified in various ways to form different types of mature
collagen fibers that work with other fibrous tissues to form cables that add strength and structure to most
tissues (McCance, Huether, Brashers, & Rote, 2014). In addition, collagen fibers are part of the extracellular
matrix between cells and tissues that functions to hold tissues together and promote communication between
and among cells.
The production of different types of procollagen and the modification steps are genetically controlled.
Gene mutations can affect the production and composition of any collagen type or interfere with its proper
modification, assembly, or association with other molecules. Any of these problems can result in the pheno-
typic expression of a collagen disorder.
The five main types of collagen within the human body are as follows (many minor types also exist):
• Type 1 collagen is the most COmmon and is a major component of bones, the dermal layer of skin,
tendons, ligaments, corneas, intervertebral disks, and the walls of arteries and other blood vessels. It is
coded for by the eOLlAl gene located on chromosome 17q21.33.
• Type 2 collagen is the major type of collagen found in cartilage and is coded for by the eOL2Al gene
located on chromosome 12q 13.11.
• Type 3 collagen is a major componem of connective tissue in the skin, lungs, intestinal walls, and the
walls of blood vessels. It is coded for by the eOL3Al gene located on chromosome 2q31.
• Type 4 collagen is a major component of connective tissue in the kidney and inner ear. Several subgroups
of type 4 collagen are coded for by the eOL4A genes 1 to 6, which are located on chromosomes 2 and
13 and the X chromosome.
• Type 5 collagen works with other collagen types to provide strength to connective tissues in the skin,
ligaments, bones, tendons, muscles, and the extracellular matrix. Ir is coded for mainly by the eOL5Al
gene located on chromosome 9q34.2-q34.3.
Genetic mutations in any of the collagen genes usually affece more than one type of tissue (pleiotropy) and
are involved in many genetic disorders (Table 10--3). The collagen disorders discussed in this chapter are the
osteogenesis irnperfecra and Ehlers-Oanlos syndromes. In addition, Marfan syndrome, which is a problem
of fibrillin production that normally interacts with collagen for connective tissue strength and flexibility, is
also discussed.

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 Chapter 10 Enzyme and Collagen Disorders 201

Examples of Genetic Collagen Disorders

Collagen Type Disorder/Health Problem
Type 1 collagen Arthrochalasia
Caffey disease
Ehlers-Danlos (classical)
Osteogenesis imperfect a
Osteoporosis
Type 2 collagen Achondrogenesis
Czech dysplasia
Hypochondrogenesis
Kniest dysplasia
Osteoarthritis (early onset. familial)
Stickler syndrome

_j
Type 3 collagen Ehlers-Danlos (vascular)
Type 4 collagen Alport syndrome
Type 5 collagen Ehlers-Danlos (classical)

Osteogenesis Imperfecta
Osteogenesis imperfecta (01) is a group of genetic disorders in which collagen formation is impaired, result-
ing in bones that fracture easily. Many different mutations, especially in the genes for type 1 collagen, result
in great variation in disease severity. With some mutations, bone fractures occur in the fetal period and are
lethal (osteogenesis imperfecra type II). Other mutations result in milder disease expression in which bones
are brittle and fracture more easily, but bone deformity does not occur.
Four major types of 01 occur because of mutations in a gene for type 1 collagen. All follow an autosomal-
dominant transmission pattern, although spontaneous mutations are responsible about 35% of the time
(Osteogenesis Irnperfecra Foundation, 2015). The most common type of the disease, osteogenesis imperfecra
type I, occurs in about lout of 15,000 to 30,000 births. It affects males and females equally. The most severe
form that occurs without lethality is type III. It is rare in the United States and occurs most commonly in
central and southern Africa.

Pathophysiology
The primary problem with 01 is a failure to produce at least one functional chain of procollagen that is needed
to associate with other molecules and form functional collagen in bone tissue. As a result, the developing bones
have less structural integrity and strength, increasing the risk for fractures. The severity of the phenotype is
related to both the degree of normal collagen reduction present in the bone and whether abnormal collagen
is produced.

Signs and Symptoms

The symptoms of osteogenesis imperfecta type 1 can easily be missed because the collagen produced is normal,
but the amount is reduced. Usually, the person has no increase in fractures during infancy. Fractures do occur

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in response ro relatively minor trauma throughout childhood, adolescence, and adulthood. In women, more
Fractures are seen afrer menopause. A common feature is the blue-ringed coloration of the sclera.
Osteogenesis imperfecra rype II is the most severe. Essentially, no normal collagen is produced. Bone
Fractures and skeletal malformacions, including skull deformities, occur in the prenatal period and are lethal.
The infant, ofren born prematurely, has multiple fractures and bone malformacions that can be seen on feral
x-rays or ultrasound images (Fig. 10-2).
Osteogenesis imperfecra rype III may produce fracrures in prenatal life that are present at birth and result
in skeletal deformiries. The bone collagen produced is abnormal, and fracrures continue throughout the life
span. Linear growth is limired, and fractures result in bone deformiries. Other signs and symproms may
include muscle weakness, hearing loss, farigue, joint laxity, curved bones, scoliosis, blue sclerae, and brirrle
teeth. With repeated spinal fracrures that lead to spinal deformities and kyphoscoliosis, restrictive pulmonary
disease occurs because the rib cage does nor expand appropriately.
Osteogenesis irnperfecra type IV is less severe than rypes II and III because the collagen produced is abnor-
mal but functions better than that produced in types II and III. The sclera coloracion is normal (white), and
fractures result in less deformiry.
Currently, no cure exists for OI. For individuals with mild or moderate disease, life expectancy is not
shortened. For 01 rype III, the progressive deformities reduce life expecrancy.

Figure 10-2 Osteogenesis imperiecta type II. Multiple

fractures of tubular bones and ribs, prenatally lethal. (Cour-
tesy of Hi Muller. Department of Medical GenetICS, UniversIty
Children's Hospital Basel. Switzerland.)

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 Chapter 10 Enzyme and Collagen Disorders 203

Management Strategies
Initial management strategies focus on preventing fractures, especially of the spine. Calcium supplementation
is not helpful because the genetic defect does not make bone calcium deficient. Adults with the disorder may
be treated with drugs that prevem or reduce the severity of osteoporosis (Osteogenesis Imperfecta Foundation,
2015). Other strategies involve physical therapy and safe exercise (primarily swimming); broken bone man-
agement with casts, splints, or wraps; braces to suppOrt legs, ankles, knees, and wrists; surgical implantation
of rods to suppOrt the long bones; and the use of bisphosphonate-based drugs to maintain or improve bone
strength. Canes, walkers, or wheelchairs are used to promote mobility and reduce Stresson weight-bearing bones.

Ehlers-Danlos Syndrome
Ehlers-Danlos syndrome is a group of six different inherited disorders that occur because of mutations in
the genes responsible for collagen formation or modification. The genes are located on different chromosomes
and are responsible for problems in the production of different collagen types. These disorders vary in sever-
ity and the tissues most involved. Classical Ehlers-Danlos is caused by gene mutations for type I or type 5
collagen and is transmitted in an autosomal-dominant pattern. Hypermobility Ehlers-Danlos is transmitted
as an autosomal-dominant disorder, although no specific collagen mutation has been identified. Vascular
Ehlers-Danlos is caused by a gene mutation for type 3 collagen and is transmitted in an autosomal-dominant
pattern, although spontaneous new mutations (de novo) can occur. Kyphoscoliosis Ehlers-Danlos is caused by
a mutation in a gene responsible for modifying collagen and is transmitted in an autosomal-recessive pattern.
Classical Ehlers-Danlos syndrome is the mildest form. Vascular Ehlers-Danlos and kyphoscoliosis Ehlers-
Danlos syndrome have more severe complications and are associated with early death. The incidence of all
types of Ehlers-Danlos syndrome collectively is about I in 5,000 births. The classical form is most common,
and the vascular form is the rarest. Males and females are affected equally.

Pathophysiology
The major pathology associated with all types of Ehlers-Danlos syndrome is the presence of abnormal collagen
in many different connective tissues. The exact problems that develop depend on which type of collagen is
affected and how much of the abnormal collagen is present in a specific type of connective tissue.

Signs and Symptoms

In classical Ehlers-Danlos, the skin and joints are most commonly involved. These tissues are hyperextensible
and stretchier than normal because of abnormal collagen (Fig. 10-3). Wide scars develop in areas of injury
or skin stress. The skin is fragile and bruises easily.
The major symptom of hypermobility Ehlers-Danlos is hypermobile joints, especially the knees, elbows,
fingers, toes, and the temporomandibular joint. These joints commonly become subluxated and dislocated.
Joint pain is common and chronic. The skin is more extensible and fragile than normal but not as severely
as in classical Ehlers-Danlos.
Vascular Ehlers-Danlos is severe and leads to premature death. The individual has very thin, fragile skin
and short stature. Facial features include a small, triangular face, large eyes, and a thin nose. The bigger prob-
lems are associated with the thin connective tissue in midsized and large arteries. In addition, the intestinal
connective tissue is very thin. These tissues become thinner as the child grows because no new collagen is
incorporated into the growing tissue. Scars from any skin injury heal poorly. Although the fingers and toes
may be hyperextensible, most other joints are not. The most common causes of death are hemorrhage from
arterial rupture and sepsis from intestinal rupture, usually before the age of 30.

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Figure 10-3 Stretchy skin of Ehlers-Danlos syndrome. (Used

with permission from Schaaf. CP; Zscbocke, J; Potocki, L. Basiswissen
Humangenetik. Berlin Heidelberg: SpringeJ' Verlag, 2008, 2013.)

The major features of kyphoscoliosis Ehlers-Danlos include laxity of nearly aJljoints and significant muscle
weakness, even at birth. Motor development is delayed, and a scoliosis-type spinal curvature usually develops
in infancy and progresses as the child grows. The muscle weakness also progresses, and most individuals are
unable to walk by adolescence or early adulthood. The sclera of the eye is thin and ruptures easily with minor
trauma. Premature death is associated with respiratory problems.

Management Strategies
No type of Ehlers-Danlos syndrome can be cured. Management techniques vary, depending on which mani-
festations are most prominent. Patient and family education are critical to delaying complications. Learning
how to protect the joints while maintaining mobility is important in preventing injury and reducing pain.
Activities that cause pain are avoided, and physical therapy can help the afAicted person learn how to avoid
overextending or locking the joints. Trauma, especially falls, needs ro be avoided Children are instructed to
use knee and elbow pads. Keeping pathways clear and free of objects such as throw rugs can help, as can
wearing well-fitting shoes during arnbulation.
Taking vitamin C has been recommended to reduce symptom severity, especially for vascular Ehlers-Danlos,
but the effectiveness of this therapy has not been demonstrated by Strong evidence. Surgery may be performed
when chronic dislocation affects joint function. However, because the tissue of patients with Ehlers-Danlos
heals poorly, the success of this treatment has been limited.

Marfan Syndrome
Marfan syndrome (MFS) is an inherited genetic connective tissue disorder in which rhe FBN1 gene for
the glycoprotein fibrillin is mutated. Although MFS is not a collagen disease, it is similar in that fibrillin
interacts with collagen and elastin to provide recoil strength to tissues during and after stretching. Fibrillin,
like collagen, is a glycoprotein that assembles into long Strands of microfibrils and is an essential component
of specific connective tissues, especially rhose mat respond by stretching when a force is applied. It is most
abundant in tendons, muscles, the connective tissue that surrounds large arteries, and heart valves (Lundby,
Rand-Hendriksin, Hald, Pripp, & Smirh, 2012). In addition, this protein plays a role in eye and skin devel-
opment. The FBN1 gene for fibrillin is located on chromosome 15q21.1. Although MFS is inherited as an
aurosornal-dominanr disorder, spontaneous mutations in this large gene also have occurred and result in milder

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disease expression. MFS is relatively common, occurring at a rate of lout of 5,000 births. Males and females
are affected equally, and the disorder may be underdiagnosed (OMIM, 20 l5a).
Patho physio logy
Within those connective cissues that must "give" or stretch somewhat when a force is applied, three interact-
ing components allow the stretch to occur without breaking and then return the tissue to the shape and size
it was before the force was applied. These components are collagen, elastin, and fibrillin. Static Strength is
provided by collagen, and the give or Stretch is provided by the elastin. A significant role of fibrillin is that
of limiting the stretch to help ensure a return to the original resting shape of the connective tissue when the
force is removed. So, in a sense, fibrillin adds dynamic strength to conneccive tissue.
Three major types of fibrillin have been identified. Most cases of MFS result from mutations in type 1
fibrillin. The FBNl gene is large, and many mutations occur. This mutation variability is most likely associated
with the wide variations seen in the phenotype. Due to mutations, fibrillin can fail to form at all; can form
in low amounts; can form as abnormal microfibrils; or can form as a truncated, nonfunctional microfibril.
Regardless of the mechanisms, connective tissue without sufficient amounts of healthy fibrillin is unstable,
weaker, and becomes overstretched over time. In addition to FBN1. mutations in other genes (FBN2. TGFBR2)
also affect the final function of fibrillin.
Signs and Symptoms
The phenotypes of people with Marfan syndrome vary. Because fibrillin is an important component of many
tissues, the effects are widespread (pleiotropic). Although most people do not have all signs and symptoms,
even within one family, the most common ones affect the skeletal, ocular, and cardiovascular systems (OMIM,
2015a). Most are not recognizable at birth and become more pronounced as the individual ages (Fig. 10-4).
These include the following:
• Tall, lanky stature
• "Wingspan" (arm-spread width) greater than height
• Loose or lax joints
• Very long fingers (arachnodactyly) that are hyperexrensible
• Spinal curvatures
• Chest deformicies
• Narrow, arched palate
• Crowded teeth
• Small or regressed chin
• Downward-slanting palpebral fissures
• Flat cornea
• Displaced or detached lens
• Myopia
• Small iris
• Mitral valve prolapse
• Widened aorta
• Aortic aneurysm
• Left ventricular enlargement
• Cardiomyopathy
The cardiovascular problems can significantly shorten life span. Dissecting aortic aneurysms and death
can even occur in childhood. Without management, the average life expectancy for the person with MFS is
37 years (Gonzales, 2009).

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Figure 10-4 Typical facial features of Marian syndrome and

chest deformity (pectus carinaturnl. (Used with permission from
Schaaf. CP; Zschocke. J; Potocki. L. Basiswissen Humangenetik. Berlin
Heidelberg: Springer-Verlag. 2008. 2013.)

Management Strategies
Marfan syndrome cannot be cured, and managemem is based on physical changes or sympmms. The firsr step
in management is identifying the diagnosis. This can be a problem because the phenotype can be subtle, and
the person resembles oilier family members. In addition, some of the physical changes are similar to those
of oilier disorders. Genetic testing is not practical for initial diagnosis because the large number of possible
mutations makes testing expensive. Testing is best used when a person is diagnosed based on phenotype and
family history and has a specific mutation. This information can be used [0 determine whether oilier family
members carry the mutation.
Although skeletal and ocular management are important, the primary management focuses on monitoring
and protecting the cardiovascular system. Patients are encouraged to achieve and maintain a healthy weight
appropriate for height and to avoid excessive weight gain. A balance of physical activity is needed [0 be physi-
cally fit without placing strain on the cardiovascular system. Strenuous exercise and heavy lifting must be
avoided, as should any activity in which the chest could be hit. Thus, contact sports and those that involve
running or catching a ball should be avoided. Walking is encouraged, as are less physically aggressive sporrs,
such as golfing. bowling. recreational swimming, or low-intensity bicycling. These recommendations may
be difficult, particularly during late childhood and early adulthood, when the focus on physical prowess and
participation in team sports is emphasized. Think about the 6-foot-7-inch-rall 15-year-old who is pressured
by the basketball coach to join the team. Also consider that a taller-than-average person might be expected
by friends to help move furniture or carry a heavier load.

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 Chapter 10 Enzyme and Collagen Disorders 207

The health-care provider should evaluate the patient's cardiovascular status at least yearly. Tests are needed
to assess left ventricular function and ejection fraction, mitral valve function, and aortic and pulmonary
artery width (Lundby et al., 2012). Maintaining blood pressure within the normal range is critical and may
require pharmacologic management, particularly with angiorensin-recepror blockers (OMIM, 20 15a). Surgi-
cal intervention is necessary when aortic dilation reaches a critical point and when heart valve function falls
below an acceptable level.

SUMMARY
At the present, collagen disorders and connective tissue diseases cannot be cured. Thus, accurate diagnosis and
early preventive intervention strategies are needed to delay complications and promote quality of life. Many
of these disorders are inherited in an aurosomal-dorninanr fashion; however, some also have a relatively high
rate of occurrence because of spontaneous new mutations. Health oversight by a knowledgeable health-care
professional and appropriate genetic counseling are essential components of patient and family care.

GENE GEMS

• All enzymes are gene products.

• A mutation in a gene coding for a specific enzyme usually reduces the enzyme's activity and results in
one or more physiologic problems related to the toxic accumulation of the precursor substance.
• People with phenylketonuria must adhere to a low-phenylalanine diet to prevent or slow the central
nervous system complications of the disease.
• Enzyme-replacement therapy (ERT) for lysosomal storage diseases reduces the progression of the disease
and must be regularly continued for life.
• Of the three types of Gaucher disease, type I is most common, does not affect the central nervous
system, and can be managed with ERT.
• Signs and symproms of Gaucher disease type 1 may not be present until adulthood.
• The phenotypes of Hurler syndrome and Hunter syndrome are very similar, although Hunter syndrome
has a slower onset and a less detrimental effect on intellectual function.
• The incidence of Tay-Sachs disease is 100 times greater among Ashkenazi Jewish populations than
among most non-Jewish populations.
• Many enzyme disorders can be cured by hematopoietic stem cell transplantation (HSCT), but the
procedure is both costly and dangerous.
• No therapy exists to prevent progression ofTay-Sachs disease.
• Collagen is the most abundant protein found in humans and provides both structure and strength to
many tissues.
• In mild forms of osteogenesis imperfecra, collagen is normal but is present in reduced amounts.
• In moderate and severe forms of osteogenesis imperfecra, the type 1 collagen produced is abnormal.
• About 35% of the cases of osreogenesis imperfecra occur because of a new spontaneous mutation.
• The FBNl gene for fibrillin is very large, and many different mutations can lead to Marfan syndrome.
• The most serious and life-threatening complications of Marfan syndrome occur in the cardiovascular
system.

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208 Unit III Genomic Health Problems Across the Lite Span

Self-Assessment uestions ....

1. Which clinical situation best demonstrates me concept of pleiotropy?
a. A mutation in anyone of several genes can cause the same problem or disorder.
b. The problem caused by a single-gene rnutation appears at an earlier age in each succeeding generation.
c. A specific, single-gene mutation results in the phenotype of reduced cognition, absent iris, and
exstrophy of me bladder.
d. Huntington disease, caused by a single-gene mutation present at birth, does not result in symptoms
until later in life.
2. Which normal physiologic process usually requires an enzyme?
a. Degradation of mucopolysaccharides (glycosaminoglycans) into sugar and proteins for recycling
b. Propagation of a nerve action potential from the point of stimulation to the axon terminal
c. Exfoliation (shedding) of dead skin cells from me stratum corneum of the epidermal layer
d. Movement of water across a cell's plasma membrane from an area of high hydrostatic pressure to
an area of lower hydrostatic pressure
3. Which problems result from me gene mutation associated with phenylketonuria?
a. Excessive levels of tyrosine and deficient levels of phenylalanine
b. Excessive levels of tyrosine and normal levels of phenylalanine
c. Excessive levels of phenylalanine and deficient levels of tyrosine
d. Excessive levels of phenylalanine and normal levels of tyrosine
4. How does substrate reduction therapy help manage me problems associated with Gaucher disease type I?
a. By directly decreasing the amounts of g1ucosylceramide presem in macrophages
b. By directly decreasing the amounts of f3-glucocerebrosidase present in macrophages
c. By directly increasing the amounts of glucosylceramide present in macrophages
d. By directly increasing the amounts of p-glucocerebrosidase present in macrophages
5. Why is a person with Gaucher type 1 usually anemic without therapy?
a. The excess p-glucocerebroside in the macro phages of me spleen reduces its function.
b. The excess p-glucocerebroside in the macro phages of me bone marrow reduces its function.
c. The excess glucosylceramide in the macrophages of me spleen reduces its function.
d. The excess glucosylceramide in me macrophages of the bone marrow reduces its function.
6. Why does enzyme-replacement therapy with laronidase in a child with Hurler syndrome have no effect
on slowing the central nervous system manifestations of the disease?
a. The drug does not cross me blood-brain barrier.
b. The drug is only effective on cells mat maintain the ability to divide.
c. The enlarged liver degrades me drug too quickly for it to be transported to remote body areas.
d. The type of iduronidase present in me central nervous system differs from mat in me rest of me body.
7. Which ethnic groups have me highest incidence of Gaucher type I? Select all mat apply.
a. Ashkenazi Jewish people
b. Asian people from China and the Korean Peninsula
c. Celtic people from Scotland and Ireland
d. French Canadian people from me Quebec area
e. People from equatorial African countries
f. People from the Mediterranean region

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 Chapter 10 Enzyme and Collagen Disorders 209

8. Which form of Ehlers-Danlos is severe and leads to premature death?

a. Kyphoscoliosis
b. Hypermobility
c. Classical
d. Vascular
9. If a man with Hunter disease has children with a woman who neither has the disease nor is a carrier
for the disorder, what is the expected risk pattern?
a. All sons will be unaffected; all daughters will be carriers.
b. Sons have a 50% risk for being affected; all daughters will either be affected or carriers.
c. Daughters have a 50% risk for being affected; all sons will either be affected or carriers.
d. Each child of either gender has a 50% risk of being a carrier, a 25% risk of having the disease, and
a 25% risk of neither being a carrier nor having the disease.

CASE STUDY

A 37-year-old female nurse was diagnosed with Marfan syndrome last year when her older brother was
diagnosed with the disorder at the time he had heart valve replacement surgery. Their father is still livingat
age 75 and is 6' tall.Their mother, who was 5' 11", died of a ruptured aortic aneurysm while giving birth to
her third child.This nurse is 6' 1" tall, 50 Ib overweight, and works as a labor and delivery nurse. She has
long fingers and enjoys playing the piano. She is blond with blue eyes and very near-sighted. Six months
ago, she broke her wrist when she fell on the ice and tried to break her fall.Two years ago, she had a total
hysterectomy for uterine fibroids and endometriosis. She also has scoliosis and high blood pressure. Her
leisure activities include swimming, bowling, and knitting.
1. Draw the pedigree and identify probable affected individuals.
2. What physical attributes and health problems could be associated with Marfan syndrome? Explain
your choices.
3. Are her work and leisure-time activities placing her at any particular risk? Support your choices.
4. Would genetic counseling be of any benefit to her? Explain why or why not.

References

Bijarnia, S., Shaw, P., Vimpani, A., Smith, R., Pacey,V., O'Grady, H., ... Sillence, D. (2009). Combined enzyme replacement
and hematopoietic stem cell transplan ration in Hurler syndrome. [aurnai of Paediatrics and Child Health, 45(7-8), 469--472.
DeRoche, K., and Welsh, M. (2008). Twenty-five years of research on neurocognitive ourcomes in early-treated phenylketonuria:
Intelligence and executive function. Deoelopmental Nt!lIropsyclJology,33(4), 474-504.
Ehlers-Danlos Society. (2017). \'(Ihat air tilt! Eblers-Danlos syndrollles? Retrieved from hrtps:llehlers-danlos.org/what-is-edsl
Gonzales, E. (2009). Marian syndrome. [ournal of the American AcatklllY of NlIT'Sl' Pmaitioners, 21(12), 663-670.
Little, C; Gould, R., & Hendriksz, C. (2009). The management of children with Hunter syndrome: A case study. British
[ournal oj Nursing, 18(5),321-322.
Lundby, R., Rand-Hendriksin, 5., Hald, J., Pripp, A., & Smith, H. (2012). The pulmonary artery in patients with Marfan
syndrome: A cross-sectional study. Gt!IIuics in Medicine, 14(7), 922-927.

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210 Unit III Genomic Health Problemskross the Life Span

McCance, K., Huether, S., Brashers, v., & Rote, N. (2014). Pathophysiology: The biologic basisfor disease ill adults and children
(7th ed). St. Louis, MO: Elsevier.
National Gaucher Foundation. (201G). About GallcJxr disease. Retrieved from hrrp:llwww.gaucherdisease.org
National Insrirures of Health. (2017a). Gmnic bom« uftrma: Fabry diseas». Retrieved from hrrps:lIghr.nlm.nih.gov/conditionl
fabry-disease
National lnsrirures of Health. (2017b). Guuric home uftrmce: Gaucher disease. Retrieved from hrrps:lIghr.nlm.nih.gov/conditionl
gauche r-disease
National lnsrirures of Health. (2017c). Genetir bom« n:frrma: Phmy/knonuria. Retrieved &am hrrps:lIghr.nlm.nih.gov/conditionl
phenylketonuria
Online Mendelian Inheritance in Man. (2013). Thy-Sachs diseasc; TSD. Retrieved from hrrp:llwww.omim.org/entry/272800
Online Mendelian Inheritance in Man. (2015a). Ma1illl syndromc; MFS. Retrieved from htrp:llwww.omim.org/entryII54700
Online Mendelian Inheritance in Man. (2015b). Phmy/ketonuria; PKU. Rerrieved from htrp:llwww.omim.org/enrry/2GI600
Online Mendelian Inheritance in Man. (20IGa). Gauchcr disease, rypc I. Retrieved from hrrp:llwww.omim.org/entry/230800
Online Mendelian Inheritance in Man. (201Gb). Hurler SJndromc. Retrieved from hrrp:llwww.omim.org/enrryIG07014
Online Mendelian Inheritance in Man. (201Gc). Mucopo/ySltuharidosis, rypc 1/; MPS2. Retrieved from hrrp://www.omim.ol·g/
entry/309900
Osteogenesis Irnperfecra Foundation. (2015). Abo«: 01. Retrieved from hrrp:llwww.oif.orglsire/PageServer?pagename=AOI_Facrs/
Schaefer. R.. Tylki-Szymariska, A.• & Hilz, M. (2009). Enzyme replacement therapy for Fabry disease: A sysremaric review of
available evidence. Drugs. 69(1 G). 2179-2205.
Singh. R., Rohr, F.. Frazier. D .• Cunningham. A.• Mofidi, S.• Ogata. B.•... Van Calcar. S. C. (2014). Recommendations for
the nutrition management of phenylalanine hydroxylase deficiency. Gmuics in Medicine. 16(2). 121-131.
Workman. M .• & LaChariry. L. (2016). Understanding pharmacology: Essentialsfor medication Sltftry. Sr. Louis. MO: Elsevier.

Self-Assessment Answers
1. c 2. a 3. c 4. a 5. d 6. a 7. a. d 8. d 9. a

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 Chapter ] ] __
Common Childhood-Onset
Genetic Disorders
Learning Outcomes
1. Describe the genetic/genomic contributions to sickle cell disease (SCD), inheritance patterns, and other
factors that may influence disease expression.
2. Describe the genetic/genomic contributions to cystic fibrosis (CF), inheritance patterns, and other facrors
that may influence disease severity.
3. Describe the genetic/genomic contributions to Duchenne muscular dystrophy (DMD), inheritance pat-
terns, and other factors that may influence disease severity.
4. Describe the genetic/genomic contributions to classic hemophilia (hemophilia A), inheritance patterns,
and other factors that may influence disease severity.
5. Describe the genetic/genomic contributions to von Willebrand disease, inheritance patterns, and other
factors that may influence disease severity.
6. Describe the genetic/genomic contributions to achondroplasia, inheritance patterns, and other factors that
may influence disease severity.
7. Explain the gene-environment interactions involved in the development of type 1 diabetes.
8. Explain the gene-environment interactions involved in the development of atopic asthma.

Key Terms
Achondroplasia Cystic fibrosis (CF) Insulitis
Asthma Diabetes mellitus type 1 Sickle cell crisis
Autoimmune disease Duchenne muscular dystrophy Sickle cell disease (SCD)
Classic hemophilia (DMD) Sickle cell trait

Complex disorders Dystrophin von Willebrand disease (VWD)

Hyperglycem ia

211

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212 Unit III Genomic Health ProblemsAcross the Lite Span

INTRODUCTION
Many "pure" genetic disorders, such as sickle cell disease and cystic fibrosis, manifest and are usually diagnosed
during infancy and childhood. Some disorders that have a genetic predisposition and require an environmental
Contribution for the disorder to develop also occur in childhood. Such disorders include asthma and diabetes
mellitus type 1. Even for those health problems that have a genetic mutation as the basic underlying pathology,
environmental factors can affect disease severity and age of onset. Some of these childhood-onset disorders
can be managed and their consequences delayed or altered For others, few management techniques slow the
consequences of the disease, and life expectancy and physiological function are greatly reduced. This chapter
focuses on the most common childhood-onset disorders that have a major genetic contribution.

MONOGENIC DISORDERS
As discussed in Chapters 1 and 4, a monogenic or single-gene trait or condition is one in which one gene
controls the expression of a specific structure, protein, or function. Monogenic disorders can be transmitted
in an autosomal-dominant, autosomal-recessive, or sex-linked pattern.

Sickle Cell Disease

Sickle cell disease (SeD) is a genetic disorder caused by a single-nucleotide polymorphism (point muta-
tion) in both alleles of a single gene that results in the abnormal formation of the beta chain of hemoglobin
(beta globin). The disorder is transmitted in an autosomal-recessive pattern and is most common among
people with African or other equatorial ancestry (from geographic regions near the equator). The incidence
of SCD in the United States among African Americans is about 1 in 400 to 500 live births. About 90,000 to
100,000 people living in North America have the disease. Carrier Status, known as sickle cell trait, ill which
a person has only one mutated beta globin gene allele is estimated at I in IS African Americans (Centers for
Disease Control and Prevention [CDC), 2015). Both SCD and sickle cell trait have a far greater incidence in
East Africa and other equatorial countries.

Genetic Contribution to the Disorder

Transcription and translation of the wild-type beta globin gene (HBBJ produce a 146-amino acid protein with
glutamic acid (GLU) as the sixth amino acid (the DNA triplet is CTC). In the classic form of SCD, both
beta globin alleles have a mutation in which the DNA triplet coding for gluramic acid has adenine substituted
for thymine (instead of CTC, the triplet now reads CAC). This mutation results in valine as the sixth amino
acid in the protein sequence (Online Mendelian Inheritance in Man [OMIM], 2016d).
Usually, two beta globin molecules associate with rwo alpha globin molecules and four "heme" molecules to
form normal adult hemoglobin (HbA) in red blood cells (RBCs). The function of hemoglobin is to reversibly
bind with up to four molecules of oxygen in arterial blood and unload the oxygen in various body tissues. (A
single RBC contains hundreds of thousands of hemoglobin molecules.)
When both alleles of the beta globin gene are mutated, RBCs have a high percentage of hemoglobin S
(HbS) rather than HbA. It can bind with four molecules of oxygen in the same way that HbA does. However,
HbS is very sensitive to low tissue levels of oxygen, and the shape of the four associated globin molecules
(two alpha and two beta) folds differently as tissue oxygen levels decrease. This change in folding pulls the
cell membranes inward, causing the RBC to form a sickle shape that does not flow smoothly through blood
vessels (Fig. 11-1). Instead, the sickled RBCs clump together and block blood Row, causing tissues distal to

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 Chapter 11 Common Childhood-Onset Genetic Disorders 213

Cross section of RBC Cross section of sickle cell

RBCs flow freely Sicklecells

A w~hin blood vessel B blocking blood flow

Figure 11-1 (A) Normal,smooth flow of red blood cells. (8) Clumpingtogether of sickle-shaped
red blood cells, reducing or blockingblood flow.

the blockage to be poorly perfused and poorly oxygenated, which then leads to more sickling of RBCs and
ischemia in the affected tissues. The membranes of the sickled RBCs also become abnormal and tend to stick
together, making the clumping worse. In addition, the RBCs containing largely HbS have a much shorter life
span than normal, only about 16 to 20 days instead of 120 days.
When only one beta globin allele has the mutation, the person has sickle cell trait. In this disorder, the
percentage of HbS in RBCs is usually less chan 40%. Although cells with JUStthis much HbS can assume a
sickle shape, the degree of tissue hypoxia required for this change is far greater than that needed for RBCs
with 90% or more HbS to form sickled cells (CDC, 2015).

Inher~ance Patterns
The specific gene mutation causing SCD or sickle cell trait has a low incidence of developing spontaneously.
The most common transmission is from parem to child in an autosomal-recessive pattern. Figure 11-2 shows
Punnett square transmission inheritance probability for people without a mutated beta globin allele, those
with one mutated beta globin allele, and those with two mutated beta globin alleles.
Genetic testing is not used to diagnose SCD. It is diagnosed based on the large percentage of hemoglobin S
(HbS) seen on electrophoresis. A person who has SCD usually has 80% to 90% HbS, and a person with sickle
cell trait usually has less than 40% HbS. The number of RBCs with permanent sickling also is an indicator
of SCD. Those withe ut the disease have less than 1% sickled cells, those with sickle cell trai t have less than
40%, and those with SCD may have as high as 90% permanencly sickled cells at anyone rime.

Signs and Symptoms

The poor perfusion and oxygenation of body tissues in the person with SCD results in pain, disability, organ
damage, increased infections, and early death. The short life span of the RBCs results in chronic anemia,
although these patients are not iron deficient. (In fact, transfusion therapy must be performed carefully to
prevent the person from developing iron overload.) Conditions that trigger hypoxia or poor blood flow and lead
to episodes of sickling include dehydration, infection, venous stasis, alcohol consumption, high altitude, low
environmental or body temperature, acidosis, strenuous exercise, pregnancy, and anesthesia. An acute sickling

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214 Unit III Genomic Health Problems Across the Lite Span

HbA HbA HbA HbA HbA HbS

HbA HbA HbA HbA HbA HbA HbA HbA HbA HbA HbA HbA HbA HbA HbS

HbA HbA HbA HbA HbA HbS HbS HbA HbS HbA HbS HbS HbA HbS HbS

Both parents homozygous One parent homozygous tor Both parents heterozygous
torHbA HbA; one parent heterozygous tor HbS
Risk tor SeD 0/4 (0%) torHbS Risk for SeD 1/4 (25%)
Risk tor SeD 0/4 (0%) Risk for carrier status 2/4 (50%)
Risk for carrier status 214 (50%) Risk for unaffected 1/4 (25%)

HbS HbS HbS HbS HbS HbS

HbA HbA HbS HbA HbS HbA HbA HbS HbA HbS HbS HbS HbS HbS HbS

HbA HbA HbS HbA HbS HbS HbS HbS HbS HbS HbS HbS HbS HbS HbS

One parent homozygous One parent homozygous Both parents homozygous

tor HbA; one parent homozygous tor HbS; one parent heterozygous tor HbS
torHbS torHbS Risk for SeD 4/4 (100%)
Risk tor SeD 0/4 (0%) Risk tor SeD 214 (50%) Risk for carrier status 0/4 (0%)
Risk tor carrier status 4/4 (100%) Risk for carrier status 214 (50%) Risk for unaffected 0/4 (0%)
Risk tor unaffected 0/4 (0%) Risk for unaffected 0/4 (0%)

Figure 11-2 Comparisonof risks to inherit HbA. HbS. sickle cell disease.and sickle cell trait.

period is known as sickle cell crisis. During crisis periods, extensive sickling occurs and disrupts blood flow to
an entire organ(s) or body area. Severe pain in the affected area is the most common symptom during crises.
Although some sickled RBCs resume a normal shape when tissue oxygen levels increase and the crisis is
over, some cells remain sickled, and alJ are more fragile. This fragility increases the risk for repeated sickling,
even when tissue oxygen levels fall only slightly below normal.
Over time, the repeated blood vessel blockage leads to hypoxic damage of most tissues and organs, especially
those that are highly dependent on oxygen, such as the Liver,heart, brain, spleen, kidney, bones, and retinas.
Hypoxic tissues become anoxic and ischemic, folJowed by necrosis (cell death). SmalJ infarcts and necrotic tissue
areas first appear. These areas become fibrotic and no longer function. The tissue or organ has progressively
larger areas of fibrosis and scarring with fewer areas of functional cells. Eventually, toO few functional cells
remain, and the tissue or organ is permanently nonfunctional. Table 11-1 lists the health problems caused by
SCD. Disease severity and the onset of serious complications vary greatly among patients with SCD. Most
children who receive supportive and preventive care for SCD Liveinto adulthood, but the complications of
the disease can only be delayed, not eliminated. The only cure for SCD is a stem cell transplant. However,
the many serious complications of this serious procedure, including death, and its COStlimit the use of this
treatment strategy.

Disease Variability
Sickle cell disease expression varies, with some people developing profound complications leading to death in
childhood or early adulthood, whereas others may live into their 70s (OMIM, 2016d). This is unusual for a
genetic disorder in which the actual mutation is so specific and so stable. Unlike ocher genetic disorders, such

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 Chapter 11 Common Childhood-Onset Genetic Disorders 215

Progressive Complications of Sickle Cell Disease

Pain Increased susceptibility to infections, especially pneumonia

Priapism Liver and spleen destruction and failure
Jaundice Chronic kidney disease and kidney failure
Heart failure Foot and leg ulceration
Fatigue Brain infarcts, strokes, seizures
Weakness
Joint damage

as cystic fibrosis, in which the base or bases substituted So, What Accounts for the Variability-
or deleted can vary from family to family, all people Nature (Genetic Influences) or Nurture
who have the main form of SCD have the exact same (Environmental Influences)?
amino acid change of valine for glutamic acid in the The answer is both. although the exact medlanisms
sixth position of beta globin. have not all been identified.
Environmentally, those individuals who can avoid
triggers for extreme sickling and crises have a slower onset of permanent complications. Those individu-
als whose crisis episodes are managed promptly and correctly also have better long-term physical function.
However, many people manage their disease appropriately and diligently and still have an early onset of serious
complications, disability, and death.
One of the best predictors for which patients who have SCD will have delayed complications is the percent-
age of fetal hemoglobin (HbF) that remains in circulation. HbF is a type of hemoglobin normally expressed at
high levels only during fetal life, during which all oxygen is derived secondhand from the maternal circulation.
It tolerates low oxygen conditions well without sickling. After a baby is born, RBCs begin to synthesize the
adult form of hemoglobin (HbA), and the amount of HbF usually drops dramatically during the first months.
Most people express less than 2% HbF and about 98% HbA by early childhood. Some patients with SCD
continue to express as much as 20% HbF throughout childhood and adulthood. This percentage dilutes the
percentage of HbS and results in better tolerance of conditions that could cause sickling. Continued produc-
tion of HbF is most likely a genetically controlled function, although all genes responsible have not yet been
identified. One gene, BeUlA, has been found to modify SCD severity by maintaining a higher percentage
of HbF. The product of this gene is important in the regulation of fetal hemoglobin and is usually "switched
off" in infancy. For some people with SCD, this gene is still functional and results in a higher natural circu-
lating level of HbF (OM 1M, 2016d).
The drug hydroxyurea can increase the percentage of HbF in some people with SCD. It is often used as
long-term therapy to maintain higher levels of HbF and delay the complications of SCD, although not all
people with SCD respond well to this drug. In addition, hydroxyurea is associated with significant side effects
and an increased risk for some types of malignancy.
A newly approved drug therapy for SCD is Endari. This drug is the amino acid glutamine which is taken
orally twice daily. Its exact mechanism is not known but thought to reduce oxidative stress within RBCs. In
patients taking this drug, RBCs have a longer lifespan and undergo less sickling, which reduces complications
of the disease.

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216 Unit III Genomic Health Problems Across the Lite Span

Another interesting variation in the expression of SCD occurs when the person also has a disorder of the
alpha chains of globin, alpha-thalassemia. In this genetically inherited condition, the loss of anyone of the
four gene alleles that code for alpha globin chains (twO each on chromosome 16) causes alpha-thalassemia.
This is not a case of "two wrongs making a right," but the anemia caused by alpha-thalassemia has long been
known to reduce the effects of SCD in several possible ways. First, people with alpha-thalassemia are anemic,
which reduces the number of RBCs and the RBC concentration of HbS. In addition, these RBCs are less
dense than SCD RBCs, resulting in less cell sickling and breakage. In addition, the alpha-thalassemia increases
the amount of RBC cell membrane, which then protects against cell breakage. One final difference that may
explain how alpha-thalassemia moderates the effects of SCD is that RBCs with both alpha-thalassemia and
SOC do not dehydrate and lyse as easily as SCD RBCs alone. Regardless of the specific mechanism, the
condition of alpha-thalassemia does modify the effects of SCD in a positive way.

Potential Disease Advantage

You may be asking yourself, "How can a disease such as SCD ever be an advantage?" It does actually have
one, and that may be the reason that SCD developed in the first place! In equatorial regions of the world, the
infectious disease malaria is common and deadly. The hemoglobin change caused by the genetic mutation of
SCD reduces the susceptibility to severe malaria on exposure or infection with the organism.
This benefit occurs in both those who are homozygous for (he gene mutation and in those who are hetero-
zygous (OMIM, 20 16d). Clearly, the benefit (0 people who have SCD, even in areas where malarial infection
is prevalent, is limited. However, the benefit co chose who have the [fait and live in areas in which malarial
infection is prevalenr is enormous. For people who live in areas in which malarial infection is uncommon,
having either form of SCD confers no advantage.

Cystic Fibrosis
Cystic fibrosis (CF) is a monogenic disorder in which both alleles of a gene have one or more mutations that
result in problems with the transmembrane transpon of chloride. The disorder is inherited as an aurosornal-
recessive single-gene trait and is most common among whites of Northern and Western European heritage,
although it can be found among people of all races and ethnicities. The incidence of CF in the United States
among Caucasians is about 1 in 3,000 live births. Carrier status, in which a person has only one mutated gene
allele, is estimated at 1 in 20 to 30 Caucasian Americans. About 30,000 children and adults in the United
States have been diagnosed with CF (Cystic Fibrosis Foundation, 2016).

Genetic Contribution to the Disorder

CF is caused by inheriting a gene mutation in both alleles of the cystic fibrosis transmembrane conductance
regulator CFTR gene, which is located at chromosome 7q31 (OMIM, 2016a). This gene produces a protein
that serves as a chloride channel and regulates both chloride and bicarbonate transpon. Additionally, the CFTR
gene product controls or influences other transport pathways.
The CFTR gene is very large and complex, containing different coding regions. Different parts of the protein
it produces have varying roles in development and physiological function. At present, more than 1,700 dif-
ferent mutations in this gene have been identified (Cystic Fibrosis Foundation, 2016). Mutation differences
are believed to account for much of the variance in the severity, the age of symptom onset, and differences in
organ involvement. Even with so many mutations, some are more common than others. The delta-F508 is
the most common mutation (among Caucasians) and produces the most severe disease. Interestingly, CFTR
mutations do not prevent production of the protein but instead change the protein sequence so that it still

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 Chapter 11 Common Childhood-OnsetGenetic Disorders 217

functions but with varying degrees of activity and efficiency. As a result, the mutation genotype does correlate
with the specific manifestations (phenotype) expressed by the person with CF.

Inher~ance Patterns
Transmission of CF is autosomal recessive from parent to child. This pattern follows the same probability for
the unaffected state, the affected state, and the carrier state demonstrated in Figure 11-2 for sickle cell disease.
Genetic testing is not used to diagnose the homozygous expression of CF. It is diagnosed based on physical
manifestations and the results of the sweat chloride resr. Positive results are those indicating a high concentra-
tion of sodium chloride in the person's sweat (60 to 200 mEq/L or mmollL) compared with the normal value
(5 to 50 mEq/L or mmollL). However, the heterozygous carrier can not be identified with the sweat chloride
test and has no distinctive disease manifestations. Genetic testing by direct sequencing of the CFTR gene is
useful for establishing carrier status; identifying affected children prenatally; and, to some degree, predicting
disease severity.

Signs and Symptoms

The two main organ systems affected that involve epithelial cells are the lungs and the pancreas. The epithelial
cells in these tissues produce a thick, sticky mucus due to poor chloride transport that, over time, plugs up
the glands in these organs, causing glandular atrophy and organ dysfunction or failure. Other organs that are
affected to a lesser degree include the liver, salivary glands, and testes.
The most serious complications of CF occur in the lungs from the constant presence of thick, sticky mucus.
The mucus narrows airways, reducing airAow, and permits chronic lower respiratory bacterial infections.
Due to the infections, chronic bronchitis, bronchiectasis, and increased alveolar compliance result, and lung
abscesses form. Common lung complications of CF include pneumothorax, arterial erosion and hemorrhage,
antibiotic-resistant infection, and respiratory failure.
The thick mucus also plugs the ducts of the pancreas, causing glandular atrophy and progressive fibrotic
cySt formation. These changes first reduce and rhen hair production of the digestive enzymes needed for fat
and protein digestion. This enzyme loss leads ro malnutrition, smaller stature, fatty diarrhea (srearorrhea), and
a deficiency of fat-soluble vitamins. Although the endocrine funcrion of the CF pancreas also is affected, this
occurs much later in the disease process and causes diaberes.
The liver and gallbladder also are damaged by mucus deposits, and the liver eventually fails. In many people
with CF, the salivary gland ducts dilate and produce abnormal saliva.
Male infertility is associated with CF, usually due to the failure of the vas deferens to develop (agenesis
of the vas deferens). The vas deferens is a tubular structure rhar rransports sperm from resticular storage sires
to the urethra. Without a vas deferens, the man does nor have sperm in the seminal Huid, even though he
produces sperm in the testes.

Disease Variability
CF is extremely variable in disease severity and in organ involvement, although expression of the clinical course
is less variable within a given affected family. Greater variation in severity is seen in different families, with
pancreatic problems more extreme in some families and lung problems more extreme in others. For example,
in some families, affected children are diagnosed in early infancy and often progress quickly to severe lung or
pancreatic disease before the teenage years. In other families, manifestations may nor be apparent until later
childhood or adolescence. More recently, some adults have been identified as being homozygous for CFTR
mutations but have minimal or no obvious manifestations.

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218 Unit III Genomic Health Problems Across the Lite Span

CF does not have a cure, although aggressive management of lung infections and therapies, such as lung
transplantation, can extend life. Gene therapy has been rried but is not a currently approved therapy for CF.
For those who have obvious manifestations of lung involvement, life expectancy is considerably reduced,
although it has increased from childhood to adulthood to an average of 38 years because of improvements in
medical therapy (Cystic Fibrosis Foundation, 2016).
Drug therapy is available for use in patients with specific gene mutations. One drug, ivacafror (Kalydeco),
reduces symptoms in patients with anyone of the following specific mutations in the CFTR gene: G551 D,
G 1244E, G 13490, G178R, G551S, S 1251N, S1255P, S549N, or S549R. The combination drug lurnacaftor/
ivacaftor (Orkarni) is effective for patients with the delta-F508del mutation. For CF with the mutations just
listed, these drugs increase the CFTR channel opening, so more chloride ions move across the cell membrane,
resulting in mucus that is less thick and sticky by reducing sodium and fluid absorption.

Potential Disease Advantage

The high frequency of the heterozygous carrier state for CF among Caucasians from Northern and
Western Europe suggests that being a CF carrier might have a potential advantage. Scientists now believe
people who are heterozygous for specific common CFTR mutations have greater resistance to infectious
diseases such as typhoid and cholera toxin when exposed to these disease-causing microorganisms
(OMIM,2016a).

Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a genetic disorder of progressive muscle weakness caused by any
one of a variety of mutations in an allele of the DMD gene, which codes for the protein dysrrophin. It is the
most common inherited myopathy (muscle-degrading disease). The disorder is inherited in an X-linked trans-
mission pattern and is most common among males. The incidence of DMD worldwide is about I in 3,300
to 3,500 live births of males. It occurs at about the same rate in all races (Muscular Dystrophy Association
[MDA], 2017). Becker muscular dystrophy (BMD), a milder form of the disease, results from a less-damaging
mutation of the same gene and follows the same inheritance patterns.
Female carriers, who have one normal X chromosome and one with an abnormal dysrrophin allele, can
express some manifestations of the disorder but to a much lesser degree than affected males. The actual inci-
dence of female carriers is not known.

Genetic Contribution to the Disorder

The gene for dystrophin is located on the X chromosome (locus is Xp21) (OMIM, 2016c). It is the largest
gene in the human genome, and its product, dystrophin, also is large. Muscular dystrophies of several types
are associated with mutations in this gene. Mutation types include large deletions, small deletions, large
duplications, insertions, and base changes. The most common mutation consists of large deletions, and the
disorder is exclusively genetic in origin.
Dysrrophin is a structural protein that functions to maintain muscle integrity. It is found inside skeletal,
cardiac, and smooth muscle cells. A variant of dysuophin also is found in brain cells. In muscle cells, dysrrophin
surrounds muscle fiber membranes and secures the contractile protein strands, especially actin, so they remain
anchored in place and are stable. With tOO little dysrrophin (BMD) or completely nonfunctional dysrrophin
(DMD), each muscle contraction loosens actin, gradually breaking down the muscle fibers and destroy-
ing the integrity of individual muscle cells. Because muscles are not mirocically active after birth, damaged
and dead cells are not replaced. The muscles lose muscle fibers and become filled with connective tissue
and fat.

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 Chapter 11 Common Childhood-Onset Genetic Disorders 219

Inheritance Patterns
Because the DMD gene is located on the X chromosome and males have only one X chromosome, which
is inherited exclusively from their mothers, DMD has a sex-linked (X-linked) transmission pattern. Figure
11-3 shows Punnett square inheritance probability for people without a mutated dystrophin allele, those with
one mutated dysrrophin allele, and those with twO mutated dysrrophin alleles (rare). Additionally, in about
30% to 35% of males who have DMD, the mother is not a carrier. Thus, the spontaneous mutation rate for
this gene is very high. This rate is thought to be related to the large size of the gene, making it a very large
target for mutational events during DNA replication, protein synthesis, and gametogenesis (the formation of
mature sperm and ova).
The diagnosis ofDMD is first suggested by a history of progressing muscle weakness in a male child along
with hugely elevated blood levels of the enzyme creatine kinase (CK) and the protein myoglobin. Both are
normally present inside intact muscle cells. When the cells are damaged or die, these products are released
into the blood. These levels decrease as the child ages because how much muscle is available to be destroyed
becomes limited. Additional testing can include a muscle biopsy to determine whether muscle weakness results
from muscle cell degeneration or from inflammation. Genetic testing with the polymerase chain reaction
(PCR) on blood or skin cells can determine specific areas of mutations on the DMD gene. This is useful in
identifying carrier status and the DMD status of a fetus.
For DMD, female carriers also may be identified based on elevated CK levels and the presence of slightly
weaker than expected skeletal muscle strength. However, whether these rests are conclusive depends on the
percentage of skeletal muscles in which the affected X chromosome (the maternal derived X or the paternal

x x x XOMO

x x X X X X X X X XOMO

y Y X Y X y Y X Y XOMO

Mother homozygous for normal dystrophin Mother heterozygous (carrier) for DMD
Father hemizygous for normal dystrophin Father hemizygous for normal dystrophin
Risk for inherited DMD is 0/4 (0%) Risk for DMD is 1/4 (25%)
Risk for spontaneous mutation leading Risk for carrier status 1/4 (25%)
to DMD is not known

X XDMO XOMO XOMO

XOMO XOMO X XOMO XDMO Rare and XOMO XDMO XOMO XOMO XOMO
unlikely
scenarios
y Y X Y XDMO Y Y XOMO Y XOMO

Mother heterozygous (carrier) for DMD Mother homozygous (affected) for DMD
Father affected with DMD Father affected with DMD
Risk for DMD is 214 (50%) Risk for DMD is 414 (100%)
Risk for carrier status 1/4 (25%) Risk for carrier status 014 (0%)

Figure 11-3 Comparison of risks to inherit normal dystrophin, DMD carrier status, or DMD.

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220 Unit III Genomic Health Problems Across the Lite Span

derived X) is the one that remains active. (Remember from Chapter 4 that in females, one X is inactivated in
most cells, and which X is inactivated is a random process.)

Signs and Symptoms

Muscle weakness in DMD is first seen in the neck and hip girdle muscles. Young boys who have learned to
sit up and to walk usually start to show difficulty in walking and remaining upright between 2 and 5 years
of age. The child has difficulty directly standing from a sitting position or when getting up from the Roor.
He uses his arms to push himself into an upright position rather than depending on the legs to raise the
body. The gait becomes clumsy, and falling occurs frequently. The calf muscles start to appear large in rela-
tion to the rest of the child's muscles. This size increase represents replacement of muscle fibers with fat and
connective tissue rather than a strengthening of the muscle itself. Usually, the child is unable to walk by the
teenage years.
Most boys with DMD develop cardiac muscle problems because these cells also rely on dystrophin to
maintain their integrity. The most common problems are dilated cardiomyopathy and chronic heart failure.
Although dystrophin is needed in smooth muscle, DMD has fewer effects on smooth muscles. However, some
children with DMD do develop bladder paralysis or gastric dilation.
Many but not all children with DMD develop some degree of cognitive impairment. The actual cause is
not known but is thought to be related to the facr that some dystrophin is required in the brain.

Disease Variability
The symptoms and severity of DMD do not vary much, but those variabilities that do exist are believed to
be related to the type of mutation in the DMD gene. BMD has gteater variability, depending on how much
functional dystrophia is produced. Some men have few symptOms and are not diagnosed with the disorder
until they are 30 years of age or older.
Female carriers may express considerable symptoms if the healthy X chromosome is the one that is inactivated
more frequently in muscle cells. Generally, women who are carriers have more difficulty with cardiac issues than
with skeletal muscle. The theoretical basis for this common problem is that, whereas skeletal muscle strength
is adequate when only 50% of the cells are fully functional, adequate heart activity, especially left ventricular
function, needs at least 80% of the cardiac muscle cells to be fully functional. These women often develop
dilated cardiomyopathy and left ventricular failure at earlier than expected ages. Use of angiotensinogen-
converting enzyme inhibitors (ACEls) and/or beta blockers can help manage the cardiomyopathy, although
the problem is never cured (MDA, 2017).
Currently, no cure exists for DMD. Management focuses on corticosteroid therapy, which slows the rate
of muscle cell degeneration. Weight management is used to allow weaker muscles to maintain mobility for as
long as possible. Although moderate exercise is recommended, [00 much exercise causes faster muscle break-
down. Cardiac and respirarory suppon are also needed as the disease progresses. The major causes of death
are respiratory failure, pneumonia, and heart failure in the late teenage years or early adulthood. No therapy
prevents these outcomes; however, appropriate suppOrt can delay functional organ failure.

Classic Hemophilia
Classic hemophilia (hemophilia A) is a monogenic disorder in which the production of blood-clotting facror
VIII is either absent or well below normal levels. The disorder is inherited as an X-Linked single-gene trait and
is most common among males. The incidence of classic hemophilia worldwide is about 1 in 5,000 live births
of males (National Hemophilia Foundation (NHFJ, 2017a). Ir occurs at about the same rate in all races and
ethnicities. A less common form of hemophilia is hemophilia B, formerly known as Christmas disease (the first

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 Chapter 11 Common Childhood-Onset Genetic Disorders 221

child identified with this form of hemophilia had "Christmas" as his last name). The clotting factor affected
by this disease is factor IX, the gene for which is also located on the X chromosome.

Genetic Contribution to the Disorder

The gene for factor VIII is located on the X chromosome (Xq28) and is known as F8 (OMIM, 2016b).
This clotting factor (also known as antihemophilic foetor [AHFJ A and antihemophilic globulin (AHG» is one
of many synthesized in the liver that are required to be activated and work in a cascade-like series to form a
stable blood clot after blood vessel injury (Fig. 11-4). When factor VIII is activated, its purpose is to work
with other activated clotting factors and with von WiUebrand factor to form a complex of several activated
factors, platelets, and calcium. This complex is known as prothrombin activator, and its purpose is to activate
prothrombin to thrombin. Thrombin is an active enzyme that converts fibrinogen to fibrin molecules. Once
fibrin molecules are present, they then rapidly self-assemble into long strands that form a network or scaffold
that serves as the basic frame upon which platelets, proteins, and blood cells collect to create a stable clot
(Fig. 11-5). When little or no factor VIII is present, the cascade StOpSbefore it generates the complex needed
to activate prothrombin. As a result, fibrinogen is not converted to fibrin, the scaffold does not form, and
blood does not clot.

Formation of
----+ Villa -----+ prothrombin
~~a_cti_'v_a_to~r_co_m_p_l_ex
__ ~
~
Inactive Active
factor VIII factor VIII

Prothrombin
von Willebrand activator
factor complex

Inactive Active
factor IX factor IX

Fibrinogen
activated to fibrin

Inactive Active
factor X factor X Fibrin scaffold and
completed clot

Figure 11-4 Basic parts of the blood-clotting cascade. highlighting the roles of factor VIII
and von Willebrand factor.

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222 Unit III Genomic Health Problems Across the Lite Span

~ ?'_p_tid_e +
Fibrinogen Conversionof inactivefibrinogen Rbrin moleculewithout
into active fibrin by activated fibrinopeptides
thrombin

Self-assemblyof 5 fibrin moleculesforming a fibrin strand

Networkof fibrin strands formingthe scaffold for a blood clot

Figure 11-5 Activation of fibrinogen to fibrin and formation of the scaffold structure
upon which a stable blood clot can be generated.

The F8 gene is large, and a variety of mutations can impair irs function. Commonly, a unique, specific
mutation is responsible for the expression of classic hemophilia within a kindred. Mutation types include point
mutations, deletions, errors in messenger RNA splicing, and a problem in which the area of the X chromo-
some where F8 is located is inverted (OMIM, 20 16b). This essentially results in "backward" gene encoding
that cannot be transcribed or translated.

Inheritance Patterns
The FB gene is located on the X chromosome (Xq28). Because males have only one X chromosome, which is
inherited exclusively from their mothers, hemophilia has a sex-Linked {X-Linked}recessive transmission pacrern.
This pattern follows the same probability for the unaffected state, the affected state, and the carrier state, as
demonstrated in Figure 11-3 for Duchenne muscular dystrophy. Additionally, in about 25% to 30% of males
who have classic hemophilia, the mother is not a carrier, indicating that the spontaneous new mutation rate
for this gene is relatively high.

Signs and Symptoms

Babies born with classic hemophilia usually have no symptoms of excessive bleeding at birth, and many may
have only minimal bleeding in the immediate neonatal period, even when circumcised. Bruising and excessive
bleeding begin to occur in response to any trauma during infancy. The episodes of bleeding increase when
the infant begins to crawl and walk (because the child is not as protected from small environmental traumas
as he was when he was less mobile). Interestingly, petechiae do not form in areas of trauma and bruising.
In addition to hemorrhage, the most common problem associated with hemophilia is the extensive joint
damage that occurs in weight-bearing joints (hips, knees, and ankles), with spontaneous bleeding into the joint

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 Chapter 11 Common Childhood-Onset Genetic Disorders 223

from normal walking. Clorring factor replacement therapy provides hope that younger people with hemophilia
will no longer suffer this debilitating and activity-limiting damage.
The diagnosis of classic hemophilia is made first based on a history of excessive bruising and bleeding.
Clotting studies demonstrate a normal prothrombin time (PT) coupled with an abnormally prolonged partial
thromboplastin time (PTT). Blood levels of factor VIII are low to absent. Carriers can be identified by the
presence of lower-than-normal levels of factor VIII, longer-than-average PTT, and F8 gene sequencing to
determine the presence of the specific mutation identified within the family.
Female carriers commonly have excessive bruising and bleeding from low factor VIII levels. The amount
of factor VIII produced by carriers varies, depending on the percemage of liver cells that have the normal
F8 gene inactivated. Many have significantly less than 50% of normal factor VIII levels, but the amount
usually is more than enough to prevent spontaneous bleeding, major hemorrhage from trauma, and damage
from joint bleeding.

Disease Variability
The degree of excessive bruising and bleeding correlates with the abnormal levels of factor VIII. Patients
who have I% to 2% of normal factOr VIII levels have very severe disease and excessive bleeding. Those with
5% to 10% of normal factor VIII levels have moderate disease and bleeding. Those with 15% or higher of
normal factor VIII levels have only mild disease and episodic bleeding.
The only cure for classic hemophilia or hemophilia B is a liver transplant. The scarcity of this organ for
transplantation, the expense, and the dangers inherent in the procedure make this an uncommon form of treat-
ment. Synthetic forms of both factor VIII and factor IX are now available through the process of recombinant
DNA technology. This process virtually eliminates the danger of blood-borne disease transmission that existed
when the factors were obtained from pooled human serum (cryoprecipitate). Regularly scheduled infusions of
recombinant factor VIII have increased the life expectancy of a person with classic hemophilia from less than
5 years (in the early 20th century) to about 65 years (NHF, 2017a).

von Willebrand Disease

von Willebrand disease (VWD) is a monogenic disorder in which the affected person produces less-than-
normal amounts of von Willebrand factor (vWf). The disorder is inherited as an autosomal-dominant trait
and is the most common inherited blood-clotting disorder worldwide, with an incidence of 1 to 3 out of
100 live births (CDC, 2016b).

Genetic Contribution to the Disorder

The gene for von WiUebrand factor is VWF and is located on chromosome 12p13.3 (OMlM, 2013b). This
factor is produced by blood vessel endothelial cells and works with factor VIII as a "glue" that holds various
blood-clotting factors together to form the prothrombin activator complex needed to convert prothrombin
to thrombin in the blood-clotting cascade (see Fig. 11-4).
vWf also activates platelets. Although extensive blood vessel damage can change the production of vWf in
a body area, deficiency is really a genetics-based problem.

Inher~ance Patterns
Because the VWF gene is located on chromosome 12, the most common forms of the disorder are from muta-
tions inherited in an autosomal-dominant parrern. However, because of reduced penerrance, a family pedigree
can sometimes give the appearance of an autosomal-recessive parrern, although without a true carrier status.
However, with reduced penerrance, a person who does nor manifest the disorder can transmit the affected

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gene to his or her children, who then may express the disorder. In addition, the rarest form of the disorder,
which is also the most severe, is autosomal recessive.

Symptoms and DiseaseVariability

Three main rypes or categories of VWD exist, depending on the degree of von Willebrand factor produced
(NHB 2017b). In addition, each main type has many more subtypes.
Type 1 VWD is the most common, and people with this type have lower-than-normal circulating levels of
vWf. Although inherited in an autosomal-dominant pattern with reduced penetrance, variability is complicated
by blood type. People with the mutation who have the 0 blood type are more likely to express the VWD
phenotype (OMIM, 2013b), with mild to moderate bleeding intensity. The person has frequent nosebleeds,
occurring without trauma, that bleed for prolonged periods (more than 30 minutes). Excessive mouth bleeding
with tooth eruption, tongue biting, and after tooth extractions or aggressive dental work is common and may
require medical intervention to stop, Skin lacerations cause bleeding for 30 minutes or longer. Large bruises
form with minimal trauma. In girls who are menstruating, menstrual Row is heavy and may cause anemia.
Many children and adults in this category remain undiagnosed.
Type 2 VWD, the second most common form, also is inherited in an autosomal-dominant pattern. This
type is associated with abnormal or defective vWf, even though the amount produced is normal. Syrnptorns
range from mild to moderate, depending on the type of defect in vWf. It is often the most difficult to diag-
nose because the vWf levels are normal, and further testing is required to determine the specific subtype. In
addition, among the different subtypes, levels of vWf may not correlate to disease severity.
For both types 1 and 2, affected individuals may not be diagnosed during childhood because symptoms are
not viewed as serious, others in the family have the same problems and have learned how to manage them, or
too few serious bleeding episodes have occurred in the younger years. Heavy menstruation and postpartum
bleeding are often the triggers for investigating a genetic cause in young adulthood.
Type 3 VWD is the rarest and has the most serious bleeding problems. The levels of vWf are extremely
low, and bleeding is so excessive that the person may first be thought to have hemophilia. This form of the
disorder has an autosomal-recessive pattern of inheritance.
Mild to moderate symptoms of VWD are managed with desmopressin injections or nasal spray. This
synthetic analog of vasopressin increases both vWf levels and, to some extent, factor VIII levels. It is believed
to do this by releasing preformed factors from cellular storage sites. The effect is rapid but temporary. When
bleeding is severe, caused by eype 3 VWD, or fails to respond to desmopressin therapy, the patient may need
infusions of plasma with concentrated levels of vWf.

Achondroplasia
Achondroplasia is a monogenic disorder of human shore-limbed dwarfism that occurs because of a mutation
in the FGFR3 gene that codes for the fibroblast growth factor receptor 3. It is the most common disorder of
dwarfism and occurs in all races and ethnicities at an incidence rate of about 1 in 15,000 to 40,000 live births
(National Institutes of Health [NIH], 2017). The word achondroplasia literally means "without cartilage." This
designation is not accurate because people with achondroplasia do have normal cartilage in appropriate locations.
However, bone formation starts with cartilage in the embryonic stage, which then hardens (ossifies) to become
bone. Problems in the formation and growth of the long bones result from mutations in the FGFR3 gene.

Genetic Contribution to the Disorder

Although short stature and disordered bone growth can have environmental causes, achondroplasia is direcdy
caused by a mutation in the FGFR3 gene. Normally, the product of this gene is a protein that is involved in

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 Chapter 11 Common Childhood-Onset Genetic Disorders 225

the development and maintenance of bone (and brain) tissue. It is a receptor that limits the formation of bone
from cartilage, especially in the long bones. Two specific point mutations are responsible for 99% of all cases
of achondroplasia. Either of these mutations results in the substitution of the amino acid arginine for glycine
in position 380 of the protein (OMIM, 20 13a). The protein produced by this mutation is an excessively active
receptor for fibroblast growth factor, which results in shortened long bone growth during embryonic and fetal
life. Other bones, including those that compose the trunk and face, are less affected.

Inher~ance Patterns
The FGFR3 gene is located on chromosome 4p 16.3 and, in about 10% to 15% of cases, is inherited in an
autosomal-dominant pattern of transmission (OMIM. 2013a). However. this large gene has a high rate of
spontaneous new mutations, and close to 80% of affected children do nor have a parent with achondroplasia.
The spontaneous new mutations arise most often due to advanced paternal age. The disorder is highly pen-
etrant. The homozygous condition is associated with excessive pregnancy loss and mortality in the neonatal
period (NIH, 2017).

Signs and Symptoms

The initial appearance of achondroplasia in a newborn is striking. The infant's head and tOrSOappear generally
normal, but the extremities are disproportionately short. These proportions are maintained throughout life.
although the head is large (Fig. 11-6). The humerus and femur are more disproportionately short than are
the lower arms or legs. The skin and soft tissues on the arms and legs form extra creases (as if the skin and
soft tissue are longer than the bones). The neck is very short with an abnormal junction between the poste-
rior head and neck. This abnormality can compress the cervical spinal cord and is believed to be a factor in
the common occurrence of sleep apnea in these individuals. In addition, infants with achondroplasia have a
higher incidence of sudden infant death syndrome (5[D5) than children without achondroplasia. which may
be attributable to the abnormal head and neck junction or to stenosis of the opening in the skull through
which the spinal cord exits (fommen magnum). The face has a large and prominent forehead (bossing). The
midline of the face is somewhat less developed than the upper segments. Intelligence and cognitive function
have the same ranges as seen in the general population.
Most children with achondroplasia have delayed motor development. As they grow. the teeth are crowded.
and poor bite commonly occurs. Otitis media is a frequent occurrence because of the position of the Eusta-
chian tubes within the less developed facial midline. When the child starts to walk. an exaggerated lordosis
spinal curvature develops (Fig. 11-7).
Achondroplasia cannot be cured. Reconstructive surgery can alter the physical appearance. Bone-lengthening
surgery can increase overall height. making the everyday activities of adults with achondroplasia a little easier,

Figure 11-0 Physicalappearance of an infant with achondroplasia.

(Used with permission from Schaaf. CP; Zsdiocke, J; Potocki,
L. Basiswissen Humangenetik. Berlin Heidelberg: Springel'Verlag, 2008,
2013.)

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226 Unit III Genomic Health Problems Across the Life Span

Figure 11-7 A comparison between a typical Typical male Male wilh growth Malewith
adult male, someone with adtondroplasia dwarf- (72 inches tall) hormone deficiency achondroplasia
ism, and a man who had growth hormone (52 Inchestall) dwartism
deficiency. (48 inchestall)

although this practice is controversial (Shirley, 2009). Injections with growth hormone are minimally effec-
tive (or not at all) at increasing height because these individuals are not deficient in growth hormone. Weight
control is advised to reduce stress on hip and leg joints and to prevent obstructive sleep apnea.

Disease Variability
Most of the physical features of achondroplasia are present in all individuals who have the disorder. One
variable feature is hydrocephaly. This occurs in some but not all children with the disorder. If hydrocephaly
is not corrected, brain damage results.

COMPLEX DISORDERS
Complex disorders are those that require both genetic and environmental input to develop. The genetic
input increases the individual's suscepribiliry co developing the health problem, but unless one or more specific
environmental triggers occurs at the right time, the problem may never develop. In many cases, the genetic
component of complex disorders involves more than one gene, and these are often not identified. Two common
complex disorders that manifest in childhood are rype 1 diabetes mellitus and asthma.

Diabetes Mellitus Type 1

Cells require glucose to generate the chemical energy needed to perform all cellular work. Glucose comes
from the carbohydrates we eat and from liver production of glucose. To be used as cellular fuel, glucose must

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 Chapter 11 Common Childhood-Onset Genetic Disorders 227

enter cells even though many cells have membranes that are impermeable to glucose. This is where insulin is
needed. In addition to the digestive portion of the pancreas, the endocrine portion contains about 1 million
small glands, known as the islets of Langer halls, scattered through the organ. Within these islets are beta cells
that produce and release insulin when blood glucose levels are elevated (hyperglycemia). Insulin enters cir-
culation and binds to insulin receptors on cell plasma membranes. The result of insulin binding to an insulin
receptor is a change in the membrane structure so that glucose can cross the membrane and enter the cell for
metabolic purposes.
Insulin's main function is related to carbohydrate metabolism by preventing hyperglycemia. Other func-
tions of insulin are related to the regulation of fat and protein metabolism. Table 11-2 lists the body's positive
responses and actions to the presence of insulin.
Diabetes mellitus type 1 (also known as type J diabetes) is an autoimmune, metabolic, endocrine disor-
der in which insulin-producing cells in the pancreas have been destroyed such that the person can no longer
synthesize insulin to prevent hyperglycemia. An autoimmune disease is one of inAammation and immune
action excess in which components of a person's immune system no longer recognize the person's own cells,
tissues, and organs as "self" and attack them as if they were invading organisms. The predisposition to devel-
oping an autoimmune response leading to diabetes mellitus type 1 is inherited; however, expression of the
autoimmune disorder requires additional input from the environment. In addition, although the incidence of
such disorders is higher in some families than in the general population, it does not follow any specific pattern
for single-gene inheritance. Usually, diabetes mellitus type 1 as an autoimmune disease manifests in childhood,
sometimes as early as age 4 to 6 weeks, although this young age at onset is rare (Rich & Concannon, 2015).

Genetic Contribution to the Disease

Diabetes mellitus type 1 has a high rate of concordance in monozygotic twins, which suggests a relatively
strong genetic contribution (Stankov, Bene, & Draskovic, 2013). Susceptibility to the development of diabetes
mellitus type 1 as an autoimmune problem is partially determined by the inheritance of certain human leu-
kocyte antigen (HLA) genes coding for a specific tissue type located on chromosome 6. The tissue types most
closely associated with an increased risk for diabetes mellitus type 1 are the HLA-DR and HLA-DQ tissue
types (remember that the tissue type is expressed on all your cell membranes and serves as a unique universal
"product code" for you) (Rich & Concannon, 2015; Steck er al., 2013). However, even though inheritance of
these particular tissue types increases the risk for autoimmune responses, most people with these tissue types
do not develop diabetes mellitus type 1 or any other autoimmune disease.

.. ,~:t~.m~ _

Positive Physiological Responses to the Presence of Adequate Insulin Levels

Prevention of hyperglycemia
Increased amino acid uptake by cells
Increased production of cellular proteins
Decreased muscle cell breakdown
Increased cell division
Increased liver storage of excess glucose as glycogen
Movement of fats, especially triglycerides and cholesterol, out of the blood and into fat cells (reduced
blood lipid levels)

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The overall risk for developing any autoimmune disease

So Why Doesn't Everyone or Even Most
of the People Who Have That Tissue Type in the general population is about 1%. In examining
Develop an Autoimmune Disease? 100 people who have any autoimmune disease,especially
whites, at least 90 of them also will have the HLA-DR and
The risk is present for all of them, but unless at least
one environmental event occurs at a particular time, HLA-DQ tissue types (Stankov et al., 2013). However,
the risk does not lead to disease expression. Actual if we checked 100 people who have the HLA-DR or
expression or development of the disease requires HLA-DQ tissue type, only about 2% of them also have an
that an environmental factor must interact with the autoimmune disease. So, having an HLA-DRor HLA-DQ
genetic predisposition (increased susceptibility). tissue type doubles the risk for developing an autoirn mune
disease (from 1% to 2%), but the risk is still low.
The risk for diabetes mellitus type 1 in the general population ranges from 1 in 400 to 1 in 1,000. This
risk increases to 1 in 20 for those people who have one parent with diabetes mellitus type 1 or another
autoimmune disorder.
In addition to specific tissue types increasing the risk for the development of autoimmune disease, other
no n-Hl.A genetic variations may also increase this risk (Stankov ec aI., 2013; Steck et al., 2013). These varia-
tions and mutations have been found in the insulin gene (INS) and in the PTPN22 and UBASH genes. The
products of both genes normally help control the activity of immune system cells. Decreased or loss of function
of either gene could promote immune excess. Genome-wide association studies (GWASs) that examined the
DNA sequences from large numbers of people who have specific health problems (in this case, autoimmune
diseases) and consistent single nucleotide polymorph isms, particularly on chromosomes 6 and 18, showed an
association with type 1 diabetes, Crohn disease, and inAammation (Hindorlf et al., 2009). Although these
associations are not strong, and some occur in regions where no genes have yet been identified, their potential
common role in autoimmune disease development needs to be explored.

Environmental Contribution to the Disease

Although type 2 diabetes is an autosomal-dominant inherited disorder that requires a genetic contribution for
expression, type 1 and type 2 diabetes are not genetically linked or co-inherited. In addition, obesity and a
sedentary lifestyle do not increase the risk for diabetes mellitus type 1 but strongly influence the development
of type 2 diabetes. The most common environmental cause associated with diabetes mellitus type 1 appears
to be related to certain viral infections, such as mumps, rubella, and Coxsackie virus infection, which trigger
autoimmune destruction of pancreatic beta cells (Srankov et al., 2013). In the typical course, the child becomes
ill with a viral infection, such as Coxsackie B4. Symptoms of this viral infection include fever, headache,
sore throat, gastrointestinal distress, and muscle aches. The child is sick for 3 to 5 days and then recovers in
seemingly good health. However, about 6 weeks later, the child appears thinner and is constantly hungry and
thirsty. He or she is tired and does not engage in his or her normal activities. The child also remarks about
needing to urinate frequently. The parents notice a change in behavior and decide to consult their health-care
provider. A random check of blood glucose level reveals a value of 340 mg/dL (normal is less than 140 mgt
dL). Other tests are made, and the child is diagnosed with diabetes mellitus type 1. The mother tells the
health-care provider that her twin sister has had diabetes since age 5.
How a Viral Infection Leads to Diabetes
First, when a virus infects the body, it invades many individual cells. The virus uses the cell's internal mecha-
nisms to make more viruses, including breaking and entering the cell's DNA. As a result, the infected cell
expresses some viral proteins on its surface. White blood cells, especially natural killer cells (NK cells or CD 16
cells), recognize the viral signal on the infected cell's surface and exert cytotoxic actions against the infected
cell. The plan is to destroy the infected cell and all irs viral contents to prevent the infection from spreading

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throughout the body. When the Coxsackie B4 viruses infect the body, they also infect the beta cells of the
pancreas, where insulin is produced. The viruses do not directly kill or even really damage these cells; rather,
the person's own white blood cells (natural killer cells) take out the infected body cells. Unfortunately, when
most or all beta cells of the pancreas are infected, they are all attacked and can be destroyed by the immune
system cells. Biopsy of the pancreatic tissue at that time will show insulitis, which is infiltration of the islet
cells by white blood cells, resulting in inAammation of these cells. In addition, other immune system cells
make antibodies against the islet cells (islet cell autoanribodies). The islet cells, including the beta cells, die,
and the islets become fibrotic and nonfunctional over time. The pancreas weighs less because of fibrosis
replacing glandular tissue.
When enough of the islet beta cells have been destroyed by inflammatory and immune responses, the
pancreas no longer produces insulin. The person has symptoms of hyperglycemia, and islet cell autoantibodies
can be detected in the blood, along with other markers of inAammation.
Although infection with the Coxsackie B4 virus is known to lead to islet cell autoimmune destruction and
beta cell loss, it is not the only infectious organism that can stimulate this reaction. Only a small percentage of
people who become infected with the virus go on to develop islet cell destruction and diabetes. Most recover
without islet cell damage. Only those people who have a genetic predisposition or susceptibility respond to
the infection this way. Proposed mechanisms include that their immune systems overreact and respond inap-
propriately by attacking and destroying self cells, even though they are virally infected. Another proposed
mechanism is that the islet cells of some people are less resistant to infection and more easily express proteins
of the infecting virus, making these cells better "targets" for immune system attack.
Other Factors
Interestingly, even among people with increased genetic susceptibility to islet cell damage from a viral infec-
tion, the timing of the environmental event that can trigger the self-cell destruction also affects the outcome.
Apparently, some periods of life are a window of increased susceptibility to a gene-environment interaction
leading to autoimmune disease, such as early childhood for diabetes mellitus type 1. If the environmental
exposure occurs much later than this age window, the disease does not result. The "window of susceptibility"
is speculated to be different for specific diseases and may, in facr, be different among individuals. In addition
to the timing of exposure to a criggering event, gender also makes a difference in susceptibility. Females are
affected by autoimmune disease about four times more often than males. The basis of this gender difference
is not known.
Other evidence for a gene-environment interaction that stimulates an autoimmune response against islet
cells includes the association of diabetes mellitus type 1 with allergy to cow's milk. (This is a true allergy to
the milk proteins, not lactose intolerance. The person with a milk allergy has circulating antibodies directed
against cow's milk proreins.) In addition, many people who have diabetes mellitus type 1 also have another
autoimmune disease or have other first-degree relatives who have an autoimmune disease. Table 11-3 lists
examples of disorders that have an autoimmune componenr.
More recent investigation has focused on epigenetic influences on development of diabetes mellitus
type 1. Increases in DNA methylation, histone modification, and microRNA dysregulation have been found
in individuals with diabetes mellitus type 1 who have no other obvious risk factors for the disease (Srankov
et al., 2013).

Signs and Symptoms

The person who has diabetes mellitus type 1 has a serious lack or absence of insulin and must inject insulin
from other sources for the rest of his or her life. The initial symptoms of diabetes mellitus type 1 are related
to the lack of insulin and the resulting hyperglycemia. The high blood glucose levels increase blood osmolarity,

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Examples of Disorders With an Autoimmune Basis

Addison disease (chronic adrenal insufficiency)

Alopecia areata
Autoimmune thrombocytopenia purpura
Celiac disease
Crohn disease
Dermatomyositis
Diabetes mellitus (type 1)
Hashimoto thyroiditis (hypothyroidism)
Goodpasture syndrome
Graves disease (hyperthyroidism)
Guillain-Barre syndrome
Multiple sclerosis
Myasthenia gravis
Pernicious anemia
Psoriasis
Rheumatoid arthritis
Scleroderma
Sjogren syndrome
Systemic lupus erythematosus
Ulcerative colitis

stimulating thirst. The person starts ro drink much more than normal (polydipsitt), and most often, the person
craves water. The increased water intake coupled with the increased osmolariry of the blood drawing inter-
stitial fluid into the vascular space leads to excessive urinarion (polyuria). Although the blood glucose levels
are high, little glucose enters cells, making the person feel hungry and tired. In response, he or she eats more
(polyphagia) but does nor gain weight (in fact, loses weight). The fatigue leads to increased sleepiness and a
loss of interest in usual activities, If the condirions continue, the person starts using fats for cellular fuel. A
by-product of fat breakdown is the formarion of ketone bodies, which are acidic. When these products become
excessive in the blood, the person experiences diaberic ketoacidosis, a life-threatening condition that requires
careful insulin therapy to resolve.
When a person uses insulin from other sources rather than from his or her own pancreas, blood glucose
levels can fluctuate widely, and chronic hyperglycemia is common. The effects of long-term hyperglycemia
dramatically change blood vessels, generally thickening their basement membranes and making vessel walls
more fragile, so the exchange of nutrients and waste products at the tissue level is reduced. Over rime, cells
in many organs are damaged from chronic hypoxia and the buildup of waste products. Complications result
from poor tissue circulation and cell death. When enough cells in any organ are damaged beyond repair, the
organ fails to funcrion. The long-term results of hyperglycemia are the same whether the hyperglycemia is
caused by diabetes mellitus rype 1 or 2 (see Chapter 12). For most people with diabetes, the cause of death

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 Chapter 11 Common Childhood-Onset Genetic Disorders 231

Long-Term Consequences and Complications

of Diabetes

Atherosclerosis
Bladder atony
Cataract formation
Cerebrovascular accidents
Charcot foot
Coronary artery disease
Dysphagia
Erectile dysfunction
Gastroparesis
Hyperlipidemia
Hypertension
Increased risk for infection
Increased risk for lower limb gangrene with progressive
amputation
Myocardial infarction
Nephropathy and kidney failure
Orthostatic hypotension
Peripheral neuropathy
Poor intestinal peristalsis
Poor wound healing, stasis ulcers
Retinopathy leading to blindness

is from the organ complications of the disease rather than from the diabetes itself. Table 11-4 lists the many
long-term consequences and complications of the chronic hyperglycemia associated with diabetes. Maintain-
ing good conrrol over blood glucose levels, which means keeping the level within the individual target range
through drug therapy, diet, and exercise, can delay or even prevent these serious complications.

Asthma
Breathing to inhale oxygen is a vital function. Entrance of oxygen into the blood occurs deep within the lungs
at the alveolar-capillary membrane. The tubular structures (airways) of the upper aerodigesrive tract and lungs
are critical to moving air into and out of the alveoli (ventilation) so oxygen can enter the body and carbon
dioxide, a waste gas formed during metabolism, can exit. For ventilation to be effective, the airways must be
patent and of a sufficient internal diameter to allow free airflow.
Asthma is a chronic inflammatory disease of the airways that is usually characterized by intermittent
periods of reversible airflow obstruction. (For some people, some degree of airway obstruction is always
present, but this is nor common.) The intermittent episodes are commonly called asthma attacks. Asthma
can result from one or a combination of three possible mechanisms: (I) constriction of the smooth muscles

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surrounding the smaller airways, (2) swelling of the mucous membranes lining the airways, or (3) excessive
mucus collecting in and plugging the airways. The most common type of asthma is atopic asthma, which
is a hypersensitivity reaction (allergic response) involving the release of immunoglobulin E (IgE). This type
of asthma can have anyone or even all three mechanisms occurring at the same time. It usually begins
in childhood and is often present in more than one family member. Because of this familial connection,
asthma was once thought to be a learned, attention-getting behavior. This misconception has been pretty well
debunked for all asthma, especially atopic asthma, in which specific chemical and laboratory changes can be
identified.
Most people have mild to moderate asthma that can be controlled easily with proper drug therapy and the
avoidance of environmental triggers. A severe arrack, however, can greatly impair gas exchange. More than
3,600 deaths from asthma occur yearly in the United Stares alone (CDC, 2016a).

Genetic Contribution to the Disease

The observation that asthma appears to "run in families"
So, Who Was Right, and Which Genes Are
has been noted for years and suggestS a possible genetic Involved in Atopic Asthma?
influence in its development. Studies conducted more
Between 50 and 100genomic variationsare known
than 20 years ago provided evidence to support this
to be consistently associated with development
suggestion, although opinions differed on the degree of of atopic asthma (OMIM, 2015; Weiss. Raby, &
heritability. As early as 1997, scientists proposed possible Rogers. 2009).
candidate genes as those in which mutations were most
likely to result in increased expression of asthma (Holgate, 1997).
Some have greater influence than others, especially within certain racial or ethnic groups, and may act alone
in causing asthma. Others, although consistent, appear to have lesser influence and may require a "group effort"
for atopic asthma expression. Common areas of identified genomic variation associated with atopic asthma
include lq31 (especially among African Americans and Euro-Americans): Ip32 (especially among Hispanic
Americans); Sq31, 6p21 (especially among Euro-Arnericans): 8p23, IIq21 (especially among African Ameri-
cans); and 12q22, ISqI3, and 17q21 (especially among Euro-Arnericans) (Moheimani et al., 2016; OMIM,
2015; Sieiman er al., 2010). Many of these areas are where the genes coding for proteins that are important
in regulating inflammatory reactions and immune responses are located
The strongest associations currencly identified with susceptibility to asthma involve single-nucleotide
polymorphisms of the DENNDIB gene, the GSDMB gene, and the ORMDL gene. DENNDI B produces
a protein strongly active in the secretion of the inflarnmarory protein rumor necrosis factor (TNF), espe-
cially in macrophages and mast cells. Both cell types are involved in nonspecific inflammatory responses
and in acquired (adaptive) immune responses that develop individually in susceptible people when they are
exposed to an allergen. Some of these acquired responses are mediated by the antibody IgE along with various
intracellular inflammatory biochemicals (e.g., histamine, bradykinin, rumor necrosis factor, inrerleukin 13
[ILl3]).
GSDMB produces a protein that is important in epithelial cell function, including those of the airways
(Zhao et al., 2015). Mutations in this gene may increase the responsiveness of these airway ceLIsto irritants.
ORMDL3 produces a family of proteins important in regulating calcium levels in the endoplasmic reticulum
of inflammatory and epithelial cells. Changes in the levels of this protein are associated with inducing inflam-
mation. The asthma-associated responses of mutations in these genes appear to vary with erhniciry (Zhao
et al., 2015).
The major generic/genomic issues of asthma are, as suspected decades ago, an increased responsiveness of
airway tissues when contacted with an environmenral irritant (hyperresponsiveness) and an increased amount

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 Chapter 11 Common Childhood-Onset Genetic Disorders 233

of the mediators of inflammation, especially immunoglobulin E (IgE). In addition, asthma is more common
among people who have the DR and DQ HLA subtypes (Moheimani et al., 2016).

Environmental Contribution to the Disease

All people have airways that respond with bronchoconsrriction and inflammation to contact with major irri-
tants in the air we breathe, such as heavy smoke or chemical particles. The presence of these irritants stimu-
lates nerve fibers in airway tissues, causing constriction of bronchial smooth muscle. However, children with
hyperresponsive airways have these reactions even when only a small amount of irritant is presen t, Common
environmental irritants that make airways respond with constriction of bronchial smooth muscle include cold
air, dry air, or fine airborne panicles; microorganisms; aspirin; and exercise that increases the respiratory rate.
For the allergic (hypersensitivity) responses of swelling of the mucous membranes and producing excessive
amounts of mucus, the immune system must adapt and learn how to release mediators of inflammation and
IgE rapidly in response to the presence of a specific environmental allergen. Immune system "learning" is a
complex process that starts with exposure to a particular substance (which substances a person becomes aller-
gic to can be unique to the person, although many common allergens exist). This ability to produce IgE as a
response to exposure to an allergen and the degree of response is genetically controlled and related to genomic
variations; however, the exposure needed to start the process is environmental.

Signs and Symptoms

The tissue changes that lead to narrowing of the airways start at the cellular level in the person who has a
genetic variation and result in airway hyperresponsiveness. Environmental triggers come into contact with the
airway tissues, and they respond by constricting the bronchial smooth muscle.
The inflammatory and immune responses to the presence of an allergen involve different airway tissue
changes. The allergen, which is most commonly inhaled but can enter the body in other ways, binds to spe-
cific antibody molecules, especially IgE. These molecules are attached to mast cells and basophils. These cells
are filled with granules conraining biochemicals such as histamine, which start an immediate inflarrunatory
response that dilates blood vessels, increases capillary leak, and causes the mucous membranes to swell and
produce large amounts of mucus. These cells also secrete other biochemicals that prolong the inflammatory
responses. In addition to stimulating tissue inflammation, these substances attract more eosinophils, macro-
phages, and basophils to the area, causing the release of even more inflammatory-inducing mediators. When
the tissue swelling and/or mucus production is extreme, the airways can be blocked internally. Usually, these
tissue responses also stimulate nerve endings in the airways and result in constriction of the bronchial smooth
muscle, causing external airway obstruction in addition to internal airway obstruction.
Most children with atopic asthma have no symptOms between asthma attacks but often have other allergic-
type problems, including rhinitis, skin rash, or itching. During an asthma arrack, the child has some difficulty
breathing along with chest tightness, coughing, wheezing, and increased mucus production. Audible wheezing
is the most common recognizable symptom. At first, the wheeze is louder on exhalation, but, as the attack
worsens, loud wheezing also is heard on inhalation. The respiratory cycle (one inhalation followed by one
exhalation) is longer and requires more effort, especially exhalation. Usually, when the attack is severe and the
work of breathing increases, the child uses the accessory muscles. This response shows as muscle retractions
at the sternum, the suprasternal notch, and between the ribs. Shortness of breath may become so intense that
the child can speak only a few words between breaths. The Lipsand nail beds may show cyanosis.
Pulse oximetry shows hypoxia with oxygen saturation below 90%. A peak-flow meter reading shows a
decrease in peak flow below the child's usual value. The arterial oxygen level {Pao~ decreases during a severe

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asthma attack, and the arterial carbon dioxide level (Pacoj) rises. Other laboratory tests obtained during an
atopic asthma attack commonly show an elevated serum eosinophil count and IgE levels.

SUMMARY
Common monogenic disorders that usually manifest in childhood include sickle cell disease, cystic fibrosis,
Duchenne muscular dystrophy, hemophilia, von Willebrand disease, and achondroplasia. Those that have
obvious anatomic manifestations, such as achondroplasia, or those that show other problems early, such as
sickle cell disease, cystic fibrosis, and hemophilia, may be diagnosed within the first few weeks or months of
life. Patterns of inheritance are clear, although disease expression can vary considerably. Some of these disorders
have such severe associated problems that death in childhood was common. At present, even though most dis-
orders cannot be cured, berter supportive care has resulted in people with these disorders living into adulthood.
The complex disorders of diabetes mellitus type I and atopic asthma have less identifiable genetic origins
and considerable variability in susceptibility. They both require an interaction with environmental factors for
disease expression.

GENE GEMS

• Sickle cell disease (SCD) and sickle cell trait have a far greater incidence in East Africa and other
equatorial countries.
• SCD results in most of a person's hemoglobin being HbS instead of normal adult hemoglobin (HbA).
• HbS does bind oxygen in the same way that HbA does; however, HbS is very sensitive to low tissue
levels of oxygen and makes the red blood cell pull inward, forming a sickle shape when tissue oxygen
levels decrease.
• A person with sickle cell trait can form sickled red blood cells, bur rhe degree of hypoxia must be severe
and prolonged for this to occur.
• The genetic mutation that causes SeD is the same for every person who has the disease, does not arise
spontaneously, and is the most stable of the disease-causing mutations.
• Genetic testing is not needed for the diagnosis of SeD.
• Pain is the most common symptom associated with SeD.
• Two additional genetic factors that moderate SeD effects are a higher percentage of fetal hemoglobin
(HbF) and the coexisting presence of alpha-thalassemia, another genetic disease.
• Carriers for SeD have an inherent reduced susceptibility to death from malarial infection.
• Cystic fibrosis (CF) is most common among Caucasians from Northern and Western Europe, although
it can be found in any race or erhniciry,
• More than 1,700 mutations in the cystic fibrosis gene (CFTR) have been identified and are thought to
be responsible for the extreme variation in expression of disease severity.
• The most common clinical test used to diagnose CF is the sweat chloride test, Genetic testing is used
to identify carrier status, specific mutations, and an affected fetus.
• Carriers of CF appear to have an inherent reduced susceptibility to death from typhoid and cholera.
• Duchenne muscular dystrophy (DMD) is the most common inherited muscle-degrading disease; a
milder form is Becker muscular dystrophy (BMD).
• DMD is an X-linked recessive disorder that affects males more severely and more commonly than females.

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 Chapter 11 Common Childhood-Onset Genetic Disorders 235

• The DMD gene is the largest gene in the human genome and is very susceptible to mutation, including
a high percentage of spontaneous mutations.
• The spontaneous mutation rate for the large gene responsible for classic hemophilia (the F8 gene) is high.
• Many different mutations of F8 can cause hemophilia, and these may vary trom family to family, making
genetic testing for hemophilia more difficult.
• Most forms of von Willebrand disease (VWD) are inherited as an autosomal-dominant trait, and it is
the most common inherited blood-clotting disorder worldwide.
• Most people who have VWD have the mildest form and commonly have never been diagnosed with
the disorder.
• Two specific point mutations in the FGFR3 gene are responsible for 99% of all cases of achondroplasia.
• The FGFR3 gene is very large, and at least 80% of achondroplasia is a result of spontaneous new muta-
tions associated with advanced paternal age.
• Most children with achondroplasia have delayed motor development and normal intellectual development.
• Obstructive sleep apnea is a potentially lethal complication of achondroplasia.
• Diabetes mellitus type I is an autoimmune disease that results from an increased genetic susceptibility
coupled with an environmental trigger, most commonly a viral infection.
• The tissue types most associated with diabetes mellitus eype I, asthma, and other autoimmune diseases
are the HLA-DR and HLA-DQ tissue types.
• People who have the HLA-DR and HLA-DQ tissue types are twice as likely to develop an autoimmune
disease than the general population, but the risk is still low (2%).
• A person with diabetes mellitus type 1 has a loss of pancreatic islet cells and produces no insulin.
• Unlike type 2 diabetes, obesity and a sedentary lifestyle have no role in the development of diabetes
mellitus type I.
• The chronic hyperglycemia and hyperlipidemia associated with any type of diabetes are responsible for
pathological changes starring at the blood vessel level in almost all tissues and organs.
• Asthma is an airway disease problem and does not cause changes in the alveoli.
• Genome-wide association studies link variations in 50 to 100 genes to increased risk for developing
atopic asthma.
• Gene variations most strongly associated with asthma differ among races and erhnicities.
• The major genetic/genomic issues of asthma are an increased responsiveness of airway tissues when
contacted with an environmental irritant (hyperresponsiveness) and an increased amount of the media-
tors of inflammation, especially immunoglobulin E (IgE) .

...
Self-Assessment Questions .
1. For which genetic problem does the heterozygous state confer an advantage?
a. Achondroplasia
b. Diabetes mellitus eype 1
c. Classic hemophilia
d. Sickle cell trait
Continued

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236 Unit III Genomic Health Problemskross the Lite Span

2. Which of the autosomal-dominant genetic disorders has the highest penetrance?

a. Achondroplasia
b. von Willebrand type I
c. Diabetes mellitus type 1
d. Duchenne muscular dystrophy
3. A 16-year-old girl whose older sister just had a baby boy diagnosed with hemophilia is pregnant with
a male fetus. Her boyfriend (the baby's father) does not have hemophilia and does not have any rela-
tives with the disorder. She asks what the chances are that her son could be affected. What is your
best response?
a. "Because it is likely that you are a carrier and your boyfriend does not have any affected relatives,
only your daughters can develop the disease."
b. "Because you may be a carrier and your boyfriend does not have any affected relatives, your son
will not have the disease but could also be a carrier."
c. "Because your sister's baby has hemophilia, the risk for your children having the disorder is 50%
wi th each pregnancy."
d. "Because we do not know your carrier status for the disease, we cannot predict whether your son
will have hemophilia."
4. Why are some women who are carriers for Duchenne muscular dystrophy (DMD) at risk for cardiac
disease, especially cardiomyopathy?
a. They have more fatty tissue in the heart than do men.
b. The DMD gene is located very close to the main gene for cardiac function.
c. Cardiac muscle requires 80% active dysrrophin to maintain cardiac muscle function.
d. Having a child with DMD who is not very mobile increases the workload on the mothers' hearts.
5. A son with classic hemophilia is born to parents with no family history of the disease. Genetic testing
reveals that the mother does not have the mutation on either of her X chromosomes. What is the
most likely explanation for the son's disorder?
a. The son is not biologically related ro the mother.
b. One of the mother's ova had a spontaneous mutation of the X chromosome.
c. One of the father's sperm had a spontaneous mutation of the X chromosome.
d. The son's DNA underwent a spontaneous mutation during the second trimester of pregnancy.
6. What is the most likely cause of a child with achondroplasia being born to a couple with a normal-
stature phenotype?
a. Expansion of maternal trinucleotide repeat sequences within the FGFR3 gene during gametogenesis
b. Incomplete penerrance of the autosomal-dominant FGFR3 gene
c. Random X-chromosome inactivation in a carrier mother
d. Advanced parental age at conception
7. Which common childhood disorder requires a genetic contribution and a significant environmental
contribution to develop fully?
a. Achondroplasia
b. Sickle cell disease
c. Diabetes mellitus type 1
d. von Willebrand disease

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 Chapter 11 Common Childhood-Onset Genetic Disorders 237

8. Which factor or condition suggestS a strong genetic contribution to the development of diabetes
mellitus rype I?
a. Monozygotic twins show a high concordance of the disease.
b. Most individuals with the disease are diagnosed before age 20 years.
c. A large percentage of affected individuals are both obese and have a sedentary lifesryle.
d. The disorder occurs most often in children born to parents who are advanced in age at the time
of conception.
9. Which types of genes have been implicated in the development of childhood asthma?
a. Genes controlling mucus production
b. Genes involved in inflammatory responses
c. Genes important in the growth of lung alveoli
d. Genes that produce proteins needed to break down inhaled pollutants

CASE STUDY

Edward is a 32-year-oldman who has had diabetes mellitus type 1 since he was 8 years old. His identical
twin brother also has the disease,as did his paternalgrandmother.Edward's wife, Ellen, had gestational
diabetes when she was pregnant with their son (Frank),who is now 5 years old. Ellen's older sister and
her mother also had gestational diabetes. Her mother now has diabetes mellitus type 2. Frankis being
evaluatedyearly by his pediatricianfor signs and symptoms of diabetes. Currently, he has no indication
of the disease,
1. Draw the pedigree and indicate any obvious pattern of inheritance.
2. Does Ellen'sfamily history of gestationaldiabetes and type 2 diabetes increaseFrank'srisk for
development of diabetes mellitus type 1? Explainyour response.
3. Is the concern that Edward'sand Ellen'sson may develop diabetes mellitus type 1 valid?
4. Can Frank'sparents do something to prevent the development of diabetes mellitus type 1?

References

Centers for Disease Control and Prevention. (2015). Sick/" Ct!/Ldisease: Data and statistics. Retrieved from http://www.cdc.gov/
ncbddd/sicklecell/data.htmi
Centers for Disease Control and Prevention. (2016a). Asthma. Retrieved ITomhttps://www.cdc.gov/asthmal
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dara.hrrnl
Cystic Fibrosis Foundation. (2016). What is CF? Retrieved from https://www.clf.org
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of epithelium in asthma. Respiratory Research, 17, 119-134.

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Muscular Dystrophy Association. (2017). Facts about Duchenne lind Becker muscular dystrophies: DMD lind BMD. Retrieved
from hrrps:llwww.mdsusa.org
National Hemophilia Foundation. (2017a). Bluding disorders: Hemophilia A_ Retrieved from https:llwww.hemophilia.org/
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National lnsrirures of Health. (2017). Gnwics home uforma: Achondroplasia. Retrieved &om hrrps:llghr.nlm.nih.gov/condirionl
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enrry/310200
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Self-Assessment Answers
I. d 2. a 3. d 4. c 5. b G. b 7. c 8. a 9. b

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 Chapter 12_
Common Adult-Onset
Genetic Disorders
Learning Outcomes
1. Discuss the genetic and environmental factors that affect the expression of the single gene disorders of
alpha I antitrypsin deficiency and hereditary hemochromatosis.
2. Distinguish between genetic causes of diabetes mellitus type 2 and maturity-onset diabetes of the young
(MODy).
3. Discuss the genetic and environmental contributions to complex autoimmune disorders.
4. Compare the genetic risk for family members of patients with early-onset Alzheimer disease and those
with late-onset Alzheimer disease.
5. Compare genetic contributions to age-related vision and hearing impairment.

Key Terms
a-1 Antitrypsin deficiency Hereditary hemochromatosis Rheumatoid arthritis (RA)
(AATD) (HFE-HHC) Self-tolerance
Age-related macular Human leukocyte antigen Systemic lupus erythematosus
degeneration (AMD) (HLA) (SLE)
Alzheimer disease (AD) Maturity-onset diabetes of the
Compound heterozygous young (MODY)

Gestational diabetes mellitus Multiple sclerosis (MS)

(GDM) Presbycusis

INTRODUCTION
Like many other genetic disorders, adult-onset disorders can be multifactorial, with a tie to environmental
exposure throughout childhood and into adulthood to factors that can change the DNA and increase the
susceptibility to disease, such as diabetes mellitus type 2 or asthma. Many monogenic disorders are first appar-
ent during childhood, although adult-onset diseases, such as hemochromatosis and Huntington disease, also
exist. This chapter discusses disorders that have their initial onset during adulthood.

239

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240 Unit III Genomic Health Problems Across the Lite Span

The environment carries many factors that can further alter the DNA, including the chromatin and the
nucleosome, to affect transcription and ultimately the protein necessary for healthy function of cells and tissue.
As people get older, they are more likely to have been exposed to environmental factors that can trigger the
onset of disease if they also have a genetic susceptibility. Finding our what genes increase a person's susceptibility
to a complex (multifactorial) disease that clearly runs in the family is a continuing challenge. Knowing who
is most likely to get a particular disease based on their genome variations allows the targeting of interventions
to those people who are at highest risk.
Families with a history of adult-onset genetic diseases will need to address a unique set of problems. These
include multiple questions, when and if a person might develop a disease, when and if genetic counseling is
appropriate, when and if a person should have genetic testing to determine their risk, and when and if prophy-
lactic treatment should occur or when to begin monitoring. For example, in 2001, the American Academy of
Pediatrics (AAP) (and several other organizations) recommended against predictive genetic testing of children
at risk for adult-onset disorders, unless there is a clear benefit to the child (Nelson er aI., 2001). Therefore,
testing children for the gene variant that causes Huntington disease would nor be supported, whereas testing
a 6-year-old for the gene mutation associated with familial adenornatous polyposis (FAP) colon cancer would
be useful because guidelines now suggest monitoring by colonoscopy by age 10 for those with an APe muta-
tion. This policy statement was reaffirmed in 2005 and in 2009. In 2013, the AAP and American College
of Medical Genetics (ACMG) reviewed their policies and continued to affirm the need to test children only
if an intervention for the management of the adult-onset disease exists (Ross et al., 2013). Later, another
publication focused on recommendations for reporting incidental findings in clinical exome and genome
sequencing (Ross et aI., 2013).
More about pediatric onset disorders is available in Chapter 11. This chapter discusses disorders that more
commonly appear during adulthood and considers the genetic contributions to each of them. A number of
adul t-onset disorders, such as cardiovascular diseases and many cancers, are described in later chapters.

MONOGENIC DISORDERS
A few disorders with symptOmS that appear during adulthood are caused by single-gene problems. For some,
why no obvious signs and symptoms appear until adulthood is clear, but for others, it is a bit puzzling. Three
relatively common adult-onset single-gene problems are hemochromatosis, maturity-onset diabetes of the
young (MODy), and chronic obstructive pulmonary disease (COPD).

«-l Antitrypsin (AAT)Deficiency

a-I Antitrypsin deficiency (AATD), now also known as a-t proteinase inhibitor deficiency, was first described
as a risk faeror for chronic obstructive pulmonary disease (COPD) in 1963. Today, it is well known that the
deficiency leads to increased risk of both lung and liver disease, although through different pathogenic pathways.
AATD is caused by mutations in the SERPINAI gene, which codes for the protein product c-I antitrypsin,
a neutrophil elastase. This powerful enzyme is produced in the liver and secreted from white blood cells to
fight infection. If not kept in check by n-I antitrypsin, this enzyme can target normal lung tissue, specifically
destruction of the alveoli. It has also been associated with the hypersecretion of mucus found with chronic
bronchitis.

In he rita nee Patte rns

Deficiency in AIT is inherited in an aurosomal-codorninanr pattern in which twO different versions of the
gene can be expressed together and contribute to the genetic trait, The most common allele, M, is associated

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 Chapter 12 Common Adult-Onset Genetic Disorders 241

with normal levels of a-I antitrypsin. Most individuals have two copies (MM). Other alleles lead to lower
levels of a-I antitrypsin, with the S allele producing moderately low levels of the enzyme, Z very low levels,
and twO ZZ alleles most commonly linked to the deficiency. Those who smoke and have the SZ allele com-
bination are likely to develop emphysema and other types of lung diseases. Globally, 161 million people have
one copy of the alleles S or Z and one copy of M (MS or MZ) in each cell. A cell with copies of MS or SS
probably has enough protein to prOtect the lungs from disease. A person with MZ has a slightly increased
risk of impaired function of the lung or liver.
Persons with COPD and AATD are labeled as AATD-COPD, whereas those without AATD are desig-
nated as AAT-replete COPD. The different nomenclature allows clinical questions that focus on detection in
at-risk populations, diagnostic testing, and clinical evaluation with treatment as necessary (Sandhaus et al.,
2016).

Mechanisms
Trypsin is a proteolytic enzyme (or proteinase) that breaks down proteins into their peptides and amino
acids during digestion. Trypsin is produced in its inactive form by the pancreas. a-I Antitrypsin (AAT) is
an antiproteinase enzyme that is produced by the liver. It protects lung tissue and bile ducts from damage
by destructive proteins such as trypsin. Not having enough AAT leads to inflammation in the lungs, emphy-
sema, liver cirrhosis, and liver fibrosis. Too much trypsin (or not enough antitrypsin) can be very damaging
to tissue.
The air we breathe often contains microscopic particulate matter that can irritate and damage the lungs.
Thus, the lungs have proteolytic enzymes to break down these particulates and protect the lungs. However,
these "protective" enzymes must be controlled so that their effects are directed only against particulate matter
and not the lung tissues. o-i Antitrypsin limits the activity of these enzymes and prevents them from auto-
digesting a person's lung tissues. So, when a person does not produce enough active AAT, the normally pro-
tective enzymes go beyond degrading inhaled particulate matter and begin degrading the lung's elastic tissue.
Over time, the loss of elastic tissue leads to early-onset emphysema.

Genetic Contributions
The severity of AATD depends on which forms of the gene are inherited. People who are homozygous for the
allele associated with the most severe deficiency (the Z allele) have very little o-I antitrypsin in their serum;
therefore, their lungs and Liversare most vulnerable to destruction by excess trypsin. This genotype is described
as PI-ZZ, and it is passed through families as an autosomal-recessive trait. People with twO ZZ alleles account
for 95% of all people with AATD (Schlade-Barrusiak & Cox, 2008). The other alleles are M and S, and they
confer varying degrees of risk (Table 12-1). Severe AATD is found in only 1% to 2% of all people who have
emphysema. Other forms of COPD are more complex and clearly involve the actions of several susceptibility
genes working together with the environment.

Environmental Contribution
Although AATD is considered a single-gene disorder, environmental factors can nevertheless affect the clinical
progression of the disease. For example, tobacco smoking greatly increases the risk of COPD in a person who
carries the AAID genotype. For smokers who are at genetic risk, respiratory disease begins between the ages
of 40 and 50 years, or even younger. In nonsmokers, lung disease may not appear until they are well into
their 60s. People at genetic risk are counseled to avoid not only active and passive smoking, but also exposure
to environmental pollutants such as mineral dust, gas, and other fumes. AATD genetic testing is available for
persons at genetic risk (Table 12-2).

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242 Unit III Genomic Health Problems Across the Lite Span

.'!.':jlll:ar..c:ll
Ct-' Antitrypsin Genotypes
Genotype Level of AAT and/or Risk for Disease

MM Results in normal concentrations of AAT

MZ Heterozygotes have a slightly increased risk of poor lung function.
SZ A higher risk of lung problems among smokers but not usually associated with increased
risk in nonsmokers
ZZ Often associated with clinical disease and a plasma concentration of AAT that is less
than 20% of normal

Adapted from Schtade-Bartuslak,K.. & Cox. D. w. (2008). Alpha-l anrjtrypsjndeficjency. Reuievedfrom hnp://WNw.ncbLnlm.nih.gov/
bookshelf/br.fcgi?book=gene&pan=alphal-a

Recommended GeneticTesting for Suspected 0.-1Antitrypsin Deficiency (AATD)

• All persons with chronic obstructive pulmonary disease (COPD). regardless of age or ethnicity
• All persons with liver disease that cannot be explained
• Anyone with a diagnosis of necrotizing panniculitis. granulomatosis with polyangiitis. or unexplained
bronchiectasis
• First-degree relatives as well as extended family of persons with positive mutation for AATD

Genotyping of at least Sand Z allelesis recommended as pan of diagnostic testing for symptomatic individuals.
After probandis identified.AAT level testing alone for the family is not recommended because it does not fully characterizedisease risk
iromAATD.
Adapted from Sandhaus.R.. Turino.G.. Bran~y.M.. Campos.M.. Cross. C.. Goodman. K.. & Tekman.J. (2016).The diagnosisand
management of alpha-1antitrypsin deficiency in the awlt. Journalof the COPOFoundation.3(3).668-682. For other specific pulmonary
and hepatic diagnostic testing. see the complete "Summary of Recommendations" at hnp:lljoumal.copdfooundatioorgIPortalsIO/
JCOPDF/Files/Nolume3-lssue3/JCOPDf-2015-0182-Sandhaus.jpdf

Hereditary Hemochromatosis
Hereditary hemochromatosis (HFE-HHC) is associated with excessive absorption of dietary iron by me
gasrric mucosa. This excess iron accumulares in me skin, Liver,pancreas, heart, joinrs, and testes. Accumula-
rion in me skin causes the affected person ro have a bronzelike skin discoloration. An older name for this
disorder was "bronze diaberes."
The adult-onset diseases are classified as rype 1, me most common, and rype 4. Even though an affecred
person has had me genorype since birth, clinical symproms for types 1 and 4 usually do not begin in men until
age 40 to 60 years and after menopause in women. Types 2 and 3 develop in adolescence and prior ro age 30,
respectively. Ir rakes some rime for the buildup of iron to damage the organs and cause clinical evidence. The
first symproms a patient norices are lethargy, weakness, abdominal pain, and weighr loss. Unless me disease is
identified early and treatment is begun, affecred people will develop liver cirrhosis, hepatocellular carcinoma,
diaberes mellirus, cardiomyopathy, arrhythmias, arthritis, and hypogonadism.

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 Chapter 12 Common Adult-Onset Genetic Disorders 243

Inheritance Patterns
Affected people carry mutations in the HFE gene. About 11% of the general population of Caucasians is
heterozygous for one of the mutations that cause HFE-HHC. European countries with the highest prevalence
of hemochromatosis include Ireland, France, and Denmark. Mitochondrial DNA studies reveal no linkage to
African ancestry, so this disorder is believed to have corne to North America with the Vikings and other Euro-
pean explorers. Some suggest that persons with iron-loading associated with hemochromatosis had a biological
advantage and were better able to survive the potato famine and bubonic plague. Type 1 HFE-HHC is inherited
as an autosomal-recessive trait; people who are either homozygous or compound heterozygousare at risk. Remember
that heterozygous means having one copy of the mutant allele. Someone who has twO different mutant alleles is
said to be compound heterozygous. Fortunately, the penetrance for HFE-HHC is quite low, so not everyone
who carries the genotype will show the phenotype. This makes the biochemical rather than the genetic testing
of people who are at risk most useful. What matters most is whether the person is clinically affected.

Mechanism
The transferrin-iron saturation test is the biochemical test that is used clinically to exclude the presence of
HFE-HHC or to suppOrt the need for further evaluation, such as genetic testing or liver biopsy. Several dif-
ferent types of genetic testing can be useful in families that are at risk for HFE-HHC. For example, diagnostic
testing can be used to confirm that a person who shows the phenotype has this disease and not something
else that causes similar symptoms. Carrier testing can identify hererozygores who are at risk of passing on the
trait to their offspring. Predictive testing can be used to identify people who are homozygous or compound
heterozygous for the genotype and therefore at risk of developing symproms over time. These people can be
monitored periodically for iron overload, so if symptoms do occur, they can be treated promptly.
Therapeutic phlebotomy is a simple, effective, and inexpensive treatment that can bring iron levels close
to normal. Blood removal should be 500 mL or one unit of blood weekly or monthly based on the patient'S
ability to tolerate 200 to 500 mg of iron. (Each unit of whole blood, 400-500 mL, normally contains
160-200 mg of iron.) Enough blood needs to be removed to bring the transferrin level to less than 50 ng/L.
The hemoglobin and hematocrit levels should be checked prior to the phlebotomy to prevent lowering these
to less than 80% of initial or 20% of prior levels (Bacon, Adams, Kowdley, & Powell, 2011). Many people
affected with HHC have regularly scheduled phlebotomies. Restoring iron levels with blood removal can take
from 1 month to 3 years with a mean average of 13 to 31 months. Some may only require one to two units
annually (Bacon er al., 2011). Women with HFE-HHC commonly do not show signs of iron overload until
well after menopause because the menstrual cycle provides narural and regular blood iron loss every month
(Emanuele, Tuason, & Edwards, 2015). Without treatment, excess iron accumulates in the organs and tissues,
causing fatigue, joint pain, and abdominal pain. Over the long term, iron overload leads to arthritis, liver
cirrhosis, diabetes, cardiomyopathy, heart failure, and hypopituitarism.

Maturity-Onset Diabetes of the Young

Maturity-onset diabetes of the young (MODy) is a single-gene problem that causes hyperglycemia, usually
before the age of 30, and includes 1% to 2% of persons with diabetes (philipson & Carmody, 2015). Although
the focus of this chapter is adult-onset diseases, changing information suggests that young-onset and adult-
onset diabetes share similar etiologies and pathophysiologic processes that lead to diabetes.

Inheritance Pattern
MODY is transmitted in an autosomal-dominant panern, and mutations in six differenr genes cause the six
major types of MODY. Recently, additional genes have been identified in low percentages, but their relevance

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244 Unit III Genomic Health Problems kross the Lite Span

to actual susceptibility is in question. Although MODY types 7 through 13 have also been identified, approxi-
mately 85% of people with MODY have types 1,2, or 3. Genetic testing for these three groups is COSteffective,
although still pricey and largely not paid for by insurance. After testing, the variant should be included with the
MODY designation to clarify MODY types and the most effective treatment (Philipson & Carmody, 2015).
Clinical genetic testing is available for next-generation sequencing of the 25 genes, including the 2 most
common major genes, associated with MODY. Sometimes people with MODY have been misdiagnosed as
having diabetes mellitus type 1 (DMT1) or type 2 ([20M). Genetic testing can confirm or refute whether a
person has MODY. Even though the name implies that MODY affects the young, some people with MODY 3
do not have symproms until they are older, suggesting either a gene-environment interaction or variability
in expression. One study of people with MODY 3 found that persons with the HNFJA mutation devel-
oped diabetes by age 25 in only 50% of those who carried the gene mutation. MODY 3 was diagnosed in
90% of study subjects by age 50. This gene is highly penetrant, explaining the increase in development of
T2DM over time (Philipson & Carmody, 2015).

Genetic Contribution
Each of the genes involved in MODY plays a role in glucose metabolism, insulin action, or insulin release
from the pancreas. The major types of MODY and the genes that have been identified as causing them are
listed in Table 12-3.
Mutations in hepatocyte nuclear factor 1 a gene (HNF-J a), located on chromosome 12, cause MODY 3,
which accounts for approximately 65% of cases. HNF-J a is involved in the metabolism of glucose, choles-
terol, and fatty acids. Defects in the glucokinase gene (CCK) on chromosome 7 (CCK) cause MODY 2. Some
children who carry CCK mutations will have mild hyperglycemia, and some cases of gestational diabetes are
also caused by mutations in this gene. Glucokinase regulates the release of insulin from the beta cells of the
pancreas in response to the presence of glucose in the blood. People with MODY 2 tend to have a less severe
form of the disease, but they need higher levels of glucose in the blood to trigger the release of insulin than
do people with glucokinase that is working properly. MODY 1 is caused by mutations in hepatocyte nuclear
factor 4 a (HNF-4a), which is located on chromosome 20. Variations in this gene result in problems with
insulin secretion .

.. r~:t~~~ __
Genetic Defects of Beta Cell Function Associated With Diabetes Mellitus
Chromosome Gene Incidence
-
MODY 1 20 HNF4a. -5%
MODY2 7 GCK -15%
MODY3 12 HNF-la -50-90%
MODY4 13 IPF 1 Very rare
MODY5 17 HNF-l/3 <3%
MODY6 2 NeuraD 1 Very rare
MODY7 9 Carboxyl ester lipase Very rare

Adapted from American Diabetes Association. (2014). Diagnosis and classifeation of diabetes mellitus. Diabetes Care, 37(11. S81-S91;
and Philipson. L H.• & Carmody. D. (2015), Who needs marurity-onset diabetes of the young (MODY) screening? Pediatric Endocrinology,
229-233. doi:10.1210/MTP4.9781936704941.ch44

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 Chapter 12 Common Adult-Onset Genetic Disorders 245

Because MODY is transmitted as an aurosomal-dominant trait, only one copy of the defective gene is needed
for a person to have the disease. Rarely, people are homozygous (or compound heterozygous) for mutations in
one of these genes and tend ro have more severe forms of the disease. Those who are homozygous for defects
in the gene that codes for glucokinase can have severe diabetes mellitus (DM) as a newborn (severe neonatal
DM). Those who are homozygous for mutations in the IPF] gene, which causes MODY 4, may not grow a
pancreas at all (pancreatic agenesis).

COMPLEX DISORDERS
Many more complex (multifactorial) disorders have adult onset than single-gene disorders with adult onset.
However, finding the genes that contribute to the risk of complex diseases is always difficult. Multifactorial
disease is often due to a large number of genes, each exerting a small effect, combined with environment.
Advances in genetic testing technologies, such as genome-wide association studies (GWASs), have added greatly
to our ability to find genes associated with adult-onset complex diseases. These are often among our tOP causes
of morbidity and mortality, so finding who is genetically susceptible before they develop symptoms could have
a powerful impact on public health. When people find out they are at genetic risk for a particular disease,
they tend to follow recommendations for monitoring their health better than when they just know that a
disease runs in their family. In this section, we will discuss diabetes mellitus type 2, obesity, and autoimmune
disorders. (Table 12-4 offers clinical resources for diabetes rnellitus.)

Diabetes Mellitus Type 2

Many different types of diabetes mellitus (DM) exist, and together, they affect approximately 29.1 million
people in the United States. Furthermore, 8.1 million of these people with all types of DM are believed to be
undiagnosed and untreated (Centers for Disease Control and Prevention [CDC], 2014). Chapter 10 discusses
type 1 diabetes mellitus. MODY was described earlier in this chapter with other monogenic disorders of adult
onset. This section focuses on DM type 2 and gestational diabetes. The fasting blood glucose levels that are
diagnostic for impaired glucose rolerance and actual DM are listed in Table 12-5. When people have random
blood glucose levels of200 mg/dL or higher, plus clinical signs such as increased urination and increased thirst,
fatigue, blurred vision, and poor wound healing, they should have further testing to determine whether they
have DM (National Institute of Diabetes and Digestive and Kidney Disease [NIDDK], 2016).

Clinical Manifestations
All forms of DM share persistent hyperglycemia and its profound impact on the health of affected people.
When the body's organs are exposed to high blood sugar levels for long periods of time, severe damage or
failure of organ systems can occur. The most commonly affected organs are the heart and blood vessels, the

TABLE 12-4.~'
Clinical Resources for Diabetes Mellitus

American Diabetes Association http://www.diabetes.org/diabetes-basics/type-2/

University of Chicago http://monogenicdiabetes.uchicago.edu/
Exeter/Peninsula Medical Center http://www.diabetesgenes.org#sthash.6eza1c73.dpuf

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246 Unit III Genomic Health Problems kross the Lite Span

Fasting Glucose Values and the Diagnosis

of Diabetes Mellitus
Plasma Glucose Result (mg/dL) Diagnosis

99 or below Normal
100-125 Impaired fasting glucose
126 or above* Diabetes

'This value must be contirmed by repearingthe test on another day.

Adapted from American DiabetesAssociation. (2014).Diagnosis and classification

of diabetes mellitus. Disbetes Care,37(1). 581-S91.
-

eyes, the kidneys, and the nerves. An accompanying loss of lipid control can also be seen. The result is the
macrovascular and microvascular complications found in patients with OM.
OM type 2 (T20M) is the most common form of OM, accounting for about 90% to 95% of all people
with OM (American Diabetes Association [ADA], 2014). T20M is caused by a relative (rather than an abso-
lute) problem with the secretion of insulin or, more commonly, a severe decrease in insulin recepror sensitivity
(insulin resistance). This means that even when insulin is produced in normal amounts, it fails to bind well
to the insulin receptor. The correct binding of insulin to its recepror changes a cell's permeability to glucose
(see Chapter 11). Excessive liver glucose production and a decrease in the cellular uptake of glucose are also
seen. Therefore, even though people with T20M can make insulin, they cannot make enough to compensate
for the difficulty they have in using insulin. Many older people with T20M are not diagnosed early because
symptoms tend to appear graduaJly over time, so they may not identify the classical signs of OM, such as
polyuria or polydipsia.
Some people do not find OUt they have T20M until they starr experiencing complications, such as reti-
nopathy or neuropathy. Often, T20M is found during laboratory testing for an unrelated problem. The
NIOOK (2016) suggests that nearly 6 million people in the United States have T20M and have not been
diagnosed. This is surprising because we know that T20M dearly runs in families. As health-care providers,
we would hope that when a person has a first-degree relative with T2DM, he or she would be on the lookout
for signs and symptoms in himself or herself. We can help alert patients to their increased risk ofT20M and
suggest periodic monitoring in accordance with guidelines (Agency for Healthcare Research and Quality, 2014).

Genetic Contribution
Although the contribution of genetics to the onset ofT20M has been demonstrated in a large number of
studies, because this disease does not follow simple rules of Mendelian inheritance, teasing out the specific
genetic factors that contribute to its onset can be very difficult. About 9.3% of people in the general popula-
tion had a diagnosis ofT20M at some point in 2012. If one parent has T20M and was diagnosed before
age 50, a child of that parent has a 1 in 7 chance of developing the disease. If the parent was diagnosed after
age 50, the risk is 1 in 13. If the parent with T2DM is the mother, the child's risk is greater. The risk is 50%
for people who have two affected parents (ADA, 2016). With T20M becoming more and more prevalent,
having two affected parents is not uncommon.

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 Chapter 12 Common Adult-Onset Genetic Disorders 247

Another way of determining how big a part genetics plays in the risk of having a complex or multifactorial
disease is to look at twin concordance studies. You may remember from Chapter 4 that twin concordancerefers
to the percentage of second twins who are affected with a disease that affected the first twin. In T2DM, the
monozygotic (identical) twin concordance rate has been estimated at between 60% and 90%. That means that
if one twin is affected, the other twin will be affected 60% to 90% of the time. That is very strong evidence
for a genetic contribution because monozygotic twins share their genotypes in common. The twin concordance
rate for dizygotic (fraternal) twins is usually estimated at about 30%. Remember that dizygotic twins share
only about 50% of their DNA in common, JUStlike regular siblings.
Even though most people who have T2DM are diag- r-----=:...._---------------...,
So Why Have Obesity and T2DM
nosed in middle to late adulthood, diagnosis of younger Become So Prevalent?
people is rising disturbingly. Children and adolescents are
being diagnosed with T2DM (not MODY, but actually One theory that attempts to explain this disturb-
ing phenomenon describes what was called the
DM type 2). A recent study found that females from "thrifty genotype" (Neel, 1962). Historically.when
minority groups whose mothers are also affected are populationsexperiencedperiods of plenty followed
at highest risk (World Health Organization [WHO], by times of famine, thosepeople who were better
20 16a). The incidence ofT2D M is increasing drarnati- at storing fat survived to pass on their genes to
cally worldwide, and it is most often associated with their offspring. Peoplewho were not metabolically
sedentary lifestyle,decreased physical activity, and obesity, "thrifty" vvouldbe less able to store fat, and they
which is also increasing at an alarming rate. Despite the would not survive during times when food was
goal to halt the rise of global weight gain by 2025, obesity scant. Now, when many people have access to
has continued to increase. WHO (201Gb) reported that lots of calorie-dense food, the ability to get the
globaUy, approximately 33% of adults over 18 years old most energy from every calorie and easilv store
were overweight in 2014, and 10% were obese. Women fat is not such a great advantage!
were more obese or overweight than men. The highest
weight statistics were in the Americas, and the lowest were in the region of Southeast Asia (WHO, 2016b).
People with so-called thrifty genotypes are so good at storing fat that they carry around lots of excess body
weight. This leads to the increasing prevalence of obesity and T2DM. The most important risk factors for
T2DM are obesity and its usual parmer, a sedentary lifestyle. Obesity, which is discussed in the next section,
causes some degree of insulin resistance aU by itself. One theory is that fat stored in the abdominal cavity
(visceral adiposity) is associated with excess Lipidcollection in the Livercausing a problem with insulin signal-
ing by the cell. In addition, the adipose tissue in the abdomen is prone to inflammarion and production of
inflammarory cytokines, which also add to impaired insulin signaling (Hardy, Czech, & Cervera, 2012). Even
if the thrifty genotype explains why obesity and T2DM are on the rise, lots more research, like that being
done on visceral adiposity and insulin impairment, must be undertaken to identify the specific genetic factors
that would make someone's genotype "thrifty" in the first place.

Candidate Genes Associated With Diabetes Mellitus Type 2

Candidate-gene studies and GWASs have identified almost 70 genes that increase susceptibility to T2DM,
and these vary somewhat from population ro population. For example, calpain 10 (CAPNIO) is a gene that
appears to be very important in the onset ofT2DM in about 40% of Mexican American family clusters,
whereas it has much less importance for people of British descent (Brunetti, Chiefari, & Fori, 2014). Exactly
how CAPNIO increases the risk forT2DM is still unclear, but we do know that it has a role in breaking down
proteins (it is a protease), and it affects the action of other enzymes. How that connects to impaired glucose
metabolism remains to be seen.
Genes are considered candidates for study if the proteins they encode have an important role in path-
ways of insulin secretion or insulin action. One example of a great candidate gene for T2DM is peroxisome

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proliferaror -activared receptor-gamma (pPARy). PPARyencodes a protein involved in both lipid and adipocyre
(fat cell) metabolism. One form of this gene decreases insulin sensitivity significantly. This gene variant is also
very common among Caucasians. About 98% of Europeans are at least heterozygous for this allele, so having
one copy apparently does not cause T2DM all by itself; otherwise, 98% of people of European descent would
have T2DM. Even though the number of affected people is growing, it is not quite that high!
ATP-binding cassette, subfamily C, member 8 (ABCC8) is a gene that encodes a sulfonylurea receptor, and
it is joined with a potassium channel encoded by the gene KCN]!!. These genes are important in controlling
the release of hormones such as insulin and glucagon from the bera ceLIsof the pancreas. Of note, patients with
T2DM have trouble with the therapeutic response to sulfonylureas when they have a mutation in the A BCC8
or KCN]!! genes. Researchers are interested in these genes, along with PPARy, because they are important
targets for drugs used to treat T2DM. When mutated, the PPARy is associated with higher fasting insulin
levels and reduced insulin sensitivity. Variations in these genes may affect how patients respond to their oral
antidiabetic drugs in addition to placing them at higher risk for having T2DM.

Gestational Diabetes Mellitus

Although numbers vary from study to study, up to 9.2% of pregnancies are complicated by gestational
diabetes mellitus (GDM). In 20 II, the ADA Standards of Care were changed to recommend that pregnant
women with no known diagnosis of diabetes have an oral glucose roleranee test at 24 to 28 weeks of gestation
(ADA, 2011). Because of the concern for undiagnosed T2DM, a woman with a GDM history is screened 6 to
12 weeks postpartum. Some women with GDM need insulin therapy, and sometimes diet alone is sufficient
to normalize their blood sugars. Typically, the elevations in blood sugar are first noticed around 28 weeks
of gestation, and they resolve after delivery. It is thought that a genetic predisposition is triggered by insulin
resistance that occurs during pregnancy. However, GDM does seem to run in families. Also, mutations in
some of the genes that can cause MODY have been found in women with GDM (Philipson & Carmody,
2015). Women who develop GDM are at a higher risk of developing T2DM later in life.

Genetic Syndromes Associated With Diabetes Mellitus

Some genetic syndromes include an increased risk of OM. These include chromosomal problems such as
Turner and Klinefelter syndromes (Chapter 7) and Down and Prader-Willi syndromes (Chapter 9). Single-
gene disorders can also result in increased incidence of OM. As noted previously, this includes MODY-related
genes as well as the insulin resistance found with Donohue and Rabson-MendenhaLI syndromes.

Obesity
Obesity is a problem that affects growing numbers of people worldwide. Having a body mass index (BMI)
greater than 25 defines overweight, and a BMI greater than 30 is considered obese. According to the WHO,
1.9 billion adults were overweight in 2014, and 600 million were obese (WHO, 2016b). In the United
States, 36.5% of adults are currently obese and at high risk for many concerning health problems, includ-
ing musculoskeletal disorders, T2DM, cancer, and heart disease. Finding genetic links to obesity could be
key in developing therapies that work to alleviate the burden of this major health problem. Obesity runs in
families. A high BMI can be an indicator of body fatness. Genetics accounts for between 40% and 70% of
the variation in BMI (Visscher, Brown, McCarthy, & Yang, 2012). However, finding the genes responsible
is an enormous challenge.

Candidate Genes Associated With Obesity

Many interesting locations on the genome have been found using candidate-gene or linkage studies, but very
few of these have been supported by additional studies. Since 1996, people searching for genes associated with

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obesity have been able to catalogue their findings in the Human Obesity Gene Map. This map lists 253 genes
that have been associated with obesity in at least one study (Rajender Rao, Lal, & Giridharan, 2014). These
are simply associations, and researchers are not saying that they have found the genes that "cause" obesity.
The melanocortin 4 receptor(MC4R) was the first candidate gene validated to affect body weight. It plays
a critical role in both the regulation of food intake and the regulation of energy balance. Recently, one varia-
tion in this gene (fl03) has been found to be protective against obesity. People who carry this variant have a
lower risk of being obese than do people who do not carry this variation. However, it does not seem to carry
a huge weight-loss ability; heterozygous carriers of this variant weigh approximately 3 pounds less than other
MC4R carriers without the J 103 variant. This variant has a frequency of about 3% in the German population
(Hebebrand, Knoll, Volckmar, & Scherage, 2013).
The fat mass and obesity-associatedgene (FrO) has also been associated with T2D M and BM I levels. In the
European population, 49% are heterozygous for this gene mutation, and 16% are homozygous. Of interest,
these carriers of the obesity risk allele take up 200 more kilocalories per day (Hebebrand et al., 2013).
Prohormone conuertase 113 (PCSK1) looks like another promising choice. This gene encodes an enzyme
that is important in the regulation of energy metabolism, and people with rare mutations in this gene suffer
from an extreme form of childhood obesity. The Human Genome Epidemiology (HuGE) review identified a
correlation of obesity with PCSK1 in Caucasians but not Asians (Stijnen er al., 2014).
Brain-derived neurotrophic factor (BDNF) has a role in obesity by controlling appetite regulators in the
brain. A recent study revealed that a variation of the gene produced lower levels of the BDNF protein.
The researchers suggested that increasing BDNF protein levels could be an intervention for persons with
the rs 12291 063 CC genotype. This variation is found more commonly in African Americans and Hispanics
than non-Hispanic Caucasians (Mou et al., 2015).
The adrenergic [33 receptorgene (ADRB3) is involved in the regulation of lipid breakdown and in thermo-
genesis. Diet-induced thermogenesis refers to the increase in the metabolic rate above baseline that happens
following the ingestion of food. It is of major importance in determining daily energy expenditure. Several
studies have been inconclusive, but one variation of this gene was found to be associated with a higher BMI
in East Asians but not in other populations (Vimaleswaran & Loos, 2010).
Although GWASs have idenrified interesting loci that may be useful in determining risk for obesity in the
future, the results of association studies are not clinically useful in the short term. In 2007, a study found
an association between common variations (single-nucleotide polymorph isms or SNPs) in the fot mass and
obesity-associated(FTO) gene and BMI by 1.2-fold. This gene encodes a protein that plays an important
role in controlling both feeding behavior and energy expenditure. The effect of the SNPs on obesity traits
in persons of African and Asian ancestry was similar or a little less than that of European populations, but
the BMI-increasing allele was not as evident (Loos & Yeo, 2014). Remember that even if an association
exists between a gene or locus and a disease process (such as obesity), this does not mean that one causes
the other.

Autoimmune Disorders
The immune system is very complex. The work it does is challenging. It must identify foreign invaders and
destroy them, but it also must be able to identify self-cells and keep them safe. This ability to distinguish self
from non-self-cells is tricky. It usually works amazingly well, but sometimes it breaks down. When immune
factors starr to attack self-cells, autoimmune disease results, which can have devastating symptoms and be very
difficult to treat. We do not completely understand the mechanism for self-tolerance, the ability of immune
system cells to recognize and not arrack the cells of the body in which they reside. This chapter discusses
systemic lupus erythematosus (SLE), multiple sclerosis (MS), and rheumatoid arthritis (RA).

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Most autoimmune diseases are complex, and the genetic contribution is not that easy to tease out, although
many autoimmune problems do seem to run in families. Although the twin concordance is higher in mono-
zygotic twins than in dizygotic twins, it is still not 100%, so factors other than genotype make someone more
likely to get an autoimmune disease. These factors are most likely from the environment.
Some investigators have suggested that environmental factors that affect epigenetic changes may be the
key to environment-gene interaction in autoimmune disease (Farh er al., 2015). This is an important area
of ongoing research. For example, we know that women are much more vulnerable to autoimmune diseases
than are men, but we do not really understand why this is. SLE is nine times more common among women
than among men. Some have suggested that the inactive X chromosome, which all women carry, could be
the culprit because it carries many of the immune-related genes.
Remember that in each cell of a woman's body, one X is inactivated, so she does not make twice as much
protein as men do from the genes on her twO X chromosomes. This is an epigenetic effect on gene expression
in the genome. It is JUStone place that researchers are looking because it represents a clear difference between
the genetics of men and women (Wang et al., 2016). You can read more about epigenetics in Chapter 5 and
X-chromosome inactivation in Chapter 4.
Even though it is difficult, finding genetic contributions to common autoimmune disorders can provide
a valuable contribution to understanding the mechanisms and pathophysiology of the disorders. Therefore,
locating susceptibility genes is an area of great interest. As we have seen with OM type 2 and obesity, genome-
wide scans have helped to move the science forward.

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a classic autoimmune disorder caused by immune cells attacking
self-cells all over the body. Symptoms appear in the skin, heart, lungs, kidneys, joints, and the nervous system.
Affected people often have a "burrerfly" rash over the cheeks of the face, a patchy skin rash, light sensitivity,
arthritis, ulcers of the mucous membranes, pericarditis, pleuritis, or seizures. It certainly seems that the body
is attacking itself. SLE usually begins between 20 and 45 years of age, although approximately 20% of SLE
cases occur in people over age 50. Women are affected much more often than men, with African American
individuals affected four times more often than other races (Ghodke-Puranik & Niewold, 2015).
Some women with SLE experience worsening of their symptoms around the time of menstruation. This
might indicate that the hormones women produce during this time could be involved in SLE onset. The
disease does seem to be more active in persons younger than 40 and in the early years of their diagnosis.

Genetic and Environmental Contributions

The genetic contributions to SLE susceptibility are significant. Twin studies show that the twin concordance
rate for monozygotic twins is between 25% and 75%. For dizygotic twins, the concordance rate is only
between 2% and 9% (Hewagama & Richardson, 2009). Remember that monozygotic twins share close to
100% of their genotype, whereas dizygotic twins share only about 50% of their genotype. Not surprisingly,
several areas of the genome have been associated with SLE, but because monozygotic twin concordance is not
100%, environmen tal factors must be playing a role as well. Suggested environmental triggers for the onset
of SLE in genetically susceptible people include viruses, drugs, and exposure to sunlight.
One region of the genome that is implicated in many problems with immunity and autoimmunity is the
human leukocyte antigens (HLAs) coded for by the major histocompatibility complex (MHC) genes located
on chromosome 6 (Fig. 12-1). Remember that the HLAs function as unique identifiers on the surface of
almost all cells in the body. When an immune system cell recognizes an invader, the immune cell "examines"
the HLA proteins on the invader's surface to determine if it is a self-cell or a non-self-cell. If the proteins do

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 Chapter 12 Common Adult-Onset Genetic Disorders 251

HLA
MHC complex

HLA-A_
21.32p

21.31p

21.2p

HLA-C",

HLA-S/

q
arm
HLA-OR",

HLA-OQ/

HLA-OP/

Human chromosome 6 Figure 12-1 Human leukocyte antigen loci on chromosome 6.

not perfectly match me body's HLAs, men the cell is identified as foreign, and me attack begins. There are
about 40 different major HlAs and an unknown number of minor HLAs.
Genes-encoding proteins in me complement pathway are also found in this region. The complement
system includes several different plasma proteins that are activated in a cascade to destroy pathogens. These
proteins either destroy invaders directly or they "complement" me accion of ancibodies. Because both HLAs
and the complement system are important for efFecciveimmune functioning, it is not surprising that genes
in this region are associated with autoimmune disease. Complement 3 and 4 components in the blood may
be tested because me levels may be lower man normal with active SLE.
Monogenic causes of SLE are associated with complement deficiencies, including C4A and C4B apoptosis
defects, so that programmed cell death of impaired Tor B cells does not occur. People with SLE have been
found to have lower levels of me enzyme DNasel. This enzyme's job is to take cellular debris and chop it
into small pieces so mat it can be disposed of more easily. A recent study of seven consanguineous families
with several SLE-afFected children identified loss-of-funccion mutations in the DNASEJLe gene (Lo & Tsokos,
2014). It seems possible mat a mutation in the gene that codes for this enzyme could interfere with me body's
ability to dispose of cellular waste and trigger an autoimmune reaction, causing SLE.

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Multiple Sclerosis
Multiple sclerosis (MS) is the most common autoimmune disorder that involves the nervous system. In this
disorder, the myelin coating of neurons is destroyed by inflammation (demyelination). Scattered regions of
plaque found in the white matter of the central nervous system damage the myelin sheath until it becomes
toO thin to allow the transmission of neural impulses from the brain to the spinal cord and periphery. The
disease is characterized by episodes of exacerbation and remission and is the most common cause of neuro-
logical disability in young people.
As with SLE, we have known for some time that MS runs in families. Having an affected first-degree
relative (parent, child, or sibling) raises your risk of getting MS from 1% (I in 750) to 2.5% to 5% (NMSS,
n.d.) Women are two to three times more likely to develop this disorder than men. We also know that the risk
of getting MS differs among ethnic populations. MS is most common among people whose ancestors came
from Northern Europe. Although people whose ancestors came from other regions can still develop MS, it is
much less likely. JUStas we saw with other autoimmune disorders, most people believe that an environmental
trigger sets off disease in a person who is genetically susceptible.

Genetic and Environmental Contributions

MS is clearly complex and is probably due to a combination of variations in many genes (polygenic), with risk
determined by a single moderate-effect allele, in addition ro environmental contributions (Sawcer, Franklin, &
Ban, 20 14). Some of the genes that have been implicated are those you will probably recognize as the "usual
suspects." The first gene variants associated with MS were located on chromosome 6. They are the HLA genes
that also seem to be important in the onset of SLE, as well as many other autoirnrnune problems. The first
gene variant associated with MS was the HLA DRB1"'14.01 allele. It is now recognized as a founder, with
many families having multiple relatives within a generation with MS rather than acrossmultiple generations.
Other gene variants in the HLA region (DRBJ"'13:01, DRBI"13:03, and DRBI'*03:0J) are confirmed to be
protective against MS. A significant number of people of African descent do not have these alleles, and this
may help to explain why MS can be very severe in some African Americans but not in other similar populations
worldwide. Approximately 110 additional variants have been identified outside the HLA but are still linked
with the regulatory function of the immune system. DNase I hypersensitiviry sites or secretion of cyrokines
from T-helper-2 cells are [WOexamples (Sawcer et al., 2014).
The geographical distribution of MS risk has led some to wonder if limited exposure to sunlight might
be an environmental risk factor because it reduces the body's ability to make vitamin D. Some studies have
demonstrated that having an adequate dietary intake of vitamin D reduces the risk of MS in people with the
HLA-DRBI risk allele. This is biologically plausible because vitamin D has an important role in the develop-
ment and function of both the cenrral nervous and the immune systems. There is also evidence that when
people who have the HLA-DRBI risk allele get mononucleosis, their risk of getting MS goes up (Hoppen-
brouwers & Hintzen, 2010).

Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic and progressive autoimmune disorder that most frequently affects
women and the elderly. It is considered the most common connective tissue disease, affecting more than
1.3 million people in the United States and approximately I% of the population worldwide. It is two to three
times more common in females.
RA is characterized by synovitis (inflammation of the membrane that lines the joints) and production of
autoantibodies. Rheumatoid factors, consisting mainly of IgA and IgM, attack tissue in the joints and cause
inflammation.

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 Chapter 12 Common Adult-Onset Genetic Disorders 253

Genetic and Environmental Contributions

Approximately 50% of the risk for RA is genetic. Much like SLE. variations are found in the DRBl gene from
the major histocompatibility complex. Some investigators believe that RA is best understood as a collection of
different subsets of inflammatory diseases that share a pathway leading to synovial inflammation. The genetic
factors involved seem to be different, depending on whether a patient has antibodies directed against citrul-
linared peptides (anri-citrullinared protein antibodies [ACPAsj). Being positive for these antibodies means
that a person is more likely to have progressive joint destruction and a generally poor prognosis. Differences
exist between the particular HLA alleles associated with RA in ACPA-positive and ACPA-negative patients.
Thirty different regions of the genome have been associated with RA. One of the problems is that alleles
that have been found in RA patients are very common in the general population, so they really do not help
determine who is at greatest genetic risk. One gene that has long been associated with RA is protein tyro-
sine phosphatase (PTPN22). PTPN22 is involved in many autoimmune diseases, including type I diabetes.
autoimmune thyroid disease. and SLE.
The most powerful environmental risk factor for RA development is smoking. Changes in sex hormones.
occupational exposure to certain kinds of dust or fibers, and viral or bacterial infections are also linked to this
disorder. Long-term smoking is a well-established risk factor for developing RA; it is also associated with more
severe signs and symptoms in people who have the disease (National Institutes of Health. 2017).

Autoimmune Summary
As you can see. many regions of the genome are associated with autoimmune diseases in general. This leads us
to believe that immune system dysfunction shares many common mechanisms of pathogenesis. Puzzl ingly, we
do not always see many differenc kinds of autoimmune diseases in every family that is affected by one kind.
Studies on whether this happens commonly have reported conflicting results. We know it certainly appears to
happen in some families. Autoimmune disorders share much, but not everything, in common. If we were to
construct a diagram of all the genes associated with autoimmune disorders, we would have overlapping circles.
with some genes involved in the risk of each of these diseases (such as the HLAs). some involved in two, and
some involved in only one. The unique combinations of susceptibility alleles combined with environmental
risk factors, such as smoking or lack of exposure to sunlight, is most likely what makes for the variations in
autoimmune dysfunction.

DISEASES AFFECTING OLDER ADULTS

Our bodies go through many changes as we age. Some of these changes make us more vulnerable to disease.
Certainly, aging means that our bodies have had more time (Q be exposed to environmental factors that could
interact with genetic susceptibilities, resulting in iLLness.This section will review age-related changes in vision
and hearing as well as genetic contributions to Alzheimer disease and cognitive decline.

Alzheimer Disease and Cognitive Decline

Some cellular changes that occur with aging can have profound effects on the way our brains function. However,
age-related cognitive decline does not happen to everyone in the same way, and genetic variations probably
play an important role in how aging affects our abiliry (Q solve problems and process new information. For
example, we know that telomeres, those repetitive sequences of DNA at the tips of the chromosomes, shorten
as cells age. The enzyme telomerase protects the relorneres from shortening in stem cells and many cancer cells.
The ability to preserve telomere length is partly inherited, but estimates of JUSthow heritable it is vary widely,

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from between 4% heritability to 80% heritability! Recent studies have suggested that the length of individuals'
relorneres can provide an estimate of not only their physical aging but also their mental aging and the likely
onset of dementia. How useful this will be remains unclear, but the authors suggest that measuring telomere
length could be a relatively simple way to biologically assess the aging brain (Gonzalez-Giraldo et al., 2016).
Alzheimer disease (AD), which affects 25 to 35 million people worldwide, is the most common age-
related cause of dementia. It is an irreversible disease that progresses from mild memory loss to complete
incapacitation. Neurons lose their ability to connect, and eventually, brain cells die. Approximately 50% of
cases of dementia are caused by AD, and the number of affected people is expected to grow as our population
ages. AD appears to run in families, and people have suspected for some time that there must be a genetic
contribution to disease susceptibility.
Two types of AD exist-early and late onset. A small number of AD cases (between 1% and 6%) occur
in people between the ages of 30 and 60 years. This is considered early-onset AD. The vast majority of cases
are considered late-onset AD, which occurs in people older than 60 years. Between 25% and 45% of people
older than 85 years have some kind of dementia. Distinguishing AD from other forms of dementia is difficult
without completing a postmortem examination of the brain that looks for the characteristic signs of dense
amyloid plaques and neurofibrillary tangles (Bekris, Yu, Bird, & Tsuang, 2010).

Early-Onset Alzheimer Disease

Early-onset AD occurs between 30 and 60 years of age. Genetic contributions are fairly clear with early-onset
AD. About 60% of families with one case of early-onset AD report other cases among their close family
members. An autosomal-dominant form of early-onset AD affects about 13% of these families. The genes
that have been identified wi th autosomal-dominant forms of AD are located on chromosomes 21 (amyloid
precursor protein, or APP), 14 (presenilin 1), and 1 (presenilin 2). Because the APP gene is located on chro-
mosome 21, people with Down syndrome (trisomy 21) who carry an APP gene variant get 311 extra dose of
the dysfunctional protein (Bekris er al., 2010). Mutations in any of these genes resul t in increased ~-amyloid
protein, which forms a large part of the plaques that are associated with AD.
Genetic testing is available for family members of people with disease-causing mutations in one of these
genes. Deciding whether to have predictive genetic testing for a devastating disease with limited treatment is
very difficult. Family members are encouraged to seek counseling from genetics professionals prior to agreeing
to any genetic testing, particularly when no effective treatment is available.

Late-Onset Alzheimer Disease

Most cases of AD occur after age 60 and are not caused by problems in single genes alone. They are complex
(multifactorial) and involve a combination of many gene variations that each contribute a small increase in
susceptibility along with environmental factors. We do know that even in families in which one person is
affected with late-onset AD, his or her first-degree relatives (parents, children, siblings) are twice as likely to
get AD than someone from the general population.

Genetic and Environmental Conditions

The only gene that has been associated with the complex form of AD is npolipoprotein E (APOE), which is
found on chromosome 19. APOE has four different alleles, or forms of the gene, but only three occur com-
monly (£2, £3, and £4). We each get one allele from our mothers and one from our fathers, so there are
lots of possible combinations of these three alleles. The E2 allele is less common and seems to offer some
protection from AD. The E3 allele is most common and does not appear to alter the risk for AD one way or
the other. The APO-£4 allele has the highest risk associated with "sporadic" AD and is found in about 40%

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 Chapter 12 Common Adult-Onset Genetic Disorders 255

of people who develop late-onset AD. However, the £4 allele is also carried by people who live well into old
age without any signs of dementia, so other major factors that put a person at risk for significant cognitive
decline must exist. Having two copies of the £4 allele does seem to be associated with a higher risk of getting
AD than having only one copy, and people with twO copies tend to get late-onset AD earlier than those who
carry one copy. In addition, people who carry the £4 allele tend to have poorer outcomes following head
injury or stroke. Even so, we do not completely understand how the APO£ gene variants affect brain tissue.
However, people with the £4 variant do seem to have more plaque and tangles. Women with two copies of
£4 have a 45% risk of getting AD by age 73, and men with two copies have a 25% risk, so an unknown
factor accounts for this difference between the sexes.
To make things even more complicated, approximately 42% of people who get AD do nor have even one
copy of the £4 risk allele. Individual Studies have suggested that five to seven additional genes are associated
with AD, but these studies have not been replicated, so determining whether the genes they found are really
involved in causing dementia is difficult. Clearly, other genetic risk factors exist that have not been identified,
and much work is ongoing (Bekris er al., 2010).
A few other genes have recently been associated with late-onset AD. These include CLU, associated with
clearing ~-amyloid from the brain. Research suppOrtS the theory that AD may be caused by an imbalance in
the production and clearance of ~-amyloid. Chronic inflammation of the brain is viewed as another potential
cause of AD. Researchers are looking to determine if a deficiency in the protein from the CR 1 gene may con-
tribute to chronic inflammation in the brain. Epigenetic mechanisms associated with ATP generation are also
being studied. Because cortical neurons require approximately 4.7 billion ATP molecules per second to ensure
continuous function, some studies are looking at by-produces of ATP production that seem to be associated
with neuronal loss (Devall, Roubroeks, Mill, Weedon, & Lunnon, 2016).

Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the most common cause of central vision loss among older
people in affluent countries. Approximately 1.8 million Americans over the age of 50 have vision loss due to
AMD, and that number is expected to increase to 2.9 million by 2020. Losing central vision can be devastating
because it means that what you are looking at direcdy will be me hardest to see. AMD is caused by deteriora-
tion of the retina that occurs with the accumulation of extracellular deposits of a protein called drusen. The
macula, which is located in the center of the retina, controls our ability to clearly see what is central in our
visual fields. That means that daiJy functions such as reading, recognizing familiar faces, and driving can be
challenging if not impossible because images in the area we are trying to focus on will appear blurred.
Two types of AMD exist. Atrophic or non-neouascularAMD, also called dry AMD, is caused by the break-
down of light-sensitive cells in the macula. Although dry AMD accounts for about 85% of cases, it usually
progresses slowly. Exudative or neouascularAMD is also called wet AMD, and it occurs when abnormal blood
vessels grow underneath the macula and leak protein and blood. Although wet AMD accounts for only 10%
of overall cases, those affected tend to have a rapid progression of me disease. About two-thirds of people
with advanced AMD have the wet type. As with many of me adult-onset diseases we have discussed, AMD is
complex. It is caused by a combination of variations in susceptibility genes and environmental factors.

Genetic and Environmental Contributions

Genome-wide association Studies suggest that genes in the complement pathway, which is important in
inflammation and immunity, are probably involved. Genes that have a role in cholesterol management may
be involved as well. However, we do not clearly understand how gene variants in these systems increase risk.
Inflammation seems to be particularly important in the development of wet AMD, so the involvement of

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complement and/or cholesterol makes some sense, because they each have been connected with inflammation.
Drusen deposits are "highly enriched" with cholesterol, although having high blood cholesterol levels does
not predict AMD, so the cholesterol pathways in the eye and the cholesterol pathways in the blood must be
different (Hampton, 2010).
One study, the Age-Related Eye Disease Studies (AREDS), using vitamins C and E, ~-carotene, zinc, and
copper, found that AMD was reduced by 25%. AREDS2 added lutein and omega-3 farry acids to the original
AREDS supplements and found no overall effect, but replacing the ~-carotene with a 5-to-l mixture of lutein
and zeaxanthin seemed to reduce the risk of late AMD. A lung cancer trial found that ~-Catotene increased
the risk of lung cancer in current and former smokers, but the mixture seems to be safe regardless of smoking
status (National Eye Institute, 2015).
The most powerful environmental risk factor for AMD is smoking, but all the other risk factors that we
commonly associate with coronary artery disease also seem to increase the risk of AMD. To decrease the risk
of getting AMD, people should eat lots of green, leafy vegetables; maintain a healthy weight; exercise regularly;
and not smoke! Does that all sound familiar? Remembering the AREDS research and the importance of nutri-
tion, diet also seems to playa part in protecting people from AMD. Identifying the people who are at genetic
risk and helping them to make lifestyle modifications can be important in reducing the prevalence of AMD.

Age-Related Hearing Loss

Hearing is a very complicated process, with lots of genetic causes of both syndrornic and nonsyndromic
hearing loss. Six forms of presbycusis associated with morphological changes in the inner ear continue to be
used to categorize the causes of age-related hearing loss (ARHL) (Lee, 2013; Schuknecht & Gacek, 1993).
See Table 12-6.
More than 400 different syndromes include hearing loss as a feature. These include Alporr syndrome, Jervell
and Lange-Nielson syndrome, neurofibrornarosis, Stickler syndrome, and Treacher Collins syndrome (all of
these are typically diagnosed in childhood). Other causes of hearing loss are not directly genetic, including
exposure to teratogens, infections, and trauma.

Genetic and Environmental Contributions

ARHL, which is also called presbycusis, is a complex disorder with both genetic and environmental contribu-
tions. Hearing impairment due to aging affects between 40% and 60% of people who are over age 60, with
men more commonly affected than women (Ciorba et al., 2015). Everyone experiences some hearing loss
with aging. However, for some people, the age of onset is younger and the hearing impairment more severe.
The genetic contributions to presbycusis have been supported by studies of hearing loss in monozygotic
and dizygotic twins. Genome-wide association studies identified SNPs of genes associated with hearing loss,
including KCNQ4, NAT2*6A polymorphism, grainyhead-Like2 gene, GLutamatereceptor-Zgene, and common
4977-bp mitochondrial DNA deletion (Lee, 2013). Linkage studies helped identify an autosomal-dominant
gene, MY06, to be associated with ARHL. Other genes, including DFNA4, GRM7, GRHL2, and KCNQ4,
have also been linked to ARHL (Ciorba er al., 2015).
The environmental contributions to age-related hearing impairment include ototoxic drugs (such as ami-
noglycosides, aspirin, and loop diuretics), alcohol, tobacco intake, high-fat dietary intake, and exposure to
chemicals. Medical conditions, such as diabetes mellitus, atherosclerosis, and hypertension, can also contribute.
Exposure to loud noises can cause both metabolic and mechanical damage to the cochlea. Most of the
studies of the impact of noise exposure on hearing have focused on occupational or military exposures. Now
people are investigating exposures to loud noises coming &om digital media players and the use of earbuds as
well as from loud music at concerts. Of course, all people who are exposed to the same noise levels over time

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 Chapter 12 Common Adult-Onset Genetic Disorders 257

Morphological Types of Presbycusis

Type Description

Sensory Loss of hair cells and degeneration within the organ of Corti with
symmetrical high-frequency hearing loss
Neural Loss of neurons within the spiral ganglion and loss of nerve fibers, with
diminished high-frequency hearing loss and problems discriminating
speech
Strial or metabolic Atrophy of stria vascularis cells causing problems with K+recycling and,
ultimately, hearing loss across all frequencies
Cochlear conductive Degenerative changes from stiffness in the cochlear duct, usually
causing low-frequency hearing loss
Mixed Combination of all types; low-tone loss due to loss of cochlear neurons
and decreased stria vascularis, and high-frequency tone loss due to loss
of outer hair cells
Intermediate presbycusis Changes in cilia and mechano-electrical transduction channels

Adapted from Schuknecht. H. F., & Gacek, M. R. (1993). Cochlear pathology in presbycusis. Annals of Otology Rhinology and
Laryngology, 102, 1-16; Lee, K-y' (2013). Pathophysiology of age-related hearing loss (peripheral and cemrsn. Korean Journal of
Audiology, 17(2), 45-49.
'-- -

will not experience the same impact on their hearing. Studies are now being done to identify those people
who are most susceptible to noise-induced hearing loss using candidate-gene studies and GWASs. The genes
involved in handling oxidative mess have been studied, as have the genes involved in potassium recycling.
Although we do not have clear indications about how to determine who is at risk for noise-induced hearing
impairment, one thing is certain-reducing environmental exposure to loud noises will reduce the risk for
virtually anyone (Lee, 2013; Van Eyken, Van Camp, & Van Laer, 2007).
Hearing is a very complicated process with lots of opportunities for things to go wrong. Age-related changes
can alter gene function in many of the molecular pathways associated with processing sound. For example, the
hairlike fibers in the ear, which convert sound waves into nerve signals, are partly maintained by the proteins
~- and "{-actin. Studies in mice have indicated that variations in the genes that encode these proteins may be
involved in age-related hearing loss.

SUMMARY
Common adult-onset diseases are usually complex, involving conrribucions from both genes and the environ-
ment. Because environmental exposures increase over time, environmental contributions dearly become much
bigger factors in disease onset as we age. The good news is that for many of these diseases, particularly those
associated with aging, making lifestyle changes can have an impact on age at disease onset and overall disease
severity. Maintaining a healthy weight, exercising, and eating well seem to have a significant impact on risk
for many of the complex adult-onset disorders, including OM and age-related vision and hearing impair-
ment. For others, such as the autoimmune disorders, making lifestyle changes has a less clear impact. For the
rare, single-gene disorders, early diagnosis can lead to protective therapies, such as phlebotomy for people

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258 Unit III Genomic Health Problems Across the Lite Span

with hemochromatosis. As genetic/genomic knowledge progresses, options for both protective and therapeu-
tic interventions for use by professionals and patients will also increase. However, much work remains to
be done.

GENE GEMS

• As people get older, they are more likely to have been exposed to environmental factors that can trigger
the onset of disease in someone who has a genetic susceptibility.
• Hereditary hernochrornatosis is an autosomal-recessive trait with incomplete penetrance.
• Maturity-onset diabetes of the young (MODy) is a single-gene disorder that causes hyperglycemia in
people younger than age 30.
• Diabetes mellitus type 2 (T2DM) is a complex disorder with a very large genetic contribution.
• Several candidate genes for T2DM have been identified, and more are being studied.
• Genome-wide association studies have identified interesting loci that may be useful in determining the
risk for obesity; however, the results may not be clinically useful in the short term.
• Human leukocyte antigens (HLAs), located on chromosome 6, function as unique identifiers on the
surface of almost all cells in the body.
• Some early-onset Alzheimer disease (AD) is transmitted in an autosomal-dominant manner.
• Some late-onset AD has been associated with the E4 allele of apolipoprorein E.
• Age-related macular degeneration has been associated with the genes involved in complement and
cholesterol managemem.
• Smoking increases the risk of both age-related macular degeneration and age-related hearing loss.
• Both genetic and environmental factors contribute to age-related hearing loss.

...
Self-Assessment Questions "
1. Your 70-year-old patient complains of loss of high-frequency hearing in both ears. You are aware this
is most likely due to which type of hearing deficiency?
a. Sensorial, with loss of hair cells and degeneration within the organ of Corti
b. Neuronal, with loss of neurons within the spiral ganglion and nerve fibers
c. Metabolic, with atrophy of stria vascularis cells causing problems with K+ recycling
d. Cochlear conductive, with degenerative changes from stiffness in the cochlear duct
2. Which test would be used to clinically exclude the presence of HFE-HHC or to suppOrt the need for
further evaluation of hemochromarosis?
a. Diagnostic genetic testing
b. Transferrin-iron saturation test
c. Hemoglobin and hematocrit
d. Carrier genetic testing
3. The type of testing that can confirm or refute whether a person has MODY is which of the following?
a. Hemoglobin Alc level
b. Genetic testing
c. BMI measurement
d. Serum glucose level

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 Chapter 12 Common Adult-Onset Genetic Disorders 259

4. Which autoimmune disorder is most commonly associated with the nervous system?
a. Alzheimer disease
b. Multiple sclerosis
c. Rheumatoid arthritis
d. Systemic lupus erythematosus
5. An elderly woman has been diagnosed with rheumatoid arthritis. Which of the following test results
would indicate a poor prognosis?
a. Positive variant for DRB} gene
b. Negative rheumatoid factor for IgM
c. Positive genetic test results for PTPN22
d. Positive result for antibodies directed against cirrullinated peptides (ACPAs)
6. An extra "dose" of the amyloid precursor protein, or APr, would most likely be associated with which
of the following chromosomes?
a. 1
b. 7
c. 21
d. Y
7. Which compound or element was identified by the Age-Related Eye Disease Studies (AREDS) to
reduce the risk of late AMD?
a. Beta-carotene
b. Copper
c. Mixture of vitamins C and E
d. Mixture of lutein and zeaxanthin

CASE STUDY

Lavona Reynolds is 78 years old and has been a cigarette smoker for most of her life. She has tried many
times to quit, most recently at age 75, but never can conquer the urge to have a cigarette. She lives with
her 85-year-old boyfriend, who also smokes. Lavona has noticed a change in her hearing. Growing up in
Illinois, Lavona enjoyed attending indoor concerts with extremely loud rock bands. Her father was a farmer
and also had problems with hearing loss.
1. Because her father was affected, what is Lavona's risk of having age-related hearing loss?
2. What is the risk to Lavona's children if she is affected? Could they do anything to reduce their risk?
3. What clinical signs might she be experiencing?
4. What environmental factor(s) might playa role in Lavona's risk of ARHL?
5. If Lavona is diagnosed with ARHL, what factors would you expect to be particularly important in
planning her ongoing care?

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260 Unit III Genomic Health Problemskross the Lite Span

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Self-Assessment Answers
I. a 2. b 3. b 4. b 5. d 6. c 7. d

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ERRNVPHGLFRVRUJ
 -~~~ UNIT IV
~~

Genomic Influences
on Selected Complex
Health Problems

263

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 Cardiovascular Disorders
Learning Outcomes
1. Describe the genetic/genomic contributions to common cardiovascular disorders.
2. Explain how genetics and the environment interact in the development and severity of coronary artery disease.
3. Compare the monogenic and multifactorial causes of stroke.
4. Explain how factor V Leiden contributes to an increased risk of blood clots.
5. Explain why finding the genetic causes of hypertension is so difficult.
6. Describe the genetic contributions to selected heart rhythm problems.
7. Discuss the genetic contributions to the different types of cardiomyopathy.

Key Terms
Acquired disease De novo mutation Genetic heterogeneity
Arrhythmogenic right Epistasis Jervell and Lange-Nielsen
ventricular dysplasia/ Factor V Leiden syndrome
cardiomyopathy (ARVD/C) Knockout mice
Familial dilated cardiomyopathy
Atrial fibrillation (AF) (DCM) Long O'T syndrome (LOTS)
Cardiomyopathy Familial hypercholesterolemia Private mutations
Channelopathy (FH) Restrictive cardiomyopathy
Coronary artery disease (CAD) Familial hypertrophic Romano-Ward syndrome
Coronary heart disease (CHD) cardiomyopathy (HCM)
Thrombophilia

264

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 Chapter 13 Cardiovascular Disorders 265

INTRODUCTION
Clinicians typically ask about cardiovascular disease
If a Person Grows Up in a House Full of
(CVD) in any relatives when they take a patient's family Smokers and Later Becomes a Smoker, Does
history. Health-care providers know that CVD "runs in That Person Become a Smoker Because His
families." We also know that environmental factors such or Her Relatives Smoke, So It Seems Like
as smoking, obesity, and sedentary lifestyle increase risk. a Natural Thing To Do, or Because He or
Trying to determine the precise genetic contribution to She and His or Her Relatives Share Genetic
CVD risk becomes difficult, however, because genetics Variations That Make Them More Likely to
also contributes to "lifestyle" risk factors, such as whether Become Dependent on Nicotine?
a person is a smoker, is obese, or has a sedentary lifestyle. Most CVD is considered complex (multifactorial)
So how can we figure Out how important a role genet- because it includes a combination of risk factors
ics plays in determining someone's risk for CV disease? from both genetics and environment, and some-
Wdl, that really depends on the disease in question. Some times these can seem hopelessly muddled!
CV diseases are primarily due to single-gene mutations
(monogenic) such as long QT syndrome, which is discussed later in this chapter. These tend to be rare, and
they account for only a small proportion of all CVD.
In the United States alone, 85.6 million adults have CVD; some have more than one type, which means
that more than 1 in 3 Americans are affected (Mozaffarian ec aI., 2016). Coronary artery disease (also called
coronary heart disease [CHD)) and hypertension (HTN) are common complex (multifactorial) disorders.
That means that many different gene mutations work together; some probably increase risk, whereas ochers
protect against disease. In addition, environment and lifestyle factors modify the severity of disease and whether
a person will get sick at all. Additionally, rarer CVD disorders, such as long QT syndrome and dilated car-
diomyopathy, are caused by mutations in single genes and generally follow Mendelian inheritance patterns
(with some variations, such as incomplete penetrance and/or variable expressivity). In this chapter, we discuss
coronary artery disease, hypertension, arrhythmias, cardiomyopathies, and stroke. This introduction provides
only a brief overview of the genetics involved in these serious cardiovascular conditions, but it should help
you understand the importance of knowing the family history when assessing a patient's CVD risk.

ATHEROSCLEROSIS AND CORONARY

ARTERY DISEASE
Coronary artery disease (CAD) clearly has strong genetic connections. If a man's father suffered from CAD,
his risk of having a myocardial infarction (MI) is double that of a man whose father did not have CAD. If a
woman's father had CAD, the risk of her having an MI is 70% higher than that of a woman whose father did
not have CAD (Mozafl'arian er al., 2016). We have known for some time that both genetics and environment
play major roles in the onset of CAD, but we are JUStbeginning to tease out the specific genes involved in
increasing a person's susceptibility to this life-threatening problem.

Genes Associated With Multifactorial Atherosclerosis

The major cause of CAD is atherosclerosis, the fatty buildup of plaque in and on the arterial walls. When
plaque ruptures, a blood clot forms more easily and limits blood flow. We can see problems due to ischemia
in major organs like the heart, brain, peripheral arteries, and kidneys. About 50% of the risk for atheroscle-
rosis has been attributed to genetics (Roberts & Stewart, 2012). That takes into consideration gene variations

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266 Unit IV Genomic Influences on Selected Complex Health Problems

associated with diseases that increase the risk for atherosclerosis, such as hypertension and diabetes mellitus
and single-gene mutations that appear to cause disease.
The process of atherosclerosis involves a series of events occurring at the level of the endothelium, the
innermost lining of arteries. These events include endothelial dysfunction, a buildup of lipids, the produc-
tion of reactive oxygen species, the oxidation of low-density lipoprotein (LDL), and inflammation. Imagine
all the proteins involved in those processes, and you can see what a complicated job finding all the genetic
Contributions can be. For example, if we JUSt look at the genes that have been found to be associated with
inflammation in atherosclerosis, we have the genes that code for the inrerleukins (IL-I, IL-Ra, IL-6, IL-IO),
cyrokines and cyrokine receptOrs (TNF-alpha, TNF-receptOr, LTA), adhesion molecules (TCAM-I, VCAM-I,
PECAM), chemokines and chernokine receptors (CS3CRI, CCR5, CCR2, CXCLl2, RANTES, MCP-I),
eicosanoids (ALOX5, ALOX5AP, LTA4H, LTC4S, PTGSI, PTGS2, L-PGDS), and many others (con-
nexin 37, TLR-4, CRP, RNFS4)! Add to those the genes that code for proteins involved in lipid and cholesterol
metabolism, endothelial dysfunction, oxidative Stress, vascular remodeling, arterial thrombosis, and cell cycle
regulation (Roy, Bhardwaj, & Yla-Herrruala, 2009). There are so many places to look for genetic contributions.
Apolipoprotein E (ApoE) is a component of very-low-density lipoprotein (VLDL). When people carry the
ApoE4 allele, they tend to have higher levels of LDL than people who carry other alleles. A meta-analysis
combining and analyzing the results of several studies found that having the ApoE4 allele increases a person's
risk of CAD by 1.4 times (Song, Starnpfer, & Liu, 2004). In one study, men with either the ApoE4 or the
ApoE2 alleles had a higher risk of CAD; however, another study showed that people who are heterozygous for
ApoE2 and ApoE3 actually have lower LDL levels. Clear evidence of exactly how much having these alleles
increases or decreases overall risk is so far lacking because atherosclerosis is usually a multifactorial problem
(Franchini, 2016; Roy et a!., 2009).
Studies of large numbers of affected and unaffected people have shown that, in most cases, atherosclerosis
is caused by many different genes working together, with each single gene having only a small effect. Study-
ing areas of interest in the genome requires the use of thousands of DNA markers (usually single-nucleotide
polymorphisms [SNPsj) and multiple studies of different large populations. Currently, the effect of the inter-
actions of some SNPs appears to vary by ethnicity. For example, the genes involved appear ro be different for
Caucasian populations than they are for the Han Chinese. When genome-wide association studies (GWASs)
are done, they must be redone in many differenc ethnic groups before we can say that these genes or loci are
truly important for people whose ancestors came from a particular geographic area.
Numerous GWASs have identified an association between a region of chromosome 9 (9p21) and the
onset of CAD. Of particular interest is roe facr that this area of the genome does not code for protein. The
locus 9p21 is in a noncoding region on the short arm (p arm) of chromosome 9 (Wellcome Trust Case Control
Consorrium, 2007). This region used to be considered part of "junk DNA." Recall from Chapters 1 and 2
that 98% of the genome does not code for proteins, so much more DNA occurs in noncoding regions than
in regions that do code for protein. Scientists have often wondered why we have so much noncoding DNA,
but now we are starting to find out.
Scientists used genetic engineering to breed knockout mice without the 9p21 region of chromosome
9. Knockout mice are bred, using genetic engineering, with one or several genes "turned off" or "knocked
out." The results of these studies indicated that not having this region affected the expression of two genes
that were located more than 100,000 base pairs away! These genes were important in controlling cell growth
in the heart (and other places) by conrrolling the cell cycle. Mice without this region often died prema-
turely, and some developed tumors (Helgadottir et al., 2007). Other studies suggest that mutations in the
9p21 region predict the onset of CAD in about 25 different populations (Horne, Carlquist, Muhlestein, Bair,
& Anderson, 2008). Studies have differed in reporting whether variations in this region increase the risk of
early myocardial infarction (MI).

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 Chapter 13 Cardiovascular Disorders 267

Some interesting work has linked areas on the Y chromosome to increased risk ofCVD. The risk of CAD has
historically been underestimated in women. Although women are certainly at risk, the risk of CAD is still higher
in men, and, overall, men develop symptoms 9 years earlier than women. Researchers have identified changes on
the male-specific region (MSY) of the Y chromosome that seem to contribute to CAD risk (Molina & Clarence,
2016). Remember, this does not mean that women are not at risk-women must be evaluated carefully when
CVD is suspected at any age. When CAD is diagnosed in a person younger than age 50, the genetic contribution
is probably much greater than environmental factors, compared with people who develop CAD at a later age.

Genetic Contribution to Nicotine Dependence

Studies of the genetic contributions to nicotine dependence are in progress. For some people, a mutation in
the gene that codes for the nicotine receptor greatly increases the risk of nicotine dependence. However, JUSt
like atherosclerosis itself, it now appears that nicotine dependence is a problem that involves the effects of
many genes working together (polygenic). Genetic studies are continuing and will need to include thousands of
people, but the early work supportS the idea that being drawn to smoking and having great difficulty quitting
has a biological basis (Bierut, 2009).

Single-Gene Causes of Atherosclerosis

Many monogenic disorders of lipid metabolism have been identified as causesof atherosclerosis.The most common
is familial hypercholesterolemia, but other single-gene disorders exist as well. Some examples include Tangier
disease, which is an autosornal-codorninanr disorder that results in very low levels of high-density lipoprotein
(HOL) or no HOL at all. Familial hyperlipidemia is transmitted in an autosomal-recessive manner and results
in both high LOL and high triglyceride levels. Familial apolipoprotein A-I deficiency is an autosomal-recessive
disease with very low levels of HO L, even though parien tS have normal levels of VLOL and LOL levels (Roy
et al., 2009). Although most of these disorders are rare, familial hypercholesterolemia is relatively common.

Familial Hypercholesterolemia
Familial hypercholesterolemia (FH) is a single-gene disease that is primarily transmitted in an autosomal-
dominant manner. About 1 in 250 persons is heterozygous for a mutation in genes associated with FH. Indi-
viduals who are heterozygous tend to have plasma cholesterol levels between 300 mg/dL and 400 mg/dL and
have a rate of CAD much higher than the general population. About 50% of men who are heterozygous die
from a myocardial infarction (MI) before the age of 60. Only about 30% of women will have a fatal MI before
the age of 60 because heart disease is less common in premenopausal women (Roeters van Lennep, 2016).
For people who are homozygous (about 1 in 1 million), the effectSof FH are much more severe. Cholesterol
levels can be between 600 mg/dL and 1200 mg/dL. If they are not treated, most hornozygores will die before
they reach age 30, and a child having an MI at 18 months of age has been reported (Marks, Thorogood, Neil,
& Humphries, 2003). Affected people sometimes have other signs of high blood lipid levels, like yellowish
cholesterol deposits in the eyelids {xanthelasmas) or the skin {xanthomas}. Xanthomas are particularly common
on the Achilles tendons, elbows, and knees.
Cholesterol can be taken in from the environmenr (eaten) and is synthesized in the liver. It is a necessary
componenr of the plasma membrane. Wherever it comes from, cholesterol is not water soluble, and it must
be carried in the blood by a complex that is water soluble. LDL, or "bad cholesterol," is one of the carriers
of cholesterol in the blood. The LDL receptor is a cell surface protein that binds LDL and takes it into the
cell by the process of endocytosis. FH is caused by having too few working LDL receptors. Without enough
working LDL receptors, cholesterol accumulates in the blood and can contribute to atheroscleroticplaques that
form on the blood vessel walls.

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The LDL receptor protein is coded for by the gene LDLR. More than 1,600 different mutations have been
identified, and they have been grouped into four different classes (Guardamagna et al., 2009).
• Class I: A defective protein is produced.
• Class II: The protein cannot move from the endoplasmic reticulum to the Golgi apparatus.
• Class III: The receptOr is unable to bind with LDL properly.
• Class IV: The protein can get where it is supposed to go on the cell's surface, and it can bind with LDL,
but it is not able to complete the process of endocytosis.
Another autosomal-dominant form of hypercholesterolemia is familial defective apolipoprotein B-100 (ApoB).
This disorder looks clinically similar to FH. ApoB is a glycoprotein that serves as a ligand (a molecule that
binds to another chemical and forms a larger complex) for the LDL receptOr. When LDL binds properly to
its receptor, twO mechanisms control its blood levels: reduced liver LDL production and enhanced enzymatic
breakdown and removal of LDL. The result of defective ApoB is reduced blood clearance of LDL, causing
plasma levels that are two to three times normal.
Dietary management has been the recommended initial treatment of people with FH, but dietary modifica-
tion alone can reduce LDL levels by only about 10%, so medications are often begun early. Bile-acid-absorbing
resins (e.g., cholesryrarnine) can be used to decrease cholesterol reabsorption into the gut and recycling through
the liver. With reduced circulating cholesterol, the liver makes more LDL receptors, and cholesterol levels are
lowered, but only by about 15% to 20%, so combination therapies are more common.
High doses of HMG-CoA reductase inhibitors (the "sratin" drugs, such as atorvasratin, rosuvastatin, and
sirnvastatin) are usually part of the initial treatment of FH. Children who are homozygous are treated aggres-
sively and may also require a cholesterol absorption inhibitor (e.g., ezetimibe) and LDL apheresis for better
control. LDL apheresis physically removes LDL from the blood in a process that is similar to dialysis.

Environmental Contributions to Atherosclerosis

The influence of environmental risk factors makes it very difficult to determine which genes are involved in
the development of atherosclerosis (Ganesh et al., 2013). In a laboratory setting, we can carefully control the
environment of the mice in our experiment. When we are studying people, who are out in the community
living their lives, accurately monitoring lifestyle choices becomes very difficult. Is there really any way to be
certain that a participant stuck to his low-fat diet and exercised every day? That means that comparing the
impact of a low-carbohydrate diet with the impact of a low-fat diet in people with certain genetic variants
can be really challenging.
In addition, some risk factors that are considered modifiable lifestyle choices have strong genetic com-
ponents. For example, let's look at tobacco use and nicotine dependence. Smokers have a risk of athero-
sclerosis that is directly related to the number of cigarettes they smoke a day. Men who smoke 20 or more
cigarettes per day have three times the risk of having an MI than nonsmokers. For women, the risk is six
times higher. Smoking directly damages the arterial wall by increasing the amount of carbon monoxide in the
blood; it also decreases (HDL) cholesterol (good cholesterol) and increases LDL cholesterol (bad cholesterol).
Using tobacco products makes the arteries more likely to constrict and increases the likelihood of blood clot
formation.

STROKE
Whatever the cause, the heart is not the only organ affected when lipids build up in the arteries, causing
inflammation and artery constriction. The brain (and really any other organ that is highly dependent on good

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circulation of oxygenated blood) can also experience ischemia and even infarction because of the reduced deliv-
ery of oxygen to the tissues. An estimated 6.6 million Americans have had a stroke (Mozaffarian et al., 2016).
Stroke is defined as a sudden-onset problem in the brain that is most likely due to a problem in the blood
vessels. It is a major cause of both morbidity and mortality and often leaves patients with significant permanent
disability. Stroke comes on suddenly and lasts for at least 24 hours (Ikrarn er al., 2009).
Genetic risk factors are important in the development of all vascular diseases, including stroke. A person
with a family history of stroke has twO to three times the risk of having a stroke than a person without a family
history. Less clear is exactly what genetic changes make a person likely to have a stroke. Strokes certainly "run
in families," and several SNPs have been associated with the risk of Stroke. Some rare single-gene disorders
can also increase the risk of stroke, but, overall, the genes involved in the development of stroke in the general
population have not yet been found.
Strokes are heterogeneous, meaning many variations exist, even within the general classifications (ischemic
or hemorrhagic) of the disease. For example, hemorrhagic strokes can be classified according to whether they
are caused by vascular malformations, saccular aneurysms, or as signs of small-vessel disease in the brain. They
can also be classified according to where in the brain the problem lies. For example, is it in the thalamus, basal
ganglia, brain stem, cerebral COrtex,or cerebellum? Ischemic strokes can be classified as atherothrornbotic (due
to an atheroma in a major artery) or cardioembolic (due to debris, such as platelet aggregates or cholesterol
from a cardiac source). A catch-all category of "unknown" is used for strokes that do not conform to clinical
or imaging standards for either ischemic or hemorrhagic stroke.
When the phenotype is not clearly defined, teasing out genetic causes can be really difficult. Stroke is usually
a multifactorial (complex) problem involving many genes working together with the environment. Each gene
may have only a small effect, but when their effects are combined, the risk for stroke is great. Whether a
person has a stroke also is influenced by whether she or he has other complex disorders such as hypertension,
hyperlipidemia, or diabetes mellitus. Add environmental risk factors (like smoking or chronic alcoholism),
and sorting OUtwhat genes are involved becomes even more difficult. Even so, investigators are applying new
genetic research techniques to help us identify those people who are at an increased genetic risk of having a
stroke. Some areas of the genome that have been associated with Stroke susceptibility are associated with other
conditions such as CAD, blood clotting disorders, or atrial fibrillation (Ganesh er al., 2013). This is really
important work because many strokes occur in people who have not reported any warning signs, so finding
out who has a genetic predisposition can help identify those who need dose monitoring.
There have been few genetic studies that separate ischemic stroke from hemorrhagic stroke, which is also
called intracerebral hemorrhage (ICH). Approximately 75% of strokes are ischemic, meaning they are caused
by a decrease in blood flow to the brain usually due to a blood clot. Only 25% of strokes are hemorrhagic,
meaning they are caused by a blood vessel in the brain breaking. For ICH, a family history increases a per-
son's risk of having a stroke about twO to six times that of a person without a family history. An even greater
gene-environment interaction with smoking is seen with subarachnoid hemorrhage compared to other causes
of stroke.

Monogenic Causes of Stroke

Less than 1% of strokes are caused by single-gene variants. Monogenic strokes occur more often in children
or young adults. Diseases such as Fabry disease, sickle cell disease, and some mitochondrial disorders can
result in stroke. People with the adult-onset disease CADASIL (an acronym for cerebralautosomal-dominant
arteriopathy with subcortical inforcts and leukoencephalopathy) begin experiencing strokes between the ages of
30 and 40 years. They may also develop migraine headaches and, eventually, dementia. Mutations in the
gene Notch 3 result in changes in the muscular wall of small blood vessels (National Institute of Neurological

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Diseases and Stroke [NINDS), 2016}. Ehlers-Danlos type IV, Marfan syndrome, and fibromuscular dysplasia
are single-gene, connective tissue disorders that increase the likelihood of artery dissections, aneurysms, and
stroke. Neurofibromatosis type I increases the risk of aneurysms, carotid-cavernous fistulas, and vessel occlu-
sions (Alberts, 2009).

Fabry Disease
Fabry disease is a lysosomal storage disease that is transmitted in an X-linked recessive manner. It is caused
by the inability to make the enzyme cc-galacrosidase A, which is needed so that people can metabolize lipids.
Although enzyme replacement therapy is available, Fabry disease is probably underdiagnosed, meaning that
many people who would benefit from treatment are not receiving it. One study found that 5% of young adults
who experienced a stroke had mutations in the gene that codes for ex-galactosidase A, even though they had
not been diagnosed with Fabry disease (Alberts, 2009). You can read more about genetic disorders that affect
metabolism, such as Fabry disease, in Chapter 10.

Mitochondrial Encephalomyopathy, Lactic

Acidosis, and Strokelike Episodes
The mitochondrial disorder mitochondrial encephalornyopathy, lactic acidosis, and strokelike episodes (MELAS)
is another single-gene cause of stroke. Because it is a problem in mirochondrial DNA, it is maternally inherited
(see Chapter 7). MELAS includes a collection of symptoms that may not appear to fit together at first. These
include diabetes, lactic acidosis, myoclonus, hearing loss, headaches, dementia, and myopathy.
Mutations in several other genes can cause ICH. Familial cerebral amyloid angiopathy causes amyloid
deposits and destruction of the capillary vessel walls. Recently, the gene that codes for type IV collagen has
been identified as a cause of hemorrhagic stroke. It is transmitted as an autosomal-dominant trait and can
greatly increase a person's vulnerability to having a cerebral hemorrhage after even minor head trauma.

Factor V Leiden
Factor V Leiden is an example of a genetic thrombophilia, which means that it is a disease that increases
the risk of blood clots. Most people who have factor V Leiden will not develop blood clots, but their risk of
having blood clots is higher than that of the general population. Between 3% and 8% of people with Euro-
pean ancestry are heterozygous {they inherited a mutation from one parent} for factor V Leiden. About 1 in
5,000 people are homozygous {they have inherited a mutant copy from each parent}.
Factor V Leiden was identified in the city of Leiden in the Netherlands. Other rarer variations in factor V
are likewise named after the cities where they were discovered, such as factor V Liverpool or factor V
Cambridge. Factor V Leiden creates problems by altering factor V of the clotting cascade. Proteins of the
coagulation cascade are supposed to be degraded by activated protein C (APC) so that they do not become
too large or stay around too long. The faeror V Leiden variation (F5) results in a protein that cannot be
degraded, so the person experiences a state of "hypercoagulation." One of the tests used to determine if
a person has factor V Leiden is the activated protein C resistance test, but genetic testing is also available
clinically.
Carrying one bad copy of the gene that codes for the facror V Leiden protein increases a person's risk of
having a blood clot in a cerebral vein by eight times that of a person without this gene variant. The situation
is even worse for women taking birth control pills (or any hormone-based contraceptive), which increase the
risk of stroke, even in women without factor V Leiden {Baird, 2010}. Remember that not everyone with
factor V Leiden is going to have a stroke, and many will not even have excessive blood clot formation. Other
examples of rhrornbophilias are caused by mutations in genes that code for prothrombin, antithrombin III,

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protein C, and protein S. Thrombophilias increase the risk of ischemic stroke, deep vein thrombosis, and
myocardial infarction.

Genes Associated With Multifactorial Causes of Stroke

Because the pathophysiology of ischemic stroke is similar to that of coronary artery disease, it is no surprise
that many of the genes associated with atherosclerosis are considered candidates for increasing susceptibility
to stroke. Association studies have found several regions of the genome that appear to be related to stroke,
but most have shown only small effects. If we consider only ischemic stroke, we can include all that was said
previously about the genetic risk for atherosclerosis, but hemorrhagic stroke is a very different condition.
One finding that has been supported by several studies indicates that a person who has the E4 allele of the
apolipoprotein E (ApoE) gene is likely to have a poorer prognosis after hemorrhagic stroke (this allele does
not seem to affect the outcome after ischemic stroke) (Alberts, 2009). Atrial fibrillation is an important risk
Factor for stroke, so genes that have been found to increase a person's risk of atrial fibrillation will also increase
the risk of stroke. Novel experimental procedures will probably uncover many more genetic variants that can
lead to the development of vascular diseases such as stroke.
One major cause of secondary stroke is hypertension-people with hypertension are four to six times
more likely to have a stroke than people without hypertension (see next section). Hypertension contributes
to atherosclerosis and directly weakens blood vessel walls, increasing the likelihood of both ischemic and
hemorrhagic stroke.

HYPERTENSION
Hypertension (HTN) is a major cause of morbidity and mortality worldwide. In the United States, 1 in
3 people has hypertension. Worldwide, more than 1 billion people are affected (Amen, 2009). Although defini-
tions of high blood pressure vary, the American Heart Association (AHA) proposes two criteria for determining
if a person has hypertension (Mozaffarian et al., 2016). A person must meet one or more of the following:
1. Have a systolic pressure greater than or equal ro 140 rnm Hg or a diastolic pressure greater than or
equal to 90 mm Hg, or take medication to treat high blood pressure
2. Be told on two or more occasions by a health-care professional that she or he has high blood pressure
Hypertension can be either "primary (essential)" or "secondary." About 90% to 95% of all people with HTN
have primary HTN, which does not have a single clear cause. It most Likelyresults from a combination of
many genes (hundreds or possibly thousands) working together, each contributing a small amount, in associa-
tion with lifestyle and environmental influences. Does that sound like a familiar scary? Blood pressure (BP) in
general is controlled by many genes that interact with each other. A gene-to-gene interaction is called epistasis.
One gene will modify the effects of another; one gene may increase the expression of another gene, whereas
another gene suppresses its expression.
Secondary HTN is a consequence of another disease; for example, a person with sleep apnea may have an
increased blood pressure that will go back down once the apnea is treated and the person is sleeping well
(Arnett, 2009). People with hormonal imbalances such as hyperaldosteronism or hyperthyroidism can also
have secondary HTN. In addition, many drugs can cause secondary HTN. For example, people who take
corticosteroids daily retain more sodium and water, which leads to hypertension. At least 13 single-gene dis-
orders (monogenic) can result in HTN. Of course, more may be found in the future.
Most of these monogenic disorders affeCt the way the kidneys control salt. When salt is retained, excess
Auid is not excreted, which can cause HTN. The genes involved are usually part of complex pathways, such

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as the renin-angiotensin-aldosterone system (RAAS) pathway, although other hormonal imbalances may also
be involved. For example, glucocorticoid remedial aldosteronism (GRA) is caused by a "crossing over" mistake
during meiosis I. The problem is on chromosome 8, and the trait is transmitted in an autosomal-dominant
manner.

Gene-Environment Interaction
We have known for a long time that HTN runs in families, but teasing out how much is genetic and how
much is environmental remains a challenge. Gene-environment interactions are suspected when two people
with the same genotype have different phenotypes. For example, a person who eats a high-salt diet, is elderly,
or is taking medication that affects the RAAS will probably have a different BP than a young person eating a
low-salt diet and not taking any medication, even ifhe or she has the same genotype for all the genes involved.
Common gene variations, or polymorphisms, can also affect the way genes interact with the environment.
For example, a common variation in the RAAS genes can affect whether hypertension responds to treatment
with a low-salt diet. In one clinical trial, people with the polymorphism AGT-6-AA had a significant decrease
in BP when they followed a low-sodium diet, but people with the AGT-6-GG genotype did not benefit from
salt reduction. Having this information before a patient starts treatment for HTN could save time and result
in betrer clinical outcomes, The way people respond ro antihypertensive medications can also differ because
of gene-environment interactions, as discussed in Chapter 17.
Even though the genetic basis of primary HTN is complex and appears to involve numerous genes in several
pathways, in which each contributes a small amount, it is still clear that HTN runs in families. Identify-
ing people at risk by collecting a thorough family history on those affected can improve the health of many
people. In most people, simple prevention strategies, such as following diet and exercise recommendations,
can reduce the risk of hypertension.

ARRHYTHMIAS
Many arrhythmic diseases have genetic causes or contributions. Some are due to problems with genes
coding for ion channels (sodium, potassium, and calcium) in the heart. These are sometimes referred to as
channelopathies. Different mutations can result in different phenotypes. For example, mutations in the
sodium-channel gene SCN5A can cause long QT syndrome, Brugada syndrome, atrioventricular conduction
defects, or congenital sick sinus syndrome. The physiological effect of the specific mutation probably causes
the different phenotypes. Although many arrhythmias have genetic causes, we will focus on atrial fibrillation,
because it is so common, and long QT syndrome, because it is a classic inherited channelopathy.

Atrial Fibrillation
Atrial fibrillation (AF) is the most common arrhythmia seen by clinicians and currently affects approximately
2% of the u.S. population and 33.5 million people worldwide (Mozaffarian er al., 2016). AF has been shown
to run in families, but how much AF is genetic in origin has yet to be determined. Studies report that having
AF in your family accounts for 40% to 60% of your risk (Christopherson & Elinor, 2016); however, lots of
different genes can probably cause atrial fibrillation, which means that this arrhythmia has genetic heterogeneity.
Likewise, a person could have AF for many reasons. It is commonly secondary to several pulmonary or cardiac
problems, and these may have genetic causes as well. In addition, AF is considered an underdiagnosed problem.
When AF is not present at birth, it is considered an acquired disease. Acquired disease can be indirectly
caused by gene variants. Srrucrural changes in the heart may lead to acquired AF, and the structural changes

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could have a genetic cause. For example, when a defect in a gene that codes for a cardiac sodium channel
(SCN5A) occurs, the phenotype can include dilated cardiomyopathy along with atrial fibrillation.
Several single genes responsible for AF have been found, but they account for only a small number of
cases. These genes code for potassium ion channels in the heart (KCNQI, KCNEI, KCNH2), and they are
involved in causing other heart rhythm problems as well as AF. We will discuss some of these genes in the
section on long QT syndrome.
Most cases of AF are rnultifactorial in origin. As with hypertension, AF is likely caused by small effectS of
many gene variants. A certain combination of gene variants might make a person more vulnerable to develop-
ing AF when conditions are right. Because AF occurs most commonly in older patients and does not always
cause consistent symptoms, studying the genetics of AF is very difficult; however, finding the genes involved is
critical because its incidence is so high. GWASs have found several areas of the genome that contain risk loci
for AF. These areas contain candidate genes that encode signaling molecules, ion channels, and transcription
factors (Christopherson & Elinor, 2016). New laboratory techniques are promising, but we are JUStscratching
the surface of knowledge related to the genetics of AF.

Long QT Syndrome
Long QT syndrome (LQTS) is a group of disorders that involve a delay in repolarization during the cardiac
cycle. This is seen on the electrocardiogram as a lengthening of the QT interval. Figure 13-1 shows a long QT
interval. Approximately 1 in 2,000 to 3,000 people are affected by LQTS. The measured length of the QT
interval must be corrected for heart rate, making the most accurate measurement the "QT corrected" or QTc.
Most clinicians define "long" as a QTc greater than 440 msec in men and 460 msec in women. This repolar-
izarion delay makes the heart vulnerable to developing a potentially lethal polymorphic ventricular tachycardia
called torsade de pointes ("twisting around a point"; Fig. 13-1). Triggers for developing this serious arrhythmia
include electrolyte imbalances; certain activities, such as swimming; loud, sudden sounds; and bradycardia.
More than 10 different genes have been found (0 cause LQTS, and hundreds of mutations have been found
in those genes. Most of the genes involved in causing LQTS code for cardiac ion channels. For example, LQTI
is caused by mutations in the potassium-channel gene KCNQJ (KVLQT1). Approximately 35% of cases of
LQTS are caused by mutations in this gene. Another 20% to 40% of cases are designated as LQT2, which
is caused by mutations in another potassium-channel gene KCNH2 (HERG) (Ackerman et al., 2011). Other
types of LQTSs involve sodium or calcium channels or their subunits. Many mutations causing LQTS are
considered private mutations, meaning mat they are unique to only one person or one kindred and are not
found consistently in the general population.
Vulnerability to a specific trigger varies with the gene involved. For example, a person is more likely to
experience a cardiac event, such as torsade de poinres, before age 10 if he or she has LQTl. Events in LQTI

Long QT interval Torsade de pointes

Figure 13-1 A long OT interval, which can lead to torsade de pointes.

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are often triggered by exercise, particularly swimming, whereas events for people with LQT2 are often trig-
gered by auditory stimuli, such as an alarm clock ringing (so a ringing alarm clock can be harmful as well as
obnoxious). In LQT3, a sodium-channel problem, events occur during periods of rest or sleep.
Although LQTS commonly does not appear until adolescence or later, evidence of LQTS can sometimes
be seen prenatally. This is considered congenital LQTS. Two types (phenotypes) are seen in congenital LQTS.
Romano-Ward syndrome usually follows aurosornal-dorninanr transmission and includes QT prolongation
and tachyarrhythmias. jervell and Lange-Nielsen syndrome has an autosomal-recessive transmission pattern,
and the QT prolongation and tachyarrhythmias are accompanied by deafness.
The effectiveness of standard treatments also varies by type of LQTS. Beta blockers work best for people
with LQT1, whereas mexiletine is often able to shorten the QT interval in people who have LQT3 but not
in people with mutations in other genes that cause LQTS.
For another subset of patients, LQTS appears only when they take certain medications. These people have
acquired LQT5. The list of drugs that can lengthen the QT interval and/or trigger torsade de poinres is growing
and includes antibiotics, antihistamines, anripsychorics, antidepressants, and bronchodilators. Credible Meds
keeps an updated list of drugs that have been shown to prolong the QT interval or trigger torsade de pointes
(Woosley & Romero, n.d.).
Genetic testing is available clinically to identify mutation carriers in affected families, but because LQTS
is so complicated, finding the family mutation is not always easy. Some people may carry the mutation and
have no symptoms at all. When laboratories test an affected person for mutations in all the genes we currently
know are linked to LQTS, the problem will only be found 80% of the time (Ackerman et al., 2011). We
know a lot about LQTS, but there is a lot more to learn.

CARDIOMYOPATHY
The several types of cardiomyopathy all involve a weakened or diseased heart muscle, which results in an
inefficient pumping of blood. Cardiomyopathy often has a genetic cause, although many other causes exist as
well. These include alcohol or cocaine abuse, viral infection, malnutrition, pregnancy, and end-stage kidney
disease. Cardiomyopathy can be caused by several genetic diseases that affect multiple systems. See Table 13-1
for a list of some of these diseases. We will discuss hypertrophic cardiomyopathy, dilated cardiomyopathy,
restrictive cardiomyopathy, and arrhyrhmogenic right ventricular cardiomyopathy. See Figure 13-2 for illustra-
tions of the major types of cardiomyopathy.
Although clinical genetic testing is available for most forms of cardiomyopathy, cardiomyopathy is diagnosed
based primarily on clinical signs and symptOms. A clinician might recommend genetic testing for a person
diagnosed with cardiomyopathy so that asymptomatic family members could be tested for a specific gene
mutation, which is much more COSteffective. Screening recommendations vary based on whether a family
member carries the family mutation. When genetic testing is chosen, the person with the clearest phenotype
(the most typical signs and symptoms) should be the one tested initially. This will increase the likelihood that
the family's mutation will be found.

Familial Hypertrophic Cardiomyopathy

Familial hypertrophic cardiomyopathy (HeM) affects approximately 1 in 500 adults, which makes it
the most common genetic cardiac disorder worldwide. In HCM, the heart muscle becomes asymmetri-
cally thick, and problems with ventricular filling and diastolic function occur. Left ventricular outflow
tract obstruction happens in some patients because of hypertrophy of the septum and movement of
the mitral valve. If you were to look at heart muscle tissue from a person affected with HeM under a

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Genetic Diseases That Can Cause Cardiomyopathy

Hypertrophic cardiomyopathy Beckwith-Wiedemann syndrome

Down syndrome
Friedreich ataxia
Fabry disease
Hunter syndrome
Noonan syndrome
Hurler syndrome
Dilated cardiomyopathy Becker and Duchenne muscular dystrophy
Emery-Dreifuss muscular dystrophy
Fabry disease
Fanconi anemia
Mitochondrial myopathy
Sickle cell disease
Arrhythmogenic right ventricular Ventricular dysplasia
cardiomyopathy Naxos disease
Carvajal syndrome

Data from Hershberger,R, E., Lindenfeld,J.. Mestro"', L., Seidman,C. E.,Taylor,M. R.,Towbin,
J. A., ... Hean FailureSociety of America. (2009). Genetic evaluationof cardiomyopathy-a Heart
FailureSociety of America practice gl.ideline. Joumal of Cardiac Fa#ur8, 15(2),83-97.

Normal Dilated Hypertrophic Restrictive

Cardiomyopathy Cardiomyopathy Cardiomyopathy

Figure 13-2 Types of cardiomyopathy.

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276 Unit IV Genomic Influences on Selected Complex Health Problems

light microscope, you would see disorganization (disarray) in the cardiac myocyres. This disorganization
makes transmission of electrical impulses through the heart difficult, which can lead to cardiac rhythm
problems.
HCM is diagnosed based on finding left ventricular hypertrophy, without any known cause, on the elec-
trocardiogram or echocardiogram. This suggests that the problem is in the heart muscle itself and is not, for
example, the result of muscle growth in order to pump larger quantities of blood against a high systemic pres-
sure. HCM is transmitted as an aurosornal-dorninanr trait, but it can also be caused by de novo mutations.
These are mutations that are not found in other family members and appear to be brand new (de novo) in
the person who is affected.
HCM and several other forms of cardiomyopathy are caused by mutations in genes that code for pro-
teins of the sarcomere. The sarcomere is the contractile unit of the cardiac muscle cell (myocyte); when
it has a structural problem, the heart loses its ability to COntract effectively. More than 1,400 mutations
in over 12 genes have been found to cause HCM. These genes encode proteins such as -rnyosin heavy
chain, myosin-binding protein C, rroponin T, troponin I, tropomyosin, and actin (Maron, Maron, &
Semsarian, 2011).

Left Ventricular Hypertrophy

Whether genetic diseases that include left ventricular hypertrophy (LVH) should be considered causes of
HCM is controversial. The argument has to do with the way HCM is often defined, which currently is
LVH that is not explained by another cardiac or systemic disease. Some genetic causes of ventricular hyper-
trophy are metabolic or infiltrative diseases, such as Pornpe disease or Noonan syndrome, which are listed in
Table 13-1, but some experts would say that these should not be considered HCM at all because the hyper-
trophy is clearly caused by a known disease (Elliort & McKenna 2009).

Genetic Testing
Although causes of HCM other than genetics exist, having more than one family member affected points to
a genetic cause. Recording and updating a complete three- or four-generation family history is very impor-
tant. HCM is commonly asymptomatic early on and has a varying age of onset and reduced penecrance.
Many affected persons are identified as they reach adolescence or young adulthood; however, HeM has been
diagnosed in infants and in 90-year-olds. Clinical generic testing is available for people diagnosed with, or
at risk for, HCM. Recommendations for the care of family members of patients include obtaining an echo-
cardiogram and electrocardiogram to screen all first-degree relatives. However, because the age of onset can
vary, one normal echocardiogram does nor mean that a person will never be affected. Some people do not
develop symptoms until they reach middle age, and rhey can have normal echocardiograms until that time.
Screening guidelines are available from the American College of Cardiology (ACe), the AHA, and other
organizations.
One of the problems in identifying people who are affected with HCM is that they can be misdiagnosed
as having asthma, anxiety attacks, mitral valve prolapse, depression, or innocent murmurs. Sometimes people
are told that they have an "athletic heart" or exercise-induced asthma. The Hypertrophic Cardiomyopathy
Association has collected data from more than 3,000 patients who have HCM; 40% of these patients were
initially diagnosed with something other than HCM, and some waited as long as 35 years before receiving a
correct diagnosis (Maron & Salberg, 2006). That is one of the reasons why genetic testing can be so helpful
in this population.
The most frequent cause of sudden cardiac death in young athletes is HCM. More than one-third of athletes
who die ftom sudden cardiac death before the age of30 have HCM. Recommendations for activity restrictions

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for HCM patients are available. In general, affecred people are told (0 avoid high-intensity physical activities,
particularly those that require a burst of effort, such as weight lifting or basketball, and ro be moderate in
all physical activities (Alpert, Day, & Saberi, 2015). The problem is that most people who die from HCM
have not been diagnosed. That makes screening young athletes before they begin competition very important.
The AHA has developed guidelines for preparticiparion sports screening in competitive athletes (Maron er
al., 2015). Of course, most young people are not competitive athletes, and they are at risk for cardiovascular
problems during activity as well. Recently, the AHA and the ACC proposed recommendations for detect-
ing cardiovascular disease in young people (ages 12-25 in general). They recommend the use of a l-i-po int
screening tool that includes data about personal and family history in conjunction with a physical exam
(Maron et al., 2014).

Familial Dilated Cardiomyopathy

In familial dilated cardiomyopathy (DCM), the left ventricle is enlarged, and the heart pumps poorly.
OCM often results in heart failure and is a common cause for heart transplantation. The heart is distended
(dilated), so contraction of either ventricle is difficult (systolic dysfunction). OCM is most often the result
of ischemic heart disease, but it can also be caused by exposure to toxins or infectious agents in susceptible
people. Clinicians diagnose idiopathic OCM when the clinical signs are present, but no cause can be found.
Clinical signs include heart failure symptoms, such as those common to congestion (edema or dyspnea) or
those associated with reduced cardiac ourput (fatigue). People can also present with arrhythmias or problems
in the cardiac conduction system, or even with blood clots or stroke.
OCM is considered familial when two or more close family members are also affected. Studies have found
that between 20% and 35% of OCM cases are inherited, but because OCM also shows reduced penerrance in
some families, finding no history in family members does not necessarily mean the disease was not inherited.
More than 20 genes can cause OCM, which is usually transmitted in an autosomal-dominant manner, with
a variable age of onset. OCM can also be transmitted as an X-linked or autosomal-recessive trait. JUSt as in
HCM, most of the genes causing OCM code for proteins in the sarcomere.
In 2009, the Heart Failure Society of America recommended that whenever a person is diagnosed with
OCM, a family history must be taken, family members must be screened, and genetic counseling should be
provided with the offer of genetic testing. All first-degree relatives of people with OCM should have echocar-
diograms, electrocardiograms, physical examinations, and a thorough medical history, looking for symptoms
such as arrhythmias and syncope. Screenings must be done at regular intervals because clinical manifestations
may not appear until adulthood (Hershberger et al., 2009).

Familial Restrictive Cardiomyopathy

Restrictive cardiomyopathy is less common than the other types of cardiomyopathy, and some sources suggest
that it is not a genetic disease. In this condition, filling during diastole is decreased because of a rigid ventricle
that does not expand as it should. Systolic function is usually normal. Some cases are idiopathic, and others
are secondary to diseases such as scleroderma, sarcoidosis, amyloidosis, lymphoma, or hernochrornarosis.
Although most cases of restrictive cardiomyopathy are probably nor directly due to single-gene problems,
families in which the trait shows autosomal-dominant transmission have been documented. Mutations in the
gene encoding troponin I have been found, but other genes may be involved as well.
One of the problems with identifying a genetic cause is that although symptoms may appear in childhood,
they also may not appear until the patient is between 50 and 60 years old. In addition, just as with the other
forms of cardiomyopathy, penetrance is reduced. In some families, patients also experience cardiac conduction
problems and skeletal muscle weakness.

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278 Unit IV Genomic Influences on Selected Complex Health Problems

Arrhythmogenic Right Ventricular

Dysplasia/Cardiomyopathy
Arrhythmogenic right ventricular dysplasialcardiomyopatby (ARVD/C) appears to be underdiagnosed.
The prevalence has been reported as between 2 and 10 per 10,000 (Mozaffarian er al., 2016). ARVD/C
carries a high risk of ventricular arrhythmias because of a fibro/fatty replacement of tissue in the ventricular
myocardial wall. As the disease progresses, the left ventricle becomes more involved. This structural change
makes the patient more likely to experience ventricular tachycardia and sudden cardiac death. It is difficult
to know how many cases of sudden death are caused by ARVD/C, but it may be as high as 20% of sudden
cardiac death in the young.
About 30% of cases are considered familial, but this is probably a low estimate because documenting pedi-
grees has not been a universal clinical practice (Bhonsale er al., 2015). ARVD/C is transmitted primarily as an
autosomal-dominant trait, and eight associated genes have been identified. These genes encode transmembrane
proteins (TMEM43), calcium channels (RyR2), and the transforming growth factor ~-3 (TGFB-3). Five of
the genes that are associated with ARVD/C code for proteins in the desmosomes or cell junctions. Other loci
have been associated, so more genes will probably be identified in the future. Some cases occur in conjunction
with systemic genetic diseases, such as Naxos disease, which is transmitted in an autosomal-recessive manner.
Autosomal-recessive transmission of ARVDIC is much less common than autosomal-dominant transmission.
JUStlike the other forms of cardiomyopathy, penetrance is reduced, and getting a good family history is essential.

SUMMARY
Both single-gene and multifactorial causes can result in cardiovascular diseases. Single-gene disorders tend
to be rare, and multifactorial disorders tend to be common. Even so, the number of people diagnosed with
cardiomyopathy seems to be on the rise. Young athletes are at particular risk of sudden death due to undiag-
nosed HCM. Atherosclerosis is a major cause of coronary artery disease, stroke, and hypertension. Although
the complete picture of the genes involved in these diseases has been elusive, association studies are provid-
ing important information about genes that are likely to be involved. Most multifactorial disorders, such as
hypertension, are probably the result of the actions of several genes working together, each contributing a small
effect, combined with environmental risk facrors. We are starting to find polygenic risk factors for complex
diseases such as atrial fibrillation, coronary artery disease, and stroke, bur when we will have a complete picture
is still unknown.

GENE GEMS

• About 50% of the risk for atherosclerosis can be attributed to genetics.

• Familial hypercholesterolemia is a single-gene problem that greatly increases the risk of coronary artery
disease.
• Both ischemic and hemorrhagic stroke can have genetic causes.
• Less than 1% of Strokes are caused by single-gene problems, and these occur primarily in people who
have genetic disorders such as Marfan syndrome or Fabry disease.
• Most strokes are probably caused by several gene variants working together combined with environ-
mental risk factors.

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 Chapter 13 Cardiovascular Disorders 279

• Thrombophilias increase the risk of stroke, and these can be caused by single-gene genetic diseases such
as factor V Leiden.
• Hypertension is caused by several gene variants working together with environmental risk factors.
• Mutations of genes involved in the renin-angiotensin-aldosterone system pathways are commonly
implicated in hypertension.
• Different mutations in ion-channel genes can cause different arrhythmic phenotypes.
• Atrial fibrillation seems to have high genetic heterogeneity.
• The heart rhythm and conduction problems caused by genetic variations in genes that code for ion-
channel proteins are called channelopathies.
• At least eight different types of long QT syndrome (LQTS) exist.
• The gene involved in LQTS affects the likelihood of certain triggers, causing torsade de poinres.
• Some drugs can lengthen the QT interval and cause an "acquired" LQTS.
• Private mutations are common in LQTS.
• Familial hypertrophic cardiomyopathy (HeM) is transmitted as an autosomal-dominant trait.
• HeM and dilated cardiomyopathy (OeM) are caused by mutations in genes that code for proteins
in the sarcomere.
• Young people and athletes with HeM are at an increased risk of sudden cardiac death during exercise.
• Familial OeM is usually rransmirted as an autosomal-dominant trait, but it can also be transmitted as
either an autosomal-recessive or an X-linked recessive trait.
• Arrhythmogenic right ventricular dysplasia/cardiomyopathy is often caused by mutations in genes that
code for proteins in cell junctions.

....
Self-Assessment Questions. ·
1. Your patient is admitted for episodes of chest discomfort. She says that she is sure it is muscular because
only the men in her family have heart disease. What do you tell her?
a. "It makes sense that only the men in your family have heart disease because most generic risk
factors are on the Y chromosome."
b. "Let's complete your family history. Generic risk for heart disease can affect both men and women."
c. "It is important that you have genetic testing to idenrify any generic risk that exists in your family."
d. "How is your diet, and do you have an exercise routine? These are the most important facrors to
reduce genetic risk."
2. You are caring for the Johnson family. Several members have been diagnosed with LQTl. You notice
on the pedigree that some F.amilymembers have both the genotype and the phenotype, whereas others
have the genotype but nor the phenorype. Why is this?
a. Phenotype variation
b. Reduced penetrance
c. Epistasis
d. Variable expressiviry
Continued

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280 Unit IV Genomic Influences on Selected Complex Health Problems

3. Your patient has hypertension (HTN). She wants to know about genetic testing because she is concerned
about her son's risk of also being hypertensive. What do you know about genetic testing for HTN?
a. Hypertension is a complex multifactorial disease in which lots of genes contribute small amounts
to risk, and it is complicated by environmental factors.
b. Genome-wide association studies can be very effective in identifying a person's risk of hypertension.
c. Factor V Leiden (FVL) is an important conrriburor to hypertension risk. Genetic testing is avail-
able for FVL.
d. Genetic testing for HTN is available, but it is very expensive because it is so new.
4. Yom HCM patient has given you a four-generation family history, and none of her relatives appears
to be affected. What could be going on?
a. HCM is an aurosornal-dorninanr disease, so she has been misdiagnosed.
b. She is nor providing accurate and complete information about her family history.
c. Some of her family members could have been diagnosed with asthma, anxiety attacks, or mitral
valve prolapse when they really had HCM.
d. HCM is autosomal recessive, so it may nor show up in a four-generation pedigree.
5. Select a reason why the low-density lipoprotein (LDL) receptor gene could cause the LDL receptOr
not to work properly.
a. The receptor might not be able to move from the endoplasmic reticulum to the Golgi apparatus.
b. The receptor could bind tOOeasily to cholesterol molecules, clogging the cell membrane.
c. High doses ofHMG-CoA reductase inhibitors could result in the production of a defective protein.
d. If a person has Tangier disease, atherosclerotic plaques cannot be properly produced.
6. What is true regarding the origins of stroke?
a. Approximately 50% of strokes are ischemic in origin.
b. Monogenic or single-gene causes of stroke do not exist. It is a complex, multifactorial disease.
c. The phenotype is well defined, which makes study much easier.
d. Genes that increase the risk of atrial fibrillation have also been linked to increased risk for stroke.

CASE STUDY

Margery's maternal grandparents moved to Cincinnati, Ohio, from Ireland before her mother was born.
Both her paternal grandparents were of Scottish ancestry. Margery recently married Sam, and they want
to put oft having children until they are financially stable. She is interested in advice about birth control and
asks for information about oral contraceptives during her routine physical examination. You take a family
history and find out that Margery's mother has a history of blood clots, and her paternal grandfather died
from a stroke.
1. Why is the history of blood clots and stroke important to consider in Margery's decision regarding
oral contraceptives?
2. How is Margery's Celtic background relevant to her risk of blood clots?
3. Should you suggest that she have genetic testing for factor V Leiden?
4. How could your concerns be handled in a professional manner consistent with your scope of
practice?

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 Chapter 13 CardiovascularDisorders 281

References

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Self-Assessment Answers
I. b 2. b 3. a 4. c 5. a 6. d

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 Chapter 14__
The Genetics of Cancer
Learning Outcomes
1. Compare the characteristics and growth regulation of benign turner cells and cancer cells.
2. Examine genetic factors influencing cancer development, including mutational events in suppressor genes
and oncogenes.
3. Compare the cancer development processes of initiation and promotion.
4. Compare the cancer development processes of progression and merastasis.
5. Analyze families for the presence of sporadic, familial, and hereditary cancer.
6. Indicate who within kindred is at an increased genetic risk for hereditary cancer.

Key Terms
Benign tumor Inherited cancer Primary tumor
Cancer Initiation Progression
Carcinogen Latency period Promotion
Cell adhesion molecules Malignant transformation Proto-on cogene
(CAMs) Metastasis Sporadic cancer
Driver mutations Neoplasia Tumor of unknown origin
Familial cancer Passenger mutations

INTRODUCTION
Fossil records of early humans, along with writings and records from ancient Egypt and Greece identify the
presence of cancer even in ancient times. Currently, cancer (malignancy) is a wordwide heath problem that
is known to have always affiicted humans, although not at the rate currently found. Worldwide cancer types
have been identified to vary over time and in different geographc areas.
Age is known to increase the risk for developing cancer. The environment is another suggested cause, though
pollution has been controversial as a source. A list of pollutants and chemicals capable of altering DNA is
on the National Toxicology Program's website. Other facrors such as smoking, poor diet, and lack of exercise
are all well-known contributors to cancer in the world today. Genetics was known to be a contributor to

283

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284 Unit IV Genomic Influences on Selected Complex Health Problems

the development of cancer, even before the completion

"All Cancer Is Genetic:' Is This a True
Statement? of the human genome sequencing in 2003. Genetics!
genomics are now used for a variety of new diagnostics
Yes,it is a true statement because cancer develop-
or prognostics for early detection and targeted therapies
ment involves changes in the genes that regulate
cell division. needed to interrupt genetic pathways for better cancer
treatment outcomes. Understanding the genetic basis for
cancer development and its progression involves applying
"All Cancer Is Inherited." Is This a True concepts previously presented for basic DNA structure
Statement? and function, control of cell division, protein synthesis,
The answer is more complex. Yes, cancer is inher- mutational events, and Mendelian inheritance. Please
ited from one cell generation to the next. No, most review the concepts in Chapters I, 2, 3, and 4 before
cancers and the risk for cancer development are studying this chapter. Anticipate reading Chapters 16
not inherited from one's parents; however; excep- and 17 as they apply information from this cancer genet-
tions exist. ics chapter to detection, prognostics, and treatment of
cancer and other diseases.
For many decades, scientists and clinicians involved in cancer research and care have considered the pos-
sibility that gene activity could be related to cancer development. Some of the early evidence supporting a
possible interaction between genetics and cancer include the following observations:
• People who have known chromosome abnormalities (such as Down syndrome [trisomy 21] and Turner
syndrome [monosomy Xl) have an increased incidence of certain cancers.
• People with broken or fragile chromosomes (Fanconi anemia or Bloom syndrome) have an increased
incidence of certain cancers.
• Some cancer types (such as breast cancer), in addition to occurring in people who do not have a family
history of cancer, also occur within families and at times appear to follow an autosomal-dominant pattern
of inheritance.
• Some families have a much higher incidence of either one type of cancer or many types of cancer than
can be accounted for by chance alone.
• Cancer cells often have abnormal numbers andlor structures of chromosomes.
• More aggressive cancer cells usually have more abnormal chromosomes.
The influence of genetic changes that affect cell growth and cancer development is becoming clearer. Such
changes result in conferring cancer cells with characteristics, responses, and growth advantages that optimize
the survival of cancer cells over normal cells. The genes most affected by mutations that result in cancer
development are those genes regulating normal cell growth-the oncogenes and suppressor genes. Recall
from Chapter 3 that proto-oncogenes are a large group of genes that produce proteins with the function of
promoting cells to enter and complete the cell cycle. Suppressor genes are a set of master control genes that
produce proteins with the function of restricting cells from entering the cell cycle and that inhibit movement
of a cell from one phase to the next within the cell cycle. When the DNA from these rwo types of genes
is changed, they are designated as driver mutations, with clear linkage to cancer development and growth
advantage, or passenger mutations, which are seen wirhin the cancer genome but are not linked to growth
advantage.

BENIGN TUMOR CELLS

Neoplasia is any new or continued cell growth that is nor needed for normal development or for the replace-
ment of dead and damaged tissues. It can be benign or malignant. Benign tumors are a type of neoplasia

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 Chapter 14 The Genetics of Cancer 285

that does not share most of the characteristics of cancer cells. Although benign tumors are abnormal, they
arise from normal cells and retain most normal cell characteristics. Their growth is not invasive; however,
depending on location, they can cause death. Some examples of benign tumors include uterine fibroids (leio-
myomas), fat tumors (lipomas), colon polyps (intestinal epithelial adenomas), nerve fibers (neurofibromas),
and skin moles (nevi).

Characteristics of Benign Tumor Cells

Appearance
Benign tumors arise from normal cells and retain a normal differentiated (specialized) appearance. Their spe-
cific morphology is the same as that of the parent cells, even if their location is not. They also retain a small
nuclear-to-cytoplasmic ratio.

Function
Benign tumors usually retain the differentiated function or specialized functions of the parent cell. For example,
not only do the cells of intestinal adenomas look like normal intestinal cells, but they also produce the same
substances.

Adherence
Benign tumors may grow in the wrong place within the body, such as the growth of endometrial tissue on an
ovary and not in the uterus, but they do produce most cell adhesion molecules. As a result, these cells adhere
tightly to one another and do not migrate.

Ploidy
With few exceptions, tumor cells that are totally benign are diploid and do not display abnormal chromo-
some numbers or structures. Exceptions include benign meningiomas, which are ofren missing the chro-
mosome number 22, and lipomas, which often have structural rearrangements of chromosomes 6, 12,
or 13.

Cell Growth
Benign tumors have continuous or inappropriate cell growth unnecessary for normal function. They serve
no useful purpose. Benign tumor cells can grow by hyperplasia or hypertrophy but do not have the ability to
invade other tissues or organs. Their growth occurs by simple, nonessential expansion. Although growth may
continue beyond an appropriate time, the rate of growth is slower than normal.

Pathologic Potential
The mere existence of benign tumor cells indicates that the strict regulation of growth has been overcome to
some degree. In many benign tumors, growth is slow and may even stop eventually. Other benign tumors,
however, carry a risk that growth regulation will continue co deteriorate and a malignant tumor (cancer)
will result. For example, intestinal adenomas have a high potential to become malignant, although consider-
able time passes (up to 10 years of growth) before this happens. (This is why everyone over 50 years of age
should have a regularly scheduled colonoscopy every 10 years so that polyps can be removed and colon cancer
prevenred.) Benign tumor cells become cancerous as the result of inhibited suppressor gene function and/or
enhancement of oncogene function.

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286 Unit IV Genomic Influences on Selected Complex Health Problems

CANCER CELLS
Cancer is a disease of cells, although it is often addressed as an organ problem (e.g., lung cancer, colon
cancer, breast cancer). As explained earlier, cancer cells arise from normal cells. Humans are constantly
exposed to personal and environmental conditions that can mutate the DNA, change the genes, and alter
the normal regulation of cell growth. Such changes can transform a normal cell into a cancer cell. This
type of transformation that causes cancer development is termed carcinogenesis, oncogenesis, or malignant
transformation. Substances capable of causing genetic mutations that lead to cancer development are car-
cinogens. The changes cause cells to always be abnormal, have no useful purpose, and invade normal body
tissues and organs. The International Agency for Research on Cancer (2016) maintains a Listof more than
1,000 compounds that may cause cancer in humans. \Vithout treatment, most cancers lead to death of the
individual.

Characteristics of Cancer Cells

Appearance
Cancer represents a continuum of progression from just barely malignant, in which a normal cell has been
transformed into a cancer cell but still has structural componenrs that cause it to remain at the site in the
tissue in which it originally developed (in situ), to a highly malignant and aggressive cell with metastatic
tendencies. Thus, there are degrees of malignancy. Over time, cancer cells eventually lose all the specific dif-
ferentiated appearance of the cells from which they arose and become anaplastic as small, round cells with a
larger nuclear-to-cytoplasmic ratio. Early in the cancer continuum, cancer cells may still show some normal
cell appearance features, but these are later lost until no parental cell features are retained. A diagnosed cancer
that has lost all features of the parem cell is designated as a tumor of unknown origin.

Function
In the evolution of cancer from nearly normal to highly malignant, cancer cells gradually lose most or all
differentiated functions that the parent cells performed. They become less differentiated in both appearance
and specialized function.

Adherence
The ability to produce cell adhesion molecules (CAMs) is usually lost in cancer cells. They adhere poorly to
each other and can easily break off from a formed tumor. This loss of adherence allows cancer cells to migrate
into surrounding tissues and enter blood vessels in order to travel to distant sites. The invasion of nearby and
dis tam tissues is unique to cancer cells and is a common cause of death. For example, if breast cancer remained
only within the breast, a nonviral organ, it would not kill the patient. However, breast cancer cells do travel,
invade vital organs (e.g., brain, bone marrow, lungs, liver), and disrupt their functions enough to cause death.

Ploidy
Early in the cancer process, the cancer cell's chromosomes may continue to be normally diploid. As they
become more malignant, they usually become aneuploid, with gains or losses of whole chromosomes,
chromosome breakage, and the structural rearrangemenrs of chromosomes. Often, the more malignant a
cancer cell becomes, the greater the degree of aneuploidy it has. Some chromosomal rearrangemems are
unique to a cancer type and can be used to identify it as a specific cancer type. These unique types of
aneuploidy may indicate which oncogenes are overexpressed in a tumor and may be able to be controlled

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 Chapter 14 The Genetics of Cancer 287

through targeted therapy. For example, a chromosome rearrangement in which the ends of the q arms of
chromosome 22 are translocated to the q arms of chromosome 9 is close to a promoter site and results
in the activation of a special tyrosine kinase (TK) that converts normal bone marrow cells into a more
rapidly growing disorder called chronic myelogenous leukemia. This special TK is inhibited by the tar-
geted therapy drug imatinib mesylate (Gleevec). This drug works only on cancer cells that overexpress this
special TK.

Cell Growth
Cancer cells no longer respond to external or internal signals. They are not contact inhibited and continue to
divide even when roo many cells are already presem and nutrition stores are low. This loss of contact inhibi-
tion allows the persistence of cancer cell division regardless of how many cancer cells are occupying a given
space. Without treatment, they persist in continued cell division until the host dies.
Cancer cells also do not respond to signals for apoprosis. They do not experience a reduction of telorneric
DNA with cell division, even though they may nor have particularly long telorneres. Cancer cells have large
amounts of telornerase, which maintains their relorneric DNA.
Suppressor gene regulation of cell division appears lost or defective in cancer cells, and oncogenes are then
overexpressed, which leads to uncontrolled mitosis. They do nor go through the cell cycle more rapidly than
do normal cells; they just reenter the cell cycle quickly, spending very little time in the reproductive resting
state of Go, during which the cell provides its specialized function. The three known cell cycle checkpoints
are not effective, allowing damaged DNA to be unrepaired as it moves through the cell division process with
prornitotic forces being unopposed. Usually, one or more suppressor genes are disabled and cannot restrict
oncogene expression. With excessive oncogene expression, cyclins and cyclin-dependent kinases (CDKs) are
overproduced, and cell division occurs inappropriately and continually. (Using the car example described
in Chapter 3, the car driver and/or the car's brakes are nonfunctional, so acceleration goes wild.) Because
highly malignant cancer cells divide almost continually, their mitotic index (the percentage of cells within
a block of tissue that are actually in the cell cycle at any point in rime) is relatively high, usually greater
than 50%.

Immortality
Cancer cells are considered immortal because they do not respond to apoptotic signals and are resistant to
natural cell death. Unlike normal cells, they do not have a preprogrammed number of cell divisions. One
feature of cancer cells is that additional gene changes continue to occur that alter the plasma membrane [Q
enhance uptake of all needed nutrients even though they can tolerate very low levels of nutrients. When limited
nutrients are present in the environment, cancer cells can take them in more efficiently than the surrounding
normal cells, leaving normal cells in a starved and weakened condition. One example is the increased cancer
growth due to the use of the nutrient glutamine by the myc oncogene.

CANCER DEVELOPMENT

Malignant Transformation
Other names for malignant transformation, the process of changing a normal cell into a cancer cell, are car-
cinogenesis and oncogenesis. This process takes time and involves many steps to overcome the body's natural
resistance to cancer (Fig. 14-1). The steps of the process are initiation, promotion, progression, and metastasis,
as shown in Figure 14-2.

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Mutationalevent

Cancer
Figure 14-1 Malignant transformation from
a normal cell to cancer cells after exposure
to a mutational event.
<i..>
Continuingexposureto promotors
cells

Altered cell
(dysplasia)

~l Tumor

More malignant

~l Metastasis
Figure 14-2 The steps of initiation and continued promotion to trans-
form a normal cell to a cancer cell and allow it to progress to a highly
malignant, metastatic state. 1
Initiation
Normal cells may become cancer cells when their oncogenes are overexpressed, which results in poorly con-
trolled cell division. The initial step in malignant transformation is mutating the DNA in such a way that
either suppressor genes cannot perform their cell growth regulation functions or oncogenes become resistant to
suppressor gene control. Any substance or event that can damage DNA has the potential to mutate suppressor
genes or oncogenes and is a carcinogen. For cancer development, this type of mutation is termed initiation.
It is an irreversible event that can lead to cancer development if the cell's mitotic ability remains intact. If a
cancer cell cannot divide, it cannot progress to widespread malignant disease. However, when conditions favor
the continuing growth of even one transformed cell, widespread malignant disease can occur. This is known
as the monoclonal ("from one cell") origin of cancer. Initiation is a required step in carcinogenesis. Without
initiation, even if the remaining steps occur, cancer does not develop.

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 Chapter 14 The Genetics of Cancer 289

.r,!1:j.:Hf;!!!Il

The Incidence of Common Cancers in United States

Cancer Type Incidence (Estimates for 2016)

All cancers 1,685,210

Lung and bronchus 224,390
Prostate 180,890
Breast, female 246,660
Colorectal 134,490
Lymphomas (all types) 72,580
Urinary bladder 76,960
Melanoma 76,380
Kidney (and renal pelvis) 62,700
Thyroid 64,300
Uterine (corpus) 60,050
Pancreas 53,070
Leukemia 60,140
Oral cavity and pharynx 48,330
Liver 39,230
Ovary 22,280
Uterine cervix 12,990

Data compiled from American Cancer Society. (20161. Cancer faels and figures 2016 (Repon No.
500816). Atlanta. GA Author.

In general, most cancers arise in cissues that have retained mitotic ability. This does nor mean that all the
cells within one organ type have rerained mitotic ability. Rather, it means that of the mixture of cells compos-
ing an organ, those that retain mitotic ability are much more Likelyto undergo carcinogenesis than those that
have not. For example, the three main types of normal cells in the uterine cervix are squamous epithelial cells,
glandular cells that secrete mucus, and neuroendocrine cells. Only the squamous epithelial cells retain mitotic
ability, and about 90% of cervical cancer arises from these cells. Although cancer can arise from cardiac muscle
cells, which are nonmirocic, this is a very rare type of cancer. Table 14-1 lists the most common cancer types
and their incidence in North America.
Carcinogenic substances capable of initiation include a wide variety of chemicals, physical agents, and
viruses. Initiation can also occur through spontaneous DNA replicacion error, which is more likely when cells
are dividing more frequendy, such as during inflammation or after injury. When initiation has occurred in
germline cells (ova or sperm), the risk for cancer development can be passed on to one's children. Children
who are born as a result of conception in which one of the rwo germline cells has been initiated essentially
have all their cells already past the initiation step of carcinogenesis. These people have a greatly increased risk
for cancer development if the other steps of carcinogenesis occur at any time throughout their life spans.
Remember that cell iniriation occurs much more frequently than does cancer development. We are con-
stantly exposed to environmental carcinogens and may have some cells initiated daily. However, we do nor

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develop cancer daily, and most people will never develop cancer at all. In the United States, about one in two
women and one in three men will develop cancer at some point in their lives. Not only are the other steps
of carcinogenesis needed for initiated cells to become malignant, but personal factors also make some people
more resistant to cancer development than others.

Promotion
Alrhough a cell initiated by a carcinogen can develop into cancer, it will do so only if promotion occurs after
initiation. Promotion is the process of enhancing the growth of initiated cells over time (see Figures. 14-1
and 14-2). It is a long, slow process for an initiated cell to form a malignant tumor. No one develops an
identifiable cancer the day after exposure to a carcinogen, even if it is an especially strong or potent carcinogen.
Time and continuing exposure to agentS that cause promotion (promoters) are needed (note that promoters are
different from the promoter regions of DNA for protein synthesis discussed in Chapter 2). The time between
initiation and the development of an identifiable tumor is the latency period, which ranges from months to
years. (People never get lung cancer 1 week after they smoke their first cigarerte.) The length of the latency
period varies depending on the following: the strength of the carcinogen (more powerful carcinogens result
in a shorter latency period), whether the tissue is also exposed to additional carcinogens (cocarcinogens), the
amount of exposure to promoters (greater exposures result in a shortened latency period), and the individual's
resistance to cancer development (discussed later in the "Personal Factors Related to Cancer Development"
section).
Promoters are substances or conditions that enhance (promote) the growth of the initiated cancer cell. Pro-
motion can also shorten the latency period. Promoters include naturally occurring hormones, such as estrogen,
testosterone, and insulin; drugs; and a wide variety of chemicals. For example, when cervical epithelial cells
have been initiated by viral infection or exposure to cigarette smoke or another chemical, growth is enhanced
by the presence of the woman's own naturally secrered estrogen or progesterone. Thus, the normal hormone
is serving as a promoter.
Some carcinogens have both initiating ability and promoting ability. These are known as complete carcino-
gens because additional exposure to another promoter is not needed for cancer to develop. A few examples of
complete carcinogens include radiation, benzopyrene, naphthylamine, and nirroquinoline.

Progression
After sufficient cancer cells have been promoted enough mar an identifiable rumor exists, other conditions
are needed for this tumor to become as malignant as possible. Progression is the continuing genetic changes
that occur in cancer cells that alrer rheir physical, biochemical, and metabolic processes, and confer survival
advantages to these cells. The most important changes allow cancer cells and tumors to develop a separate
blood supply and enhance cellular nutrition. In small tumors, nutrition occurs by diffusion, which is not
efficient after a tumor is larger than 1 cm. With increased growth, tumor cells become hypoxic and begin to
secrere angiogenesis factors like vascular endothelial growth factor (VEGF), which normal tissues may secrete
under hypoxic conditions. VEGF stimulates nearby blood vessels and capillaries to branch into the tumor,
establishing a rumor blood supply and improving the availability of tumor nutrition.
Other changes brought about by progression include membrane permeability changes. Many normal cells
require insulin and insulin receptors to allow glucose to enter the membrane. Cancer cell membranes become
direccly permeable to glucose so that insulin and insulin recepwrs are not needed. However, glucose uptake
is increased further in the presence of insulin. Cancer cell membranes become even more efficient at amino
acid uptake. As a result of these changes, cancer cells are able to meet their increased metabolic needs quickly
and often at the expense of normal cells.

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Because cancer cells have no need for differentiated functions, changes through progression result in the
loss of differentiated functions. This loss reduces the energy expenditure wasted on differentiated functions,
which now can be used for even more efficient cell division. Thus, through progression, cancer cells and
tumors acquire selection advantages that allow them to live and divide no matter how the conditions around
them change. Over time, cancer cells become more and more malignant, expressing fewer and fewer normal
cell features.
A primary tumor is the original tumor, usually identified by the tissue from which and in which it first
arose (e.g., ovarian cancer, colorecral cancer, prostate cancer). When primary tumors are located in vital organs,
such as the brain or lungs, their excessive growth interferes with the performance of vital functions and leads
to death. When primary tumors are located in soft tissue, tumor expansion can occur with little or no damage
to surrounding tissue. However, most malignant tumors do nor remain in the tissues in which they arise.

Metastasis
Metastasis is the spread of cancer cells from the primary tumor to other body areas, where they grow and
damage additional tissues and organs, often leading to death. One of the advantages acquired by cancer cells
during progression that allows metastasis to occur is the loss of cell adhesion molecules (CAMs), making cancer
cells lose their contact inhibition so that they are poorly adherent to each other. An additional advantage is
the expression of enzymes on the cancer cell's surface that makes these cells able to penetrate other tissues and
blood vessel walls. Cancer cells then form secondarytumors (metastatic tumors) by breaking off from the primary
tumor. Secondary tumors can form by extension into nearby tissues via (I) the bloodstream, (2) the lymphatic
system by lymph nodes, and/or (3) across the thoracic, peritoneal or abdominal body cavity (transcoeliomic)
to establish colonies in remote tissues. Even though the tumor is now in another organ, it is still a cancer
from the original parent tissue. For example, when prostate cancer spreads to the bone and lymph nodes, it
is prostate cancer in the bone and lymph nodes, not bone cancer and not lymphoma.
Metastasis is a complex process that requires many steps over time. Most steps result from continued genetic
changes through progression. Many cancers have a predictable pattern of metastasis. Table 14-2 lists the sec-
ondary tumor sites for metastasis of common tumors. Although other mechanisms for metastasis to distant
sites exist. cancers spread locally by spreading into the neighboring tissue. Regional spread occurs through
the blood stream travel to tissues or organs that are close to the primary site. When malignant cells travel to
distant sites. the process is called metastasis. Metastatic sites are often in distant organs with extensive capillary
networks such as the lung and liver. The most common way cancers metastasize is via the lymph nodes and
circulation. depending on the tumor type.

Cancer Causes and Risk

As discussed earlier, cancer development takes years
Does a Primary Defect Cause the
and depends on several tumor and patient factors. The
Transformation of a Normal Cell to a Cancer
three factors influencing carcinogenesis and metastasis cell? Does a Mutation of an Oncogene Affect
are environmental exposure to carcinogens (initiators and the Outcome? How Does This Occur?
promoters), immune function. and genetic predisposi-
The main defect in carcinogenesis is inappropriate
tion. These three factors explain some of the variation and excessive oncogene expression, regardless of
in cancer development from one person to another, even the specific cause.
when each person has the same environmental exposure.
In theory, mutating an oncogene could increase its activity. although such damage usually makes a gene lose
its function rather than enhance it. One way mutation of an oncogene can lead to its increased expression is
when mutation causes an increase in the number of copies of the oncogene in the affected cells (amplification).

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292 Unit IV Genomic Influences on Selected Complex Health Problems

.,!,:j.:MI'!" ....
The Usual Sites of Metastasis for Selected Cancers
Cancer Type Sites of Metastasis

Prostate cancer Bone (especially spine and legs)*

Pelvic nodes
Liver
Lung cancer Brain*
Bone
Liver
Lymph nodes
Pancreas
Breast cancer Bone*
Lung*
Liver
Brain
Colorectal Liver*
Lymph nodes
Adjacent structures
Melanoma Gastrointestinal tract
Lymph nodes
Lung
Brain
Pancreatic cancer Liver*
Lungs
Bone
Spleen
Adrenal glands
Lymph nodes
Blood vessels

'Most common site of metastasis for the specific cancer.

Instead of having one copy of the rwo alleles for a specific oncogene within one cell, as many as 500 copies
might exist. (In the car analogy, this would be like having a jet engine in a small car bur having JUStthe
normal brakes for the car. Just a little pressure on the gas pedal would make the car go very fast and not be
able to stOP with the existing brakes.) Another way is to move the oncogene (rranslocate it) to an area of the
genome not under suppressor gene control. (Think about purring a car's engine on a grocery carr that has
no brakes.)
The more common way initiation leads to excessive oncogene expression is by damaging anyone of many
suppressor genes. When a suppressor gene is damaged, it can no longer express its products in the proper
amounts to control oncogene expression. Suppressor genes, like most single genes, have two alleles. When one
allele is damaged and nonfunctional, the amount of suppressor gene product in the affected cells is reduced
by about 50%, and control over oncogene expression is not as strict (Fig. 14-3). (Using the car analogy, if the
front brakes are nonfunctional, rhe car can still be stopped before crashing, bur this requires more planning

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 Chapter 14 The Genetics of Cancer 293

c
Figure 14-3 (A) The car has both sets of brakes (suppressor gene alleles) working properly so
that the car stops well in front of the trees. (B) The front brakes (one suppressor gene allele) are
not functioning, and the car takes a longer distance to stop, but it still does not hit the trees.
(C)The front and rear brakes (both suppressor gene alleles) are both nonfunctional. The car cannot
stop and hits the trees.

by the car driver and longer distances for the remaining brakes to perform this funcrion.) When borh sup-
pressor gene alleles are nonfunctional, oncogene expression is unopposed, and mitosis occurs continually.
(When both sees of brakes are nonfunctional, the engine runs without controls, and the driver cannot stop
the car before it crashes.)

External Factors Related to Cancer Development

External factors, including environmental exposure to carcinogens, are responsible for at least 80% of cancer
in North America. Chemical carcinogens vary in how great their carcinogenic potential is. For example,

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tobacco and alcohol appear to be only mildly carcinogenic, requiring long-term exposure to large amounts
of these substances before cancer develops. (These two substances can act as cocarcinogens so that when they
are used together, they enhance each other's carcinogenic porenrial.) Chemicals with carcinogenic potential
can be found almost anywhere in the environment, including in the food chain. Dietary influences on cancer
development include chemicals in food and diets that are deficient in antioxidant substances, which tend to
repair damaged cells and reduce the effects of mutational events on mitosis.
Physical carcinogenesis occurs through direct gene damage and mutation by physical agents. Two common
physical agents that can result in cancer development are radiation and chronic irritation. Radiation can directly
mutate DNA. Potential sources of radiation include exposure to rocks and soil that contain varying amounts of
uranium and radium, x-rays for the diagnosis and treatment of disease, cosmic radiation, solar radiation from
the sun, tanning beds, and germicidal lights. Chronic irritation greatly increases mitosis in affected tissues,
increasing the likelihood of unrepaired spontaneous DNA replication error.
The infection of cells with certain types of viruses, known as oncouiruses, can lead to carcinogenesis. These
infecting viruses break the DNA of the cells they infect and then insert their own genetic material into the
human DNA. The result of breaking the DNA and inserting viral genes mutates the normal cell's DNA. These
mutations can damage suppressor genes and can allow the overexpression of oncogenes.

Epigenetics of Cancer
Epigenetic changes occur beyond those to the classic DNA sequences known to be associated with cancer. The
most studied changes are loss of methyl groups (hypomethylation) of the tumor DNA and gain of methyl
groups (hypermethylation) in the promoter region of tumor suppressor genes. Methylation can alter gene
expression and inAuence modifications in the histone structure causing changes in cancer cells. Other modi-
fications affecting gene transcription and DNA repair include histone modilication, chromatin remodeling,
and silencing of target genes by microRNA (miRNA). Histone modification includes the addition of chemical
groups to cause changes to the histone tail that affect the binding of certain proteins. Chromatin remodeling
causes tight packing of the transcription regions of DNA so that they are no longer available or are difficult
to reach, causing that region of the DNA and gene to be silenced. These general modifications, especially
hypomrhylation, may allow oncogenes to be over expressed, leading to cancer development. Hyperrnethylation
and any modification that silences DNA regions can lead to cancer development by preventing suppressor
genes from producing their growth-regulating products. See Chapter 5 for more discussionof how epigenetic
events can influence cancer development.

Personal Factors Related to Cancer Development

The personal factors of age, immune function, and genetic risk, along with lifestyle behaviors and environmental
exposures to carcinogens, can influence cancer development. Aging is a major factor in cancer development.
Consider how many more women over the age of 60 develop breast cancer than do women between the ages of
20 and 40 years. Advancing age allows for the effects of exposure to environmental carcinogens to accumulate
and simultaneously results in reduced immune function.
A well-functioning immune system protectS the body from cells that are no longer completely normal,
such as damaged cells and cancer cells. Immune system cells, especially macrophages and natural killer cells,
recognize unhealthy cells and attack and destroy them. This is most likely the protection that prevents those
daily mutational events (which result in a few cells becoming initiated) from remaining in the body long
enough to continue, preventing the rest of the carcinogenesis steps and the development of an identifiable
tumor. Anyone whose immune function is less than optimal has an increased risk for cancer. Mutation and
initiation do not occur more often; rather, they are less frequendy recognized allowing cancer to get a foothold.

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 Chapter 14 The Genetics of Cancer 295

The role of immune protection against cancer development is supported by the increased cancer incidence
seen among people who are immunocompromised, including the following groups:
• Children under age 2, whose immune systems are nor yet fully developed
• Adults older than age 60, whose immune function is gradually declining (especially the T cells that direct
the immune response)
• Patients with any form of long-term immune deficiency (especially HIV/AIDS)
• Patients who are organ transplant recipients taking immunosuppressive drugs to prevent organ rejection
• Patients who have serious autoimmune or inAammarory disease and must take cortisol or other strong
immunosuppressants to control the disease

Genetic Factors Related to Cancer Development

Although all cancer is "genetic," not all cancers are inherited. Cancers can be classified based on how frequently
they occur in a kindred and whether an inherited genetic mutation may be responsible for increased risk. These
classes are sporadic cancer, familial cancer, and inherited cancer. A confounding factor is that some cancer
types, such as breast cancer, colorecral cancer, and prostate cancer, can fall into any of these classes, and some
families may have all three classes of one cancer type within a kindred.

Sporadic Cancer
Sporadic cancer is cancer that usually occurs as a result of environmental exposure or unknown factors and
does not have any observable pattern of inheritance within a kindred. At the cell level, mutations through
carcinogenesis have occurred, disrupting the normal regulation of cell division, usually among somatic cells.
These cancers are not present in higher-than-expected levels within three or more family generations. Although
the cause of the cancer is not always known (making primary prevention difficult), individual family members
are not predisposed to it. For example, breast cancer is a common cancer, occurring in one out of eight women
in North America over the age of 60 years. In Figure 14-4, the family history of a 72-year-old woman recently
diagnosed with breast cancer is examined. Of 15 female relatives in three generations on the paternal and
maternal side, only 3 other women, none of whom is a first-degree relative, have been diagnosed with breast
cancer, and all were older than age 60 at the time of diagnosis. An importan t feature of sporadic cancers
among somatic cell tissues is that the person cannot pass on a predisposition for the cancer to his or her
children because these mutations are acquired only in the tissues mat develop the cancer. (Children do not
inherit somatic cells from their parents. They inherit only germline cell genes that are then used to develop
somatic cells.)
Mutations of different suppressor gene and oncogene somatic cells are associated with different cancer types.
Table 14-3 lists known cancers associated with specific gene mutations in somatic cells.

Familial Cancer
Familial cancer is cancer that occurs at a higher-than-expected frequency within a kindred but does not
demonstrate any observable pattern of inheritance. The family may have a higher-than-expected incidence
of other cancer types as well. However, most family members who develop cancer do so at older ages. Breast
cancer can also be familial. Figure 14-5 shows a typical pedigree for familial breast cancer. In the kindred,
5 of 15 women have had breast cancer, and all were older than 60 years at the time of diagnosis (a little higher
than expected by chance alone). In addition, 4 other family members have had cancer, some of whom were or
are first-degree relatives to each other. At this time, no specific pattern of inheritance emerges, and no specific
genetic testing is recommended. Eventually, a genome-wide association study (GWAS) may provide insight
into risk for familial cancer. (For more information on GWASs, refer to Chapter 16.)

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296 Unit IV Genomic Influences on Selected Complex Health Problems

81

II
75 68

III 72

t
Figure 14-4 A typical family history and pedigree showing sporadic breast cancer.

81 69 64
AL BC LC

II

75 75 90 72
PC BC BC CRC

= Breast cancer

= Colorectal cancer
III 65 68
= Lung cancer
BC BC

o
= Prostate cancer

= Acute leukemia

Figure 14-5 A typical family history and pedigree showing familial breast cancer.

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 Chapter 14 The Genetics of Cancer 297

.'!':jlll=-[!~j:
Examples of Cancers Caused by Mutations in Suppressor Genes,
Oncogenes, and DNA Repair Genes
Mutated Gene Cancer Types

Suppressor Genes
APC Colorectal, stomach, and pancreatic carcinomas
ATM Breast, stomach, bladder, pancreas, lung, and ovarian carcinomas
BRCA1 Breast, ovarian, genitourinary, and gastrointestinal carcinomas
BRCA2 Ovarian, breast, and prostate carcinomas
DCC Colorectal carcinomas
Rb1 Retinoblastoma, sarcomas, bladder, breast, esophageal, and lung carcinomas
PTEN Breast, prostate, and uterine carcinomas; melanomas; brain tumors (glioblastomas,
astrocytomas)
Tp53 Bladder, breast, colorectal, esophageal, liver, lung, ovarian, and central nervous system
sarcomas; lymphomas; and leukemias (Li-Fraumeni syndrome)
WT1 Wilms tumor
Oncogenes
abl Chronic myelogenous leukemia and other leukemias
c-myc Burkitt lymphoma; other lymphomas; breast, stomach, and lung carcinomas
Hras Many carcinomas and sarcomas
Kras Colorectal and pancreatic carcinomas, a wide variety of other carcinomas and sarcomas
Nras Neuroblastoma
met Osteosarcoma
myb Colorectal carcinomas, leukemias
PTCH Bladder and breast carcinomas
ret Thyroid tumors
trk Colorectal carcinomas and thyroid tumors

DNA repair genes

MLH1 Hereditary non polyposis colon cancer (Lynch syndrome); endometrium, ovary, stomach,
small intestine, liver, gallbladder duct, and upper urinary tract cancers
MSH2 Hereditary non polyposis colon cancer (Lynch syndrome); endometrium, ovary, stomach,
small intestine, liver, gallbladder duct, upper urinary tract, brain, and sebaceous skin
cancers
MSH6 Hereditary non polyposis colon cancer (Lynch syndrome); endometrium, ovary, stomach,
small intestine, liver, gallbladder duct, upper urinary tract, brain, and skin cancers;
neurofibromatosis, leukemia, and lymphoma
PMS1 Hereditary non polyposis colon cancer (Lynch syndrome)
PMS2 Hereditary non polyposis colon cancer (Lynch syndrome); glioblastomas, leukemias, and
lymphomas

Data compiled from U.S. National Library of Medicine. (2017). Genetic home reference: Genes. Retrieved from http://ghr.nlm.nih.gov/
genel

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Inherited Cancer
Inherited cancer is cancer that occurs with an observable autosomal-dominant pattern of inheritance among
much younger-than-expected individuals in a kindred. Eight breast cancer genes have now been identified
as conferring high to moderate risk of developing breast cancer. These include ATM, BRCAI and BRCA2,
CDHl, CHEIQ, PTEN, PALB2, and TP53. Figure 14-6 shows a pedigree for a family with familial breast
and ovarian cancer from a BRCA 1 suppressor gene mutation. This is a germline mutation and is present in one
BRCAl allele in aLLof a person's cells. These cells essentially have already gone halfway through initiation at
conception and require only one additional allele mutation followed by promotion for a malignancy to occur.
This is why the cancer tends to appear at earlier ages than expected. Although its presence does not absolutely
mean that the person will go on to develop breast and/or ovarian cancer, the risk is very high. In addition,
each person with one mutated BRCAl allele in every cell has a 50% chance of passing on the mutated allele
and its predisposition to children in the next generation, whether they are male or female.
Many inherited germline mutations of suppressor genes or oncogenes greatly increase the risk for cancer
development. In addition, the mutations of genes that regulate DNA repair also increase the risk for cancer.
Other family characteristics, in addition to an autosomal-dominant pattern of inheritance, that indicate the
possibility of BRCAl and BRCA2 mutations include the following:
• Cancers occurring at younger than 50 years of age
• Breast cancer in male relatives
• Breast cancer in both breasts

36 34 40
OC "Female Bone
cancer" cancer

II

44 and 54 35 40
sc x 2 Be Be

III

e = Breastcancer D = Bone cancer

IV §= Ovariancancer = Femalecancer

Figure 14-6 A pedigree showing the autosomal-dominant pattern of inheri-

tance for inherited cancer (BReA 1 positive).

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 Chapter 14 The Genetics of Cancer 299

• Triple-negative breast cancer (no estrogen, progesterone, or human epithelial growth receptors [HER2J
on the surface of the cellular membrane)
• Presence of a second primary cancer in the same patient
• Ashkenazi Jewish ethnicity
• Presence of family members with both breast and ovarian cancers
• History of pancreatic cancer in any family member
• Confirmation of a BRCAll2 genetic mutation in the family
Overall. the percentage of cancers that occur because of inheritance of a germline gene mutation ranges
between 5% and 15%. Although this is a low percentage, people who have these mutations are at great risk
for cancer development. Genetic testing for cancer predisposition is available to confirm or rule out a per-
son's genetic risk for a few specific inherited cancer types. These tests do nor diagnose the presence of cancer,
nor are they 100% predictive; they merely demonstrate increased risk. Therefore, predisposition testing for
inherited cancer should not be performed unless a family history clearly indicates the possibility of increased
genetic risk and the patient wants to have the test results. More information on predisposition testing and its
associated issues or potential problems is presented in Chapter 16.

SUMMARY
All cancers arise from normal cells that have mutations in either suppressor genes or oncogenes. These muta-
tions result in loss of the strict control of mitosis (hat normal cells have. Although all cancer is "genetic," only
5% to 15% of cancers are inherited. Cancer development is related to a person's age, exposure to carcinogenic
substances or events, the degree of efficient immune function, and genetic composition and predisposition.

GENE GEMS

• Cancer cells arise from normal cells.

• Suppressor gene products limit cell division by controlling the expression of oncogenes so that mitosis
occurs only when and to the extent it is needed.
• Proto-oncogenes are normal genes important in stimulating cell division, stopping apoptosis and con-
rrolling cell differentiation. Oncogenes are mutated versions of these normal cells.
• Benign rumors grow by simple, nonessential expansion.
• The transformation of a normal cell into a cancer cell is caused by genetic mutations.
• Whenever oncogenes are overexpressed after normal growth and developmenr are complete, the person
is at risk for cancer development.
• Tissues rhar retain mitotic ability are far more Likelyto undergo carcinogenesis than those that do not
continue to replace dead or damaged cells through mitosis.
• Malignant tumors have physical, biochemical, and metabolic advantages that allow them to survive
and invade other tissues (metastasis).
• If conditions are right, widespread cancer can develop as a result of initially having only one cell undergo
malignant transformation.
• Secondary tumors are still designated as rumors of the parent tissue.
Continued

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• The major factors that interact to influence cancer development are advancing age, exposure to envi-
ronmental carcinogens, the effectiveness of immune function, and genetic predisposition.
• Somatic cell mutations that lead to cancer development cannot be passed on to one's children as a
predisposition for cancer.
• Germline cell mutations that lead to cancer development have a 50% risk for being transmitted to one's
children and predisposing them to cancer.
• Only about 5% to 15% of all cancers result from inherited mutations.

Self-Assessment Questions. . ....

1. Which characteristics of a tumor are associated with accelerated cell growth?
a. Aneuploid
b. Driver mutations
c. Well differentiated and euploid
d. Contact inhibition
2. Which traits maintain the limited mortality of a normal cell?
a. Programmed number of cell divisions
b. Mitosis of malignant cells yielding more than twO daughter cells
c. Efficient use of limited nutrients by the cancer cell
d. Lack of response [Q apoprosis signals
3. A tumor of unknown origin resembles which cissue type?
a. Tissue in which it was transformed and currenrly resides
b. Movement of known cancer type to secondary site in different organs with original tissue
pathology
c. Distant organ(s) where a malignant lesion resides after travel via the vascular system
d. Unidentifiable parental tissue type
4. By which process does epigenecics assist in cancer development?
a. Hypomethylation of the promoter region of tumor suppressor genes
b. Hypomethylacion of the tumor DNA
c. Decreased acetyl and phosphate group changes to the histone tail
d. Chromatin remodeling so that the transcription regions of DNA are more readily available for
mutation
5. A patient is diagnosed as being at high risk of developing breast cancer. Which statement indicates
the step of promotion in carcinogenesis?
a. "My friends and 1 smoked cigarettes when we went out to bars in college."
b. "I have taken estrogen medication for 30 years."
c. "This lymph node in my neck has become swollen and hard ever since my bout with the flu
last year."
d. "Weight loss has been so difficult for me my whole life, but this time I've lost 35 pounds without
trying."

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 Chapter 14 The Genetics of Cancer 301

6. An 85-year-old patient tells you she does not perform breast self-exams because there is no history of
breast cancer in her family. What is your best response?
a. "You are correct. Breast cancer is an inherited type of malignancy, and your family history indicates
a low risk for you."
b. "Breast cancer can be found more frequently in families; however, the risk for general, sporadic
breast cancer increases with age."
c. "Because your breasts are no longer as dense as they were when you were younger, your risk for
breast cancer is now decreased."
d. "Examining your breasts once per year when you have your mammogram is sufficient screening
for someone with your history,"
7. A 36-year-old patient who has a suspicious mammogram tells you that her mother died of bone cancer
when she was 40 years old. Your follow-up question, "Did your mother ever have any other type of
cancer?" reveals a history of breast cancer. What is your next response to the patient?
a. "Have any other members of your family had bone cancer?"
b. "What were the symptoms your mother had prior to dying from bone cancer?"
c. "Are you aware that breast cancer frequendy will metastasize to the bone, causing complications?"
d. "Did your mother have regular bone density studies after her breast cancer diagnosis?"

CASE STUDY

A 26-year-old client, Leslie (designated by an arrow in Figure 14-7), has been diagnosed with breast cancer.
At age 63, her maternal grandmother, Margaret, was diagnosed with unilateral breast cancer and had a
lumpectomy followed by radiation. Margaret had 10 children, 2 girls with a breast cancer diagnosis (both
at age 62) and 8 other children who did not have any cancer diagnosis. Leslie's 57-year-old mother has not
been diagnosed with breast cancer. Leslie's maternal aunt 1 is now 67 and has recently had a recurrence.
Aunt 2 is 75 without recurrence. Leslie's maternal grandmother is now deceased but not due to breast
cancer. All her maternal first cousins live in Australia, and no one has knowledge of their cancer status.
Leslie's father is age 58. He is an only child. He is not close to his family, who live far away, but is willing
to contact them. Because of her age, the patient was eligible to be tested for a BRCA 1/2 mutation. Her
genetic testing results were BRCA 1 positive.
After talking with his family, the father learned that several diagnoses of breast and ovarian cancer
occurred in the paternal lineage. The paternal grandmother died at age 80 with no diagnosis of cancer.
The paternal grandfather died at age 81 with no cancer diagnosis but had two sisters; one was diagnosed
with breast cancer at age 31, and the other was diagnosed with breast and ovarian cancer at ages 28
and 31, respectively. They both were deceased by age 32. Each had two daughters. The two daughters of
paternal aunt 1 were also diagnosed with cancer, Janice at age 32 with breast cancer and Carla at age 28
with ovarian. Janice had a son who is 17 and disease-free. Carla, paternal aunt 2, has no children. Susie,
paternal aunt 3, was diagnosed with breast cancer at age 33. Linda, paternal aunt 4, was diagnosed with
ovarian cancer at age 54. She has an adopted 12-year-old daughter.
1. Draw the pedigree for the family (see the correct pedigree in Fig. 14-7).
2. What specific pattern of inheritance (if any) is indicated by the pedigree for the cancer in this family?
3. What pedigree criteria support your identified pattern of inheritance for this health problem?
4. Who in this family could benefit from genetic counseling and possible genetic testing? Explain
your choices.
Comimed

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302 Unit IV Genomic Influences on Selected Complex Health Problems

d.? d.?

O Breast
cancer
O Ovarian
cancer Q Ad",.. , D Mo. O Either
gender

Figure 14-7 Pedigree for Leslie's family.

References
Cahone, K., Masny, A., & Jenkins, J. (Eds.). (2010). Cm~fit:s and gmomiu ill OJuologynursing practice. Pittsburgh, PA: Oncol-
ogy Nursing Society.
Canadian Cancer Society. (2016). Canadian cancerstatistics,2016. Retrieved from http://www.cancer.ca/-/mcdialcanccr.ca/CW/
cancer%20 informarion Icancer%20 I0 l/Ca nad ian%20ca Ilcer%20s£atistics/Canadian-Ca ncer-Starisrics-Zf 16-EN .pdP.1a=en
Feero, G., Guttmacher, E., & Collins, F. (2010). Genomic medicine--An updated primer. 1\~1UEngland [ournal of Medicine,
362, 2001-20 II.
Internarional Agency for Research on Cancer. (20 J 6). Agent» clnssifid by ,hi' fARC Monographs, volumes 1-117. 20 16. Retrieved
from http://monographs. iarcJrlEN G/Classi Iication/List_oC Classifications.pdf
Markowitz, S., & Bertagnolli, M. (2009). Molecular origins of cancer: Molecular basis of colorecral cancer. NI!UJEngland fourna!
of Medicine, 361(25), 2449-2460.
National Toxicology Program (NTP). (2016). Report on carcinogens (14th ed.). Research Triangle Park, NC: U.S. Department
of Health and Human Services, Public Health Service. Retrieved from https:llntp.niehs.nih.gov/pubhealth/rodindex-l.html
Stratton, M., Campbell, P., & Furreal, A (2009). The cancer genome. Nature, 458, 719-724.

Self-Assessment Answers
I. b 2. a 3. d 4. b 5. b 6. b 7. c

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 15-
Genetic Contributions to Psychiatric
and Behavioral Disorders

Learning Outcomes
1. Discuss the genetic contributions to common psychiatric or behavioral disorders.
2. Distinguish between the potencial impact of copy-number variants and single-nucleotide polymorphisms
in psychiatric disorders.
3. Identify reasons why the dual diagnosis of mental illness and addictive behaviors is so common.
4. Describe the barriers to finding the genetic causes of psychiatric problems.
5. Explain how a disease can have an 80% heritability estimate but not be inherited in a given family.

Key Terms
Autism Behavioral phenotype
Autism spectrum disorders Biologically plausible
(ASDs) Copy-number variants (CNVs)
Behavioral genetics Externalizing psychopathology

INTRODUCTION
The primary risk factor associated with menral illness is having a close family member who is also affected. In
fact, many psychiatric disorders, such as bipolar disorder, schizophrenia, and autism, have higher heritability
than do breast cancer and Parkinson disease.
Disappointingly, most of the gene variants that contribute to major psychiatric problems offer only a glimpse
of the heritability of these disorders. As new techniques such as genome-wide association studies (GWASs) and
assessment of copy-number variants (CNVs; usually either deletions or duplications of stretches of DNA)
become more standard, the promise that some of the mysteries of mental illness will be solved seems more
and more realistic. For the health-care professional, advances in genetic knowledge will contribute to more
effective diagnoses and treatment of patients with psychiatric problems.

303

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304 Unit IV Genomic Influences on Selected Complex Health Problems

GENETICS APPLICATIONS
FOR THE PSYCHIATRIC PATIENT

Genetic Testing
Health-care practitioners in oncology commonly use genetic testing results to guide the selection of chemo-
therapeutic agents and even surgical regimens. In psychiatry, the use of genetic testing to determine medication
regimens is still in its infancy. The primary goals of the professional organization, the International Society
of Psychiatric Genetics (ISPG), are to identify genes that link risk to psychiatric disorders and also suggest a
pathway from the gene to the phenotype. In addition, the ISPG wants to identify genes that influence response
to the drugs used to treat the disorders and the resulting side effects. This group has thoughtful suggestions
for the use of genetic tests for diagnosis and identification of high-risk individuals for several neuropsychiatric
and developmental disorders, including phenylketonuria (PKU), fragile X syndrome, and Down syndrome
(trisomy 21), as well as some neurodegenerarive diseases, such as Huntington disease (HD). The test results
for these disorders are used to guide preventive treatment or long-term planning by screening at-risk individu-
als before they develop symptoms or to establish the diagnosis once symptoms have developed. Although no
effective therapies currently exist for fragile X or HD, confirming the diagnosis provides the clinician and the
family with useful information about the trajectory of the parient's illness and how to anticipate the needs of
the patient andlor caregivers (ISPG, 2017). Because these are single-gene disorders, specific testing of a gene
or mutation is appropriate.
For adult psychiatric and substance use disorders, GWASs are used to locate susceptibility genes and pos-
sibly lead scientists to biological pathways they never suspected would be involved in the cause of a disease.
This can help clinicians develop a clearer understanding of the disease process itself and, perhaps, find new
ways to treat a challenging disorder (Lee er al., 2013). Psychiatric and substance use disorders found to have
single-nucleotide polymorph isms (SNPs) that alter a single DNA base include schizophrenia, bipolar disorder,
and nicotine dependence. However, so far, these SNPs have not been shown to be significant enough to bring
about a psychiatric disorder. Instead, rhey increase or decrease the risk by a small fraction, much less than
two-fold, so testing one of these does nor warrant developing it as a diagnostic test.
Copy number variants (CNVs) are a group of short or long repeats of one or many base pairs within
a chromosomal region. These may be inherited or new (de novo) CNVs that occur during human repro-
duction a.nd can be associated with an increased risk for a range of psychiatric illnesses, intellectual
disability, autism spectrum disorders, and epilepsy, and they can even occur in seemingly healthy indi-
viduals. More research needs to be done to establish the lifetime risk for persons who carry these CNVs
(ISPG, 2017). Pa.thogenic CNV s can also help diagnose psychiatric disorders that are part of conditions
such as DiGeorge or Phelan-McDermid syndromes and the impriming disorder Peader-Willi syndrome
(ISPG,2017).
Recently, companies have marketed direct-to-consumer (DTC) diagnostic and predictive genetic tests for
some psychiatric disorders. These tests can be obtained without a physician's order and are used recrearionally
by individuals who want to learn more about their ancestry or common traits. Multiple professional genetic
groups have addressed the risks posed by the use of DTC genetic tests for medical purposes (e.g., American
Society of Human Genetics, European Society of Human Genetics, and the European Academy of Sciences).
The ISPG joins these professionals and does not recommend DTC genetic testing for medical purposes in
patients with psychiatric illnesses or their families (ISPG, 2011).
Health professionals in psychiatry would welcome genetic tests to help confirm clinical diagnoses, but
currently, no such tests are clinically valid or reliable. A more complete discussion of genetic testing can be
found in Chapter 16.

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 Chapter 15 Genetic Contributions to Psychiatric and Behavioral Disorders 305

Pharmacogenetics and Pharmacogenomics

People with depression or anxiety more commonly have resistance to therapy rather than a positive response.
Finding the right drug to treat a psychiatric illness can be extremely difficult, and patients can be prescribed
multiple drugs before the right one is found-if it ever is! Prescribed psychotropic medications may be effective
in only a small group of patients or may be only partially effective (Hirschuitt, Besrerman, & Ross, 2016).
Even when a drug is working to alleviate symptOms of mental illness, it produces side effects that range from
unpleasant to debilitating. Weight gain and tardive dyskinesia (repetitive, involuntary ticlike movements, often
of the lower face) can be a problem for genetically vulnerable people taking first-generation antipsychotics
(Ballon, Pajvani, Freyberg, Leibel, & Lieberman, 2014).
Leukopenia (below-normal numbers of white blood cells responsible for fighting infection) is a life-threatening
problem for people taking clozapine, a second-generation antipsychotic. Although newer second-generation
anti psychotics cause fewer adverse reactions and tend to work better for more people, they do cause weight
gain, metabolic syndrome, sedation, and diabetes in some (Hirschtrirr et al., 2016). Haloperidol has been
found to have more extrapyramidal (tardive) side effects, whereas clozapine has fewer (Leucht et al., 2013).
Adverse reactions can result in nonadherence in some patients. Not taking antipsychotic medication as
prescribed increases the risk of relapse to more than five times that of people who take their medication regu-
larly (Goldberg & Ernst, 2016). Because of this ongoing problem, health-care professionals specializing in
psychiatry have been at the forefront of investigations into using genetics to find the right drug for the right
patient (Hirschtritt, Besrerrnan, & Ross, 2016).
Some of the CYP450 enzymes (for example CYP2D6 and CYP2C19) are known to be active compo-
nents in drug metabolism of the antidepressants and anripsychotics. Even though using genetic information
to personalize the medication selection for psychiatric patients is exciting, much work must be done before
pharmacogenomic testing is used widely for this population. Exactly how genetic variations will affect the ways
in which people respond to their medications is still unclear. Studies have produced conflicting results. Many
different biological pathways (and many differenr genes) are probably involved in processing and excreting
these drugs (ISPG, 2017; Lee et al., 2013). In addition, environmental variants such as smoking, drinking
alcohol, and being obese could also interfere with accurate predictions of drug response based on genetics
(Lee et al., 2015). You can read more about pharmacogenetics and pharmacogenomics in Chapter L7, which
describes a specialized form of genetic testing called drug responsetesting.

Behavioral Genetics
Remember that genes do not directly control behavior-we cannot say that someone is a thief because he
inherited the "stealing" gene from his father, for example. We do know that genes are important in deter-
mining how people develop and how effectively proteins are made. The field that focuses on the way gene
variants affect how people act is called behavioral genetics. Many genes can have a significant influence on
behaviors, particularly if we take into consideration the environment in which a person interacts with others.
The interactions of genes, environments, and behaviors are very complex, and a genetic predisposition for
a certain behavior may be altered over rime with changes in diet and parenting. Experts disagree about the
implications of current knowledge in behavioral genetics (Cusio, 2015).
Many health-care professionals consider mental illness a behavioral disorder. The symptOms of illness such
as schizophrenia, personality, and mood disorders do appear as behaviors, although they may not appear as
such initially. Scientists who specialize in the field of behavioral genetics study the impact that variations in
our genomes have on our behaviors. Genetic studies are beginning to reveal that common SNPs seem to
share an influence for developing five major mental disorders (Psychiatric Genomics Consortium, 2013).
A later study by the same group located genetic pathways for three major mental disorders, once again

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providing support for shared influence for psychiatric illnesses (Wray, 2013). In this chapter, we review
genetic contributions to autism spectrum disorders, anent ion-deficit hyperactivity disorder, affective disor-
ders, schizophrenia, addictive disorders, and personality disorders. For a clear understanding of the phe-
notypes and pathophysiology of each of these disorders, consult a reference that is specifically focused on
discussing psychiatric disorders. A thorough explanation of these important problems is beyond the scope of
this text.

AUTISM
A person with autism has three groups of symptoms that include difficulty with social interactions, commu-
nication problems, and a narrow range of repetitive behaviors and interests (American Psychiatric Association,
2013). Autism is one of several syndromes that are grouped together as pervasive developmental disorders
(PODs). These include Asperger disorder and a few other less well-known problems such as Rett disorder.
The category of autism spectrum disorders (ASDs) describes collections of symptoms that are like autism
but do not quite meet the definition of PDD. Autism is common worldwide. The prevalence is estimated
between 1% and 2% overall. The actual prevalence of the entire autism spectrum is very difficult to estimate
because the phenotype is far from exact. However, many sources serving the lay community say the prevalence
of ASD is 1 in 68. Overall, ASD is four and a half times more common in males (l in 42) than females
(I in 189) (Centers for Disease Control and Prevention [CDCj, 2016).
Autism itself is widely variable and is seen as a collection of symptoms in hundreds of syndromes with
a neurological basis (Table 15-1). For example, between 10/0and 3% of people with autism have fragile X
syndrome. However, the percentage of people with fragile X syndrome who also demonstrate the behaviors
associated with autism varies with reports of prevalence between 5% and 60% (Devitt, Gallagher, & Reilly,
2015). A specific genetic cause, such as fragile X, Down syndrome, or tuberous sclerosis, can be identified in
only about 10% of children with autism though these account for less than 1% to 2% of cases (CDC, 2016).
Exposure to some teratogens (substance, disease, or condition occurring during pregnancy [especially the first
8 weeks] that can cause an identifiable birth defect) can be identified in a few cases; however, the specific
cause is unknown (CDC, 2016). The genetic causes of autism include chromosomal abnormalities, which
account for about 5% of cases, and CNVs, such as very small deletions and duplications, which account for
about 10% to 20% of cases. Single-gene neurological disorders that have features of ASD account for another
5%. Most cases of ASD are clearly the result of variations in several genes working together, probably with
an environmental trigger (Frazier er al., 2014; Greschwind, 2011).
Srudies have found that monozygotic (identical) twin concordance is between 70% and 80%, meaning that
about 80% of the time, if one twin is affected with autism, the other identical twin will also be affected. They
will both have the behavioral phenotype of autism and will both show the behavioral signs and symptoms
that are associated with autism. Dizygotic (fraternal) twin concordance is about 10%, which may not seem
very high at first glance but is about 100 times higher than the risk of autism in someone from the general
population. That is a huge difference and indicates that, for some people, autism is highly heritable. Unfor-
tunately, very little about the specific gene variants that increase susceptibility to autism is known (Frazier et
al., 2014; Greschwind, 2011).

Environmental Contributions
Although autism appears to be a complex (multifactorial) disorder involving the actions of many genes and
possibly the environment, exposure to chemicals such as valproic acid, cerbutaline, and thalidomide during
pregnancy has been identified as a cause of autism. Numerous other environmental triggers for autism likely

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 Chapter 15 Genetic Contributions to Psychiatric and Behavioral Disorders 307

Examples of Known Genetic Causes of Autism Spectrum Disorders

Chromosome abnormalities Maternally derived duplications (Angelman syndrome and Prader-Willi

syndrome)
Sex chromosome aneuploidies (XY'(. XXv. XO)
Trisomy 21 (Down syndrome)
Copy-number variants 17p11.2 deletion
16p11.2 deletion
15q13.3 deletion
Single-gene disorders CHARGE syndrome
de Lange syndrome
Fragile X syndrome
MED12-related disorder (including Lujan-Fryns syndrome)
Neurofibromatosis type 1
PTEN macrocephaly syndrome
Shprintzen-Goldberg syndrome
Smith-Lemli-Opitz syndrome
Rett syndrome
Sotos syndrome
Timothy syndrome
Tuberous sclerosis complex
Metabolic conditions Adenylosuccinate lyase deficiency
Cerebral folate deficiency
Creatinine deficiency syndrome
Disorders of creatine transport or metabolism
Disorders of ),-aminobutyric acid metabolism
Mitochondrial disorders
Phenylketonuria
Smith-Lemli-Opitz syndrome
Succinic semialdehyde dehydrogenase deficiency
Sulfation defects

Data from Schaefer.B.• & Mendelsohn. N. J. (2013).Clinicalgenetics evaluationin identifying the etiology of autism spectrum disorders:
2013guideline revisions. Genericsin Medcine. 15.399-407.
~ ---------------------- --

exist as well. Symptoms of autism develop slowly in most children. However, for about 30% of people who
are affected, symproms begin between 18 and 24 months of age. This is called regressive-onset autism. Unfor-
tunately, this is also the age at which many children are receiving immunizations, and this shared time frame
has led to a major controversy about whether childhood immunizations cause autism. Numerous studies have
refuted this connection, and the original research studies that supported it have been retracted. Even so, many
parents are fearful that immunizations can cause autism and have chosen not to immunize their children.
This has led to outbreaks of measles and increases in deaths of unprotected children (CDC, 2016; National
Institute of Mental Health [NIMH], 2016a).

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Finding Genetic Associations

GWASs have linked a number of different genes to ASD. These include genes coding for proteins that are
important in synapse formation and function and in neuronal cell adhesion and regulation. A number of
neurodevelopmenral genes have also been associated with ASD. Genes coding for sodium and calcium channels
and neurotransmitters have also been associated. These proteins are important in the transmission of electrical
and chemical signals between neurons in the brain.
When a person is diagnosed with ASD, at least a three-generation family history should be recorded. Ask
the family if any relatives have behavioral or language problems that might suggest ASD. Because the origins
of ASD for most people are still unclear, a family history of any disorders that might possibly be related should
also be included. For example, ask about and record a family history of alcoholism or other addictive disorders
and any other social or psychiatric problems (Woodbury-Smith er al., 2015). Gathering this information can
be helpful as scientists and clinicians work to understand this very complex and increasingly common problem.

ATTENTION-DEFICIT HYPERACTIVITY
DISORDER
About 5% of children in the United States may have attention-deficit hyperactivity disorder (ADHD) or
one of its forms (APA, 2013). It is more commonly diagnosed in boys than girls, with a variable range from
2: 1 to 9: 1 (Li, Chang, Zhang, Gao, & Wang, 2014). Three subtypes have been described: an inattentive
subtype, a hyperactive/impulsive subtype, and a combined subtype. Each of these types results in some degree
of difficulty with social interaction and academic performance. Although children without ADHD may become
restless and not pay attention, these problems are severe to debilitating for children with this diagnosis. For
a diagnosis of ADHD to be made, the observed behaviors must be inappropriate for the child's age and
developmental level and must be present in a variety of situations. For example, a child who shows signs of
inattention at school but can easily focus on a television program of interest to him or her is probably not
showing signs of ADHD. Determining whether a child is being hyperactive or is just full of energy can be
difficult. The diagnosis must be made by a professional with knowledge and experience in caring for children
with hyperactivity. You can view an interactive model of ADHD prevalence in the United States at https:11
www.cdc.gov/ncbddd/adhd/prevalence.html.
For most people who are affected, hyperactivity lessens as they age. However, for about 2% to 4% of
people, the problem persists into adulthood. Some of these affected adults will report problems with addic-
tions or personality disorders. Some have been involved with the criminal justice system. Moreover, diagnoses
of autism and ADHD sometimes overlap.

Finding Genetic Associations

ADHD runs in families, and people have long suspected that a genetic connection exists. The lack of an
obvious pattern of transmission in a family argues against ADHD being due to the action of a single gene,
but new research reveals that 25% to 50% of people who repon a history of hyperactivity during their own
childhoods have an affected child (Chronis-Tuscano, Wang, Woods, Strickland, & Stein, 2016).
GWASs suppOrt the idea that ADHD is a complex (multifactorial) disorder caused by the actions of many
gene variants along with environmental contributions. GWASs have found regions on more than 10 chromo-
somes that are associated with ADHD in some people. The strongest evidence comes from a meta-analysis
that combined and analyzed the results of seven different studies and found that gene variants located in a
specific region on chromosome 16 contribute to ADHD susceptibility (Li er al., 2014).

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 Chapter 15 Genetic Contributions to Psychiatricand BehavioralDisorders 309

Some large studies have found copy number variants, gene duplications or deletions that are associated with
ADHD in some children. Many of the genes that have been associated playa role in learning and behavior, so
they are considered biologically plausible. This means that a given gene is likely involved based on knowledge
of the protein it encodes. (These are also known as candidate genes.) Some genes that have been associated
with ADHD are involved in the development of neurons and transmission across the synapse. Some are the
same genes that have been associated with autism. One study found an association in four different sections
of a gene that has been associated with restless legs syndrome, a problem that is common among people with
ADHD (Li et al., 2014).
A few genes have been identified to affect response to medications used to treat ADHD. Two genes, SLC6A3
and DRD4, seem to affect response to methylphenidate and atornoxetine, Genes that affect stimulant medica-
tion response are ADRA2A, COMT, DRD5, SLC6A2, and SNP25. These are not ready for prime-time testing
but should be watched for future use in the clinical setting (Li, 2014).
Finding the specific genetic contributions to ADHO would be helpful for a number of reasons. Although
treatment is effective for many people diagnosed with ADHO, it is not effective for all. Furthermore, the treat-
ment is not a cure, and the drugs used can have some unpleasant side effects. Finding the genes responsible
for ADHO would help scientists understand the pathophysiological origins of the problem and may lead to
improved and targeted treatment. Even when a clinical diagnosis is possible, generic/genomic knowledge has
much to contribute to our ability to provide effective care.

SCHIZOPHRENIA
Schizophrenia is a potentially incapacitating chronic psychiatric disorder with a prevalence of 1.1% (NIMH,
2016b). The symptoms include episodes of psychosis with hallucinations and delusions. Often, people with
schizophrenia have dulled emotions and disorganized thoughts with language difficulty and sometimes manic
and depressive symptoms (NIMH, 2016b). Some describe hearing voices that other people do not hear and
believe others are reading their mind, controlling their thoughts, or have a plot to harm them. Symptoms
usually begin in adolescence or early adulthood, often interrupting lives that have begun with so much promise.
Laboratory tests cannot determine if someone has schizophrenia, and sometimes the variability in the
phenotype makes diagnosis based on clinical observation and self-report tricky. Not being able to clearly and
specifically define the phenotype makes studying the genetics of a problem much more difficult. Furthermore,
we do not completely understand the pathophysiology of schizophrenia or even all that much about higher
brain function!
Once again. this disease is complex (multifactorial) and is due [0 the interactions of many genes. each
exerting a small effect, combined with the environment. Epigenetic mechanisms have also been suggested as
possibly importan t in the onset of schizophrenia. Epigenetics refers to variations outside of the ONA sequence
itself, such as those that alter gene expression by altering methylation patterns or histone proteins. Epigenetic
changes can also be inherited. Epigenetic differences may account for monozygotic twin concordance for
schizophrenia being only 40% to 50%. even though the genetic contribution to schizophrenia risk is prob-
ably much higher. Table 15-2 shows the estimated risk of someone developing schizophrenia when a relative
is affected. The heritability estimate for schizophrenia is about 80%. Heritability estimates are the cause of
the variation of the phenotype within a population and not causes within a given family. For example, even
though the heritability estimate is 80%, that does not mean that if a mother is schizophrenic that each of
her children has an 80% risk of being schizophrenic. It does mean that if we look at the variations in phe-
norype in specific populations, about 80% can be attributed to genetics and about 20% can be attributed to
environment.

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310 Unit IV Genomic Influences on Selected Complex Health Problems

.'.!.':i.::alo~...j,
The Estimated Risk of Getting Schizophrenia When a Relative Is Affected
Relationship to the Person Degree of Relationship Risk of Developing
With Schizophrenia (Genes Shared) Schizophrenia

General population None 1%

First cousins Third-degree relatives (12.5%) 2%
Uncles or aunts Second-degree relatives (25%) 2%
Nieces or nephews Second-degree relatives (25%) 4%
Grandchildren Second-degree relatives (25%) 5%
Parents First-degree relatives (50%) 6%
Siblings First-degree relatives (50%) 9%
Children First-degree relatives (50%) 13%
Dizygotic twins First-degree relatives (50%) 17%
Monozygotic twins Identical twin (100%) 48%

Source: Gonesman. I. I. (1991). Schizophrenia genesis: The origin 01 madness. New York. NY; Freeman.

Environmental Contributions
Epidemiological studies have demonstrated that environment plays a role in the risk of schizophrenia. For
example, the risk of schizophrenia is higher under the following conditions:
• Obstetrical complications
• Birth in urban environments
• Birth during famines
• Exposure [0 viruses
Prenatal infections have also been implicated, as has advanced paternal age. Advanced paternal age is an
important risk factor for the development of some aurosornal-dorninant disorders. Of course, other environ-
mental factors that have not yet been identified probably exist. However, even though environmental factors
clearly increase schizophrenia risk, their contribution is very small compared with the contribution of genetic
susceptibility.

Finding Genetic Associations

GWASs indicate that CNVs probably play an importanr role in the risk of schizophrenia. Although CNVs
are common throughout the genome, sometimes they are associated with disease. Genetic causes of schizo-
phrenia may also be different from person to person. This could be a reason why finding the genetic cause
of this disease has been so difficult, even though it has such a high heritability (Bergen & Perryshen 2012).
The major histocompatibility complex (6p22.l) has been associated with schizophrenia in several studies.
The gene NOTCH4, which is important in neurodeveloprnenr, is found in this region. It is biologically plau-
sible that defects in NOTCH4 could be related to risk of schizophrenia. Other associated genes are important
in the formation of synapses; the signaling of dopamine, glutamate, and serotonin; the synthesis of glutamate;

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 Chapter 15 Genetic Contributions to Psychiatric and Behavioral Disorders 311

and catecholamine metabolism (COMT). The genes CACNAICand CACNB2, with interacting proteins, are
important in calcium signaling pathways and show some promise of causation (Bergen & Petryshen, 2012;
Tiwari, Zai, Muller, & Kennedy, 2010). JUStas symptoms overlap, the genes that have been associated with
schizophrenia and those associated with bipolar disorder also overlap.

AFFECTIVE DISORDERS
Major depression and bipolar disorder are affective, or mood, disorders. Typically, people who have only
depression (unipolar depression) do nor also have mania. However, most people who have mania have epi-
sodes of depression. This is called bipolar disorder (formerly called manic-depressiom. Both types of affective
disorders seem to be related. Many families report a history of both depression and bipolar disorder among
their relatives. We would expect to see some commonalities and some differences as we look into the genet-
ics of both. One meta-analysis of several GWASs found overlap of regions on chromosomes 2, 3, and 11
and twO on 15 that were associated with both depression and bipolar disorder in the people they studied
(Flint & Kendler, 2014).

Major Depression
Does 50% Heritability Suggest That in Every
Major depression is very common, affecting 16.9% Family, Half of the Risk Is Genetic and Half Is
persons in the United Stares. Depression affects women Environmental?
twice as often as men. Major depressive disorder (MOD) In fact, if we looked at a population with depres-
is defined as having a minimum of one 2-week episode sion, heritability of 50% could mean that in half
of depression. First-degree relatives of people with MOD the families,it was 100%genetic, and in the other
have almost three times the risk of having depression half, it was 0% environmental!
than does the general population. Several subtypes exist, If your patient has a first-degree relative with
including anxious depression, melancholic depression, major depression, she or he probably has about
MOD with psychotic features, and postpartum-onset tl'VO to three times the risk of having depression

depression. Overall, heritability is estimated at about of someone from the generalpopulationwho does
not have a first-degree relative with depression.
50%.
If her or his first-degree relative has had multiple
episodesof depression(recurrentdepression),the
Bipolar Disorder risk is even higher.
Bipolar disorder (BPD) is a serious mental health problem
with episodes of mania and depression that usually follow each other in cycles. It can be completely dis-
abling and is associated with a high suicide rate. The risk of someone having BPD over his or her Lifetime is
about 1%, although some sources estimate it as a bit higher than that, The manic episodes consist of at least
1 week of elated or irritable mood that is accompanied by racing thoughts and highly pressured speech. The
affected person is easily distractible and agitated and may engage in high-risk behaviors, including hyper-
sexuality and out-of-control spending. These patients may experience psychosis but will certainly have dif-
ficulty working or socializing as they normally do. Hypomania is a milder version, lasting at least 4 days
(APA, 2013).
The generic contribution to BPD is quite high. It has been estimated at having between 60% and 85%
heritability. First-degree relatives of a person with BPD have about 10 times the risk of BPD than does the
general population. They also have a three to four times greater risk of having unipolar depression. Mono-
zygotic twin concordance is about 40%. Clearly, BPD and major depression are complex (multifactorial)
diseases.

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Environmental Risk Factors

Which environmental exposures increase the risk for affective disorders is controversial. Use of recreational
drugs, such as cannabis or alcohol, is common among people with psychiatric disorders, but determining
whether the drug use triggered the illness or if the illness triggered the drug use is difficult. Patients may
self-medicate to help cope with distressing psychiatric symptoms. In addition, addictive behaviors have dear
genetic influences, as we will see in the next section. At this point, scant clinically useful information exists
about the link between use of drugs and the onset of affective disorders. On the other hand, recent research
suggests treating the substance use disorder is important if the patient has an early-onset bipolar disorder
(Pettinati, O'Brien, & Dundon, 2013).
Some people suggest that DNA methylation (an epigenetic phenomenon) may be important in the
onset of several different psychiatric disorders. For example, we know that BPD is more common among
children born to older fathers (advanced paternal age). This increase in risk could be caused by epigenetic
changes from the father's exposure ro environmental srressors over time (Frans, MacCabe, & Reichenberg.
2015).

Finding Genetic Associations

GWASs have the potential to identify new pathways for the targeted treatment of BPD. Those doing research
in this area report that BPD is highly polygenic, which means BPD is caused by many genes, each contrib-
uting a small effect. This means that genome-wide studies must include very large populations of patients
and controls in order to tease OUtall the genes that are involved in this disease process. The goal is not only
to berrer understand why and how BPD happens but, most importantly, also to find better ways to treat it.
Improvements in technology have allowed analysis of CNVs and GWASs. A recent meta-analysis found
pathways associated with bipolar disorders. Six were identified, including corticotropin-releasing hormone
signaling, cardiac p-adrenergic signaling, cardiac hypertrophy signaling, and others, suggesting that pathways
that regulate hormones, calcium channels, second messenger systems, and glutamate signaling have implica-
tions in BPD (Nurnberger, Koller, & lung, 2014). Not only do these findings suppOrt previous beliefs about
the neurobiology of BPD, they also offer clues to unlock approaches in treatment and prevention of this
troubling disorder.

SUBSTANCE USE DISORDERS

A substance use disorder is described as out-of-control drug use that is not consistent with adaptation and
continues despite serious adverse consequences. People are considered dependent when there are signs of
developing tolerance, they require higher doses, and symptoms of withdrawal occur when the drug is stopped.
Unfortunately, these disorders are very common. In 2014, 20.2 million American adults had a substance abuse
disorder. Research shows that adults with a mental illness are more likely to smoke. It is well known that
tobacco is associated with addiction, but did you know that 44% of all cigarettes sold in the United States
are sold to adults who also have a psychiatric disorder (NIMH, 20 16c)
People with addictive disorders often carry a dual diagnosis (comorbidiry). In one study, people who were
addicted to substances (other than nicotine) were alrnosr three rimes more likely to have a psychiatric illness
than people who were not addicted. About 13% of the U.S. population is addicted to nicotine. The percentage
is much higher, between 30% and 70%, in people who have been diagnosed with psychiatric illnesses. In fact,
persons with severe mental illness die 25 years earlier than the general population, usually due to an illness
credited to disorders of substance use. The most common causes of death among people with mental illness

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 Chapter 15 Genetic Contributions to Psychiatricand Behavioral Disorders 313

are premature cancer and heart disease, both of which can be directly linked to cigarette smoking. These two
problems are so clearly interwoven that completing genetic studies that distinguish the differences in genetic
causes has been challenging (Palmer er al., 2015).

Alcohol Dependence
Alcohol dependence is another complex (multifactorial) problem, combining the effects of genes and the
environment. The environmental contribution is fairly obvious, because a person must consume alcohol in
some form in order to become dependent. However, the genetic contributions are fairly clear as well. The
heritability estimate for addiction to alcohol is between 50% and 60% in both males and females (Hartz, Pato,
& Medeiros, 2014; Hartz & Bierur, 2010). A person with a first-degree relative who is alcohol dependent has
a risk of being alcohol dependent between three and eight times higher than that of the general population.
Of course, separating out nature {genetic input} and nurture (environmental input) can make things a bit more
complicated! Are family members of alcoholics using or abusing alcohol because of a genetic predisposition
or because they learned that alcohol use or abuse is a readily available coping strategy?

Alcohol Use and Abuse

The first genetic information related to alcohol use and abuse came from studies of people of Asian descent.
A significant number of Asians experience an unpleasant facial Aushing and sometimes vomiting when they
drink alcohol. This reaction is caused by a deficiency of the enzyme aldehyde dehydrogenase (ALDH2), which
is important in the body's ability to metabolize ethanol. This deficiency may actually protect people from
the risk of alcohol addiction. A mutation causing a deficiency in this enzyme was found in 41 % of Japanese
people in the general population but in only 2% of Japanese with alcoholism (Hartz et al., 2014; Hartz &
Bierur, 2010).

Alcohol Metabolism
This finding led researchers to look closely at the genes that code for proteins involved in alcohol metabolism,
which occurs in the liver in a two-step process. The fim step involves the conversion of ethanol to acetaldehyde.
The enzyme involved in this process is alcohol dehydrogenase (ADH). The second step is the breakdown of
acetaldehyde into water and acetate. The enzyme used in this process is aldehyde dehydrogenase (ALDH).
People carry different versions of the genes (alleles) that code for these enzymes. That means that some people
produce enzymes that are more effective at breaking alcohol down than those carried by other people. Studies
have found that people who carry alleles for the more powerful versions of these proteins are more likely
to be alcoholic. An increase in addiction co other substances in people with more efficient versions of these
enzymes is also seen. Unfortunately, investigators do not really understand why this connection exists-so far
it is simply an observation that has been described (Eden berg & Foroud, 2013,2014).
Genes that encode neurotransmitter proteins, such as y-aminobutyric acid (GABA) or acetylcholine, have
also been associated with alcohol dependence. GABA is the most important inhibitory neurotransmitter. If
you have more GABA (or more GABA receptors), fewer impulses will be transmitted across the synapse.
Evidence suggests that alteration in GABA levels are involved in some of the behavior changes that are associ-
ated with alcohol intoxication, such as a decrease in anxiety, decreased coordination, and increased sedation.
The GABAA receptor is made up of five subunits, which means that a lot of genes are involved in making an
efficiently functioning GABAAreceptor and many opportunities to make a receptor that does not work very
well (Trudell, Messing, Mayfield, & Adron, 2014). Acetylcholine is a neurotransmitter involved with memory,
reward, and learning that typically has an excitatory function. A gene that encodes one of the acetylcholine
receptors has a variant linked with alcohol dependence.

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314 Unit IV Genomic Influences on Selected Complex Health Problems

Another group of genes that has been associated with drug dependence is involved in the endogenous
opioid system. This system is composed of molecules made by the body that produce responses similar to
those produced by morphine and heroin. The drug nalrrexone is useful in the treatment of alcohol depen-
dence because it works by blocking the anion of the endogenous opioid system. The gene OPRM 1 codes for
the u-opioid receptor, and variations in this gene have been associated with alcohol dependence. Some of the
genes involved in the endogenous cannabinoid system have also been implicated (Ray et al., 2012).
Recent work has also noted other gene variants associated with the risk of alcoholism. These include
GABRA2, CHRM2, KCNJ6, and AUTS2. More research needs to include larger sample sizes to more clearly
understand the effects on the pathways (Edenberg & Foroud, 2013).

Summary of Addictive Disorders

A connection clearly exists between some types of mental illness and addictive disorders. Some authors have
suggested an overarching category of what is called externalizing psychopathology that includes problems
such as alcohol and other drug dependence. It also includes conduct disorders and antisocial personality
disorder. Experts propose that a group of gene variants can increase susceptibility to all of these categories;
however, other gene variants exist that are specific for alcohol and other drug dependence. We can expect lots
more information about these connections as the number of large studies of people with addictive behaviors
increases.

PERSONALITY DISORDERS
A personality disorder is a collection of socially distressing feelings and behaviors that are different from what
is expected in a person's culture and result in difficulty managing activities of daily living. Personality disorders
tend to have their onset during adolescence or young adulthood and have historically been considered entirely
learned behaviors. These are lifelong problems that typically do not respond well to medications and therapy.
The specific traits vary from person to person, but they tend to remain fairly consistent and inflexible over
a person's lifetime. Between 10% and 15% of adult Americans meet the criteria for at least one personality
disorder. The Diagnosticand StatisticalManual of Menta! Disorders,fifth edition (DSM-5J of the APA reports
10 classifications divided into three clusters (APA, 2013). These are listed in Table 15-3 along with the preva-
lence of each in the U.S. population (Widiger, 2012). Providing a thorough description of each personality
disorder is well beyond the scope of this text.

Multifactorial Personality Disorders

As we have seen with the other psychiatric disorders, personality disorders are complex (multifactorial) and
involve the contributions of many genes (each exerting a small effect) and the environment. Until recenrly,
little was known about the genetics of personality disorders. With the increased application of GWASs, we
are starting to learn a bit more, but we have a long way to go before the genetic contributions to personality
disorders are truly understood.
One of the major problems is the difficulty of identifying a clear phenotype. This is always a challenge, but
having the ability to accurately describe a phenotype is essential if genetic studies are going to make any sense
at all. Specialists debate whether personality disorders should be seen as separate categories or considered as
one category having differing dimensions. Seeing them as separate categories would make genetic studies much
easier because there would be clearer phenotypes. However, consensus suppOrtS viewing personality disorders
dimensionally, with some core factors that are shared (Reichborn-Kjennerud, 2010).

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 Chapter 15 Genetic Contributions to Psychiatric and Behavioral Disorders 315

Some Personality Disorders and Their Prevalence in the United States

Cluster A (odd, • Paranoid personality disorder: 0.5%-2.5%, predominantly male

eccentric) • Distrustful and suspicious
• May have aggressive outbursts or appear cold
• Schizoid personality disorder: 3%, predominantly male
• Detachment
• Limited range of emotions
• Schizotypal personality disorder: 3%, predominantly male
• Eccentric thoughts and behaviors
• Odd beliefs and magical thinking
Cluster B (dramatic, • Antisocial personality disorder: 3% of men, 1% of women
emotional) • Lack of empathy
• Manipulative
• Problems with impulse control
• Borderline personality disorder: 2%, predominantly female
• Unstable moods
• Impulsive behavior
• Difficulty in relationships
• Histrionic personality disorder: 2%-3%, predominantly female
• Highly emotional
• Attention-seeking
• Narcissistic personality disorder: less than 1%, predominantly male
• Sense of entitlement
• Grandiose ideas
• Arrogance
• Need for admiration
Cluster C (anxious, • Avoidant personality disorder: 0.5%-1 %, gender neutral
fearful) • Uncomfortable in social situations
• Fearful of rejection
• Feeling of inadequacy
• Dependent personality disorder: 0.5%, predominantly female
• Clinging behavior
• Need to be cared for by others
• Obsessive-compulsive personality disorder: 1%, predominantly male
• Preoccupied with order, cleanliness, and control
• Lack of flexibility
• Rigid conformity to rules

Data from American Psychiatric Association. (2013). Diagnostic and staristical manual of mental disorders (5th ed.]. Washi ngton, DC:
Author; and Widiger, T. (2012). The Oxford handbook of personality disorders. New York, NY: Oxford University Press, p. 206.

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316 Unit IV Genomic Influences on Selected Complex Health Problems

Heritable Personality Disorders

Normal personality traits tend to be very heritable, with between 30% and 60% of the difference attribut-
able to genetics. If your parents are shy and reserved, you are more likely to be shy and reserved than if your
parents are loud and extroverted. Of course, things are never simple; many families have wide variations in
the normal personality traits of their children. Children in the same family also share environmental factors.
Many experts believe that environmental factors may not have a major impact on the personality of the chil-
dren (Reichborn-Kjennerud, 2010). Others strongly disagree, noting that the social environment can produce
stressors requiring coping suppOrt that may be unavailable. This could result in a psychological vulnerabiliry
and learned behaviors that are dysfunctional (Eccles er al., 1993).

Categories of Personality Disorders With Hereditability

Some personality disorders have been studied far more than others. For example, the cluster A personality
disorders show significant genetic contributions. These are paranoid, schizoid, and schizotypal personaliry
disorders. Heritability has been reported to be between 300/0 and 60%, which is about the same as the herita-
biliry of normal personality traits. The heritability of antisocial personaliry disorder has been reported as being
between 75% and 80% (Gunter, Vaughn, & Philibert, 2010). As with autism spectrum disorders, antisocial
personality is sometimes considered to be a speCtrum of disorders with a common set of traits, which makes
comparing studies less useful.

Traits of Personality Disorders

Some personality disorders have big differences in prevalence between the sexes. For example, antisocial per-
sonality disorder is three times more common among men than women, and borderline personality disorder is
three times more common among women than men. Determining whether these differences have cultural or
biological rOOtSis difficult; they may have a bit of each.
Be cautious when looking at statistics about the prevalence of personaliry disorders, particularly borderline
and antisocial personaliry disorders, which can be challenging to diagnose. Diagnosis is based on behaviors
and does not necessarily follow criteria strictly. When a person is labeled with a particular diagnosis, it tends
to follow them around, whether it is accurate or not. Clinicians note that to clearly diagnose a personality
disorder, the affected person must be seen for a considerable period of time, and an accurate history must be
collected (APA, 2013).
Overall, the risk of developing a personaliry disorder seems to have a significant genetic contribution.
Nongenetic and probably environmental risk factors likewise play lesser but still important roles. The number
of people who have multiple problems. such as substance abuse, conduct disorders. and antisocial personaliry
disorder, makes finding specific genetic links challenging. Nevertheless, we anticipate results from GWASs will
make significant contributions to our understanding of the pathophysiology and susceptibility to personaliry
disorders.

SUMMARY
The genetics of psychiatric illness and behavioral disorders continues to evade definitive answers despite increased
research aimed at better undemanding the causes and interrelationships. Pharmacogenomics is identifying
which medication is correct for the right patient. The use of genetic technologies is beginning to assist in the
identification of causes of associations. although many barriers remain. This specialty holds exciting oppOrtu-
nities for persons interested in unmasking answers about mental illnesses and disorders.

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 Chapter 15 Genetic Contributions to Psychiatric and Behavioral Disorders 317

GENE GEMS

• In the future, pharmacogenetics may help clinicians find a safe and effective psychotropic drug with
minimal side effects to better treat patients.
• Complex biological pathways and the contributions of environmental factors make predicting responses
to psychotropic drugs difficult.
• A few neuropsychiatric disorders, such as Huntington disease and fragile X, are caused by problems
with single genes.
• Most psychiatric problems are complex (multifactorial), combining the effects of several genes working
together with the environment.
• Genome-wide association studies (GWASs) can be helpful in identifying genes with variations that
increase susceptibility to psychiatric disorders.
• Direct-to-consumer genetic tests exist; however, as with genetic testing to diagnose mental illness in
general, their clinical usefulness is questionable.
• Behavioral genetics is the field that focuses on the ways in which gene variants affect how people act.
• Autism is a disorder of social interaction and language use that is often viewed as a pervasive develop-
mental disorder called autism spectrum disorder. These disorders may have some genetic risk factors in
common.
• Monozygotic twin concordance for autism is between 70% and 80%, meaning that the genetic con-
tribution is very high.
• Symptoms of regressive-onset autism begin between 18 and 24 months of age, which is the age when
many children receive childhood immunizations; however, evidence does not exist that links immuni-
zations and autism.
• Genes coding for proteins important in the generation and transmission of neural impulses have been
associated with susceptibility to autism.
• Attention-deficit hyperactivity disorder (ADHD) seems to run in families; however, it does not follow
an obvious pattern of transmission.
• When phenotypes vary (e.g., schizophrenia), genetic studies are more difficult.
• Epigenetic factors may be important in psychiatric disorders such as schizophrenia.
• Both genetics and environment are important in determining susceptibility to schizophrenia.
• The heritability of major depression and bipolar disorder is very high, and both can be found in the
same family.
• Addictive disorders are closely linked to other psychiatric problems, and they have both genetic and
environmental contributions to susceptibility.
• Variations in genes that encode neurotransmitters such as y-aminobutyric acid (GABA) have been
associated with alcohol dependence.
• The difficulty in placing personaliry disorders in discrete categories makes genetic studies more difficult.
• Personality disorders are highly heritable, much like normal personality traits.

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318 Unit IV Genomic Influences on Selected Complex Health Problems

Self-Assessment uestions, . ...

1. The risk of schizophrenia is reponed co be highest under which of the following conditions?
a. Advanced paternal age
b. Binh during a famine
c. Epigenerics
d. Twinning
2. Which statement best describes why it is difficult to predict responses to psychotropic drugs?
a. Most psychiatric problems have so many symptoms that drug responses are not easy to assess.
b. Many patients are not compliant with their medication regimens due to the side effects.
c. Complex biological pathways make drug targeting difficult.
d. Most of these diseases are primarily due to environmental facrors, so targeting genes will have
minimal effect.
3. Biological factors that have a known association with bipolar disorders include which of the following?
a. Acerylaldehyde
b. Calcium channels
c. GABA
d. Major histocompatibility complex
4. An epidemiological study reveals that the overall heritability in a population with an identified per-
sonality disorder is 50%. Which of the following is incorrect?
a. Half of the risk is genetic, and the other half is environmental.
b. The heritability is 0% environmental and 100% genetic.
c. There is a 50% chance that the risk is genetic.
d. The herirabili ty is 100% en vironrnenral and 0% genetic.
5. How is the concept of "externalizing psychopathology" useful in explaining the genetics of psychiatric
and addictive disorders?
a. Conduct disorders include addictive behaviors.
b. Antisocial personality disorder is highly heritable.
c. All genes for these disorders are shared; environment determines which disorder will occur.
d. Some gene variants increase susceptibility to all of these disorders, and others are specific co each
individual disorder.

CASE STUDY

Sally has alcoholism and has suffered from bipolar disorder on and off throughout her life. Her father drank
heavily and was verbally abusive during her childhood. Sally had done well until the birth of her daughter
15 years ago when she started drinking heavily every night after dinner. She is happily married to a very
understanding man. Sally has two brothers and two sisters who also have alcoholism. The sisters have
had problems with recurring major depression but have been treated successfully with antidepressants.
They go oft the medication when they feel better. Sally is most concerned about her daughter. who shows
signs of cycling between being abnormally lively and spending irresponsibly and seeming down and not
communicating with friends or family for weeks at a time. Sally found a couple of empty beer cans in her

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 Chapter 15 Genetic Contributions to Psychiatric and Behavioral Disorders 319

room last week. The daughter is not interested in seeing a therapist and does not acknowledge that anything
might be wrong. Sally is afraid that her daughter has bipolar disorder and feels guilty about "causing" her
older daughter's problem.
1. Do you think a genetic link could exist for the problems of Sally's dad, Sally and her siblings, and
Sally's daughter?
2. Would referral for genetic counseling benefit this family? Why or why not?
3. Do you think that a medication that is successful in treating Sally's bipolar disorder might be useful
for her daughter? Why or why not?
4. Should Sally be concerned about the possibility that her daughter is drinking alcohol?
5. How might genetic information help Sally's daughter agree to seek diagnosis and treatment for her
problems?

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Woodbury-Smith. M .• Paterson. A. D .• Thiruvahindrapduram, B.• Lionel. A. C .• Marshall, CR., Merico, D .... Scherer.
S. W. (20 I5). Using extended pedigrees to identify novel autism spectrum disorder (ASD) candidate genes. Human Genetics,
134(2), 191-201.
Wray. N. (2013. February 22). (Author). Psychiatric Genomics Consortium. [World lab meeting) Genetic relationship between
fivc psycfJia"'ic disorders estimated from gmom~-lVidt: SNPs. Retrieved from http://www.med.unc.edu/pgclworldwide/
worldwide-lab-meeting-archive-jan-may-2103

Self-Assessment Answers
I. b 2. c 3. b 4. d 5. d

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Genomics and Disease
Management

321

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 Genetic and Genomic Testing
Learning Outcomes
1. Compare the different types of genetic tests.
2. Explain how differing frequencies of carriers in populations might affect the validity of genetic test results.
3. Discuss the implications of direct-co-consumer genetic testing.
4. Discuss the risks and benefits of genetic testing.
5. Identify dependable online resources for current information about genetic testing.

Key Terms
Analytical validity Fluorescence in situ Predispositional testing
Carrier testing hybridization (FISH) Preimplantation genetic
Cell-free DNA (cf DNA) Genetic testing diagnosis (PGD)

Cell-free fetal DNA (cft DNA) Genome-wide association Prenatal testing

study (GWAS) Presymptomatic test
Clinical utility
Laboratory-developed tests Whole-exome sequencing
Clinical validity
Newborn screening (WES). also known as Exome
Cytogenetic testing
Next-generation sequencing wide sequencing
Diagnostic testing
Polymerase chain reaction Whole-genome sequencing
Direct-to-consumer (DTC) (WGS)
(PCR)
genetic testing
Predictive testing
DNA sequencing

INTRODUCTION
Genetic testing is the analysis of DNA, RNA, chromosomes, proteins, and protein metabolites co identify
heritable variations in genes andlor chromosomes. Traditionally, genetic testing has been done for clinical and
research purposes only, but with the advent of direct-to-consumer (DTC) offerings, genetic testing is also
being done recrearionally, We discuss DTC testing and the risks and benefits at the end of this chapter, but
first, we will cover the types of genetic tests.

322

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 Chapter 16 Genetic and GenomicTesting 323

Currently, clinical genetic testing can be done for more than 5,000 disorders (GeneTests, 2017), but getting
a positive result for a genetic test can mean many different things, depending on the purpose of the test and
the relationship of the gene variant or mutation to the disorder. Some gene variants have been shown to cause
particular diseases.The M508 mutation in the CFTR gene causes cystic fibrosis (CF). Other variants are merely
associated with a disorder, which means that they are commonly found in people with the disorder, but we do
not know if they cause the disease. For example, 4 single-nucleotide polymorphisms have been widely studied
for their association with heart disease, but these and almost 85 other polymorphisms have also been shown
to have no association with coronary artery disease (CAD). Recent studies using a variety of technologies and
databases have reinforced the knowledge that CAD risk is more a cumulative effect of multiple common risk
alleles that individually have a small effect size rather than a few rare variants with larger effects (McPherson &
Tybjaerg-Hansen, 2016). This means CAD risk is better understood, but it does nor mean that persons with
one, or even all, of these polymorph isms will develop CAD.
The most up-to-date information about the availability of genetic testing can be found at genetests.org.
This website is linked [Q GeneReviews, funded by the National Institutes of Health (2017) and administered
by the University of \'{fashingron, Seattle. In addition to information about genetic testing, gene.tests.org
provides expert-authored, peer-reviewed articles about diseases with a genetic component and has a wealth of
other educational materials on genetics in general.
Accurate patient information about genetic testing is available from numerous medical centers.
Table 16-1 provides an example of patient information about genetic testing for hemophilia provided by
Cincinnati Children's Hospital Medical Center. It includes information about how the disease is inherited
and how carrier testing is done.

GENETIC TESTING SAMPLES

If you watch television procedural crime dramas, you know that genetic material can be obtained from the
most unlikely sources and that not a lot of genetic material is required ro identify the perpetrator. DNA
from blood, saliva, skin, hair follicles, tissue blocks obtained during surgery, or biopsy samples from living or
deceased persons can be extracted. The most commonly used samples are genetic samples of epithelial cells from
cheek (buccal) swabs or saliva and leukocytes from blood. Most samples are placed in designated collection
tubes provided by the laboratories. If not available, samples of blood require collection in special erhylenedi-
arnineretraacetic acid (EDTA) tubes (purple tops) to prevent clotting but also to inhibit DNA breakdown by
enzymes or microbes during storage or laboratory transport. Saliva collection requires polypropylene rubes.
Some additional collection requirements of saliva collection include an oral assessment and no eating/drinking
for 1 hour prior to collection or brushing teeth 45 minutes prior to sample gathering. Rinsing the mouth with
water 10 minutes prior to providing the saliva sample is recommended. Blood in the sample contaminates it,
and it should be discarded (Salimerrics, 2015).
A new sample type being used for genetic testing is from small pieces of non-genomic DNA circulating
in the blood. Known as cell-free DNA (cf DNA), it can be collected from plasma or urine. To obtain cf
DNA, whole blood is drawn into specialized tubes with a preservative to stabilize and separate the blood cells
(preventing the release of genomic DNA) from the clear liquid with cyrokines, plasma, and the buffy coat
(supernatant). The preservative prevents the release of genomic DNA from the white blood cells so that high-
quality cf DNA can be isolated. These very small pieces of circulating cf DNA originate from the placenta in
pregnant women or tumors in cancer patients. Because this technology is noninvasive, it offers a reduced risk
of complications compared to the currently used invasive technologies. Noninvasive prenatal testing (NIPT)
has been used for genotyping fetal blood groups; fetal sex determination associated with sex-linked disorders;

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Example of Information Available Online to Describe Genetic Testing for Hemophilia

Genetic Testing for Hemophilia
Hemophilia results from a defect in the genetic material of the body. This genetic material is called
deoxyribonucleic acid, or DNA. Any part of the DNA that controls an inherited trait is called a gene.
Examples of inherited traits are eye color, hair color, and blood type.
The most common forms of hemophilia result from defects in the genes that control the production of
clotting factors VIII or IX.
Genes are present within the cell in packages called chromosomes. Most of the body's cells contain a
complete copy of chromosomes and their genes. Among the chromosomes people inherit from their
parents are two sex chromosomes, labeled X and Y All males receive the X chromosome from their
mother and the Y chromosome from their father. Females have two X chromosomes, one inherited from
each parent.
I---
Role of Genes in Hemophilia
The genes that control the production of the clotting factors VIII and IX are located on the X chromosome.
Males (XY) have hemophilia when the gene for clotting factor VIII (hemophilia A. classical hemophilia) or
clotting factor IX (hemophilia B, Christmas disease) on the single X chromosome is affected.
Women (XX) who are carriers generally don't have symptoms of hemophilia because only one X
chromosome has a copy of the hemophilia gene. The other gene of the other X chromosome allows for
normal production levels of clotting factors VIII or IX. Those women who have only one affected gene
are called hemophilia carriers. Not all males with hemophilia have mothers who are carriers. Sometimes
a mutation (a genetic change) occurs resulting in hemophilia. Currently, it is not known why this
mutation happens.
Sons of women who carry the hemophilia gene have a 50 percent chance of inheriting the gene and
having hemophilia. Daughters of women who are carriers have a 50 percent chance of also being
carriers of hemophilia. In families where only one male is known to have hemophilia, it is usually
possible to determine whether the hemophilia gene was passed from a mother who carries the gene or
whether a new mutation occurred in the person with hemophilia.

Carrier Testing Procedure

The Hemophilia Center at Cincinnati Children's Hospital Medical Center can perform genetic testing and
counseling for hemophilia.
As part of genetic counseling, a physician or genetic counselor will take a family history and draw a family
tree, called a pedigree. The pedigree generally includes three generations: children, parents, aunts,
uncles, cousins, and grandparents. The pedigree helps identify people within the family who could be
carriers of the gene. Women who are possible carriers of hemophilia could then choose to be tested.

Direct Mutation Testing

For hemophilia A and B, it is possible to look for mutations within the gene. This approach is called
direct DNA testing and is the most accurate method for identifying carriers. A blood sample from the
male family member with hemophilia is checked first. In about 98 percent of cases, a mutation can
be identified. Next, a blood sample from the woman desiring carrier testing is obtained, and her DNA
is checked for the specific mutation. Such testing is performed at specialized laboratories. Results are
generally available in several weeks.

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 Chapter 16 Genetic and GenomicTesting 325

Example of Infonnation Available Online to Describe Genetic Testing

for Hemophilia-cont'd
Linkage (Indirect) Testing
In some cases of hemophilia A and hemophilia B, a mutation cannot be identified. However, it may be
possible to use indirect or linkage tests to determine the gene carrier status of females by tracking
the gene in the family. Blood samples are obtained from the male with hemophilia and other family
members. Patterns of linked DNA in the person with hemophilia are compared to the DNA in family
members to check for the same pattern. Linkage testing is not as accurate as direct testing and does
not provide information for all families. The genetic counselor will discuss these issues individually with
families.

Need for Carrier Testing for Hemophilia

Because women rarely show symptoms of hemophilia, they can be carriers of the disorder without
knowing it. Women related to a male with hemophilia, such as a mother, sister, aunt, or cousin on
the mother's side, can be carriers and may want to have carrier testing. The daughters of a male with
hemophilia are always carriers of hemophilia.
A women's decision about carrier testing or how she chooses to use that information can be influenced by
many factors. These factors include the severity of the hemophilia that occurs in her family and her own
desires and beliefs, as well as those of her partner. Women who are considering having children may
find it most beneficial to have carrier testing before becoming pregnant. Females typically are tested
for carrier status when they are old enough to make an informed decision, normally in the late teens or
older.

Prenatal Testing
A woman with a family history of hemophilia A or B may wish to have the fetus tested during pregnancy.
Making the decision to pursue prenatal screening is a personal choice and involves many factors. The
risks and benefits of prenatal screening should be discussed with an obstetrician or genetic counselor.
During the 10th or 12th week of pregnancy, an outpatient test called chorionic villus sampling can be
performed. A small amount of the developing placenta is obtained for testing. Another outpatient
procedure called an amniocentesis can be performed after 13 weeks of pregnancy. During the
amniocentesis, a small amount of fluid containing fetal cells is removed and tested for hemophilia if the
fetus is male (XY).
For additional information about genetic testing or genetic counseling, contact the Division of Human
Genetics, 513-636-4760.

Genetic Testing for Hemophilia

Sons of women who carry the hemophilia gene have a 50 percent chance of inheriting the gene and
having hemophilia.
Last Updated 10/2016

Used by permission of Cincinnati Children's Hospital Medical Cenler. Available at httpsjlwww.cincinnatichildrens.orglhealt~h/

hemophilia-lest

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326 Unit V Genomics and Disease Management

chromosomal aneuploidy derection; and diagnosis of single-gene (monogenic) disorders, such as sickle cell
anemia, cysric fibrosis, and fragile X syndrome. In oncology, cf DNA is being used ro identify informarion
abour rhe patient's rumor, including rhe generics, amounr of burden, mechanisms of progression, and drug
resistance. Another advantage of rhis developing rechnology is rhar ir costs much less. Alrhough many inva-
sive tests are costly, take significant time to receive results, and carry a risk of complications, cf DNA offers
the opposite. In addition, rhis new rechnology may offer results that enable real-rime moniroring for rumor
changes, affecting treatrnenr and management in oncology. The bottom line is real-time guidance for personal-
ized treatment in oncology Giang & Lo, 2016).
Addirional types of diagnostic testing and other caregories of clinical genetic testing are described in rhe
next section.

TYPES OF GENETIC TESTS

Diagnostic Testing
Diagnostic testing is done ro confirm or rule out a par-
Can Genetic Testing Tell Us Anything Besides
ticular diagnosis in a syrnprornaric person. For example,
Information About the Person Being Tested?
Marfan syndrome (MFS), which is transmitted in an
Yes-it provides information about other family
autosomal-dominant fashion, is usually diagnosed based
members as well. For example, your patient's
on clin ical features, but some healthy patients have a
parents may request genetic testing to confirm her
body type that resembles that ofMFS patients (mmfonoid diagnosis of CF If she tests positive, then both
physique). In some cases, even specialists are not certain of her biologicalparents are almost certain to be
that MFS is rhe correct diagnosis. Doing a genetic test CF carriers because it is an autosomal-recessive
for the gene variants known to cause MFS can make disease,and each of her current or future siblings
the diagnosis clear. For some diseases, standard clinical has a 50% risk of being a carrier and a 25% risk
or biochemical tests may be a better choice than genetic of being affected. Testingonly one person in the
testing. For example, in rhe case of cystic fibrosis (CF), family vvouldtell us something about the genetic
a sweat chloride test is still considered rhe best way to risk of several family members.
provide an accurate diagnosis, even though we know
the defective gene that causes CF.

Predictive Testing
Predictive testing is for asymptomaric people who want information about their risk of developing a genetic
disease in rhe future. Two types of predictive testing exist. A positive presymptomatic test indicates that rhe
individual will develop rhe disease he or she was tested for at some point in the future (if he or she does not
die from somerhing else first). Testing for Huntington disease (HD) is a presymptomaric test. A person who
tests positive for rhe disease-causing number of triplet repeats in rhe Huntington gene will develop HD if he
or she lives long enough. Of course, HD has age-related penetrance, and symptoms usually appear between
the ages of 35 and 55 years. HD has virtually 100% penerrance by age 80. This has made having genetic
testing for HD a very difficult choice for those at risk. We will revisit some of rhe legal and erhical issues of
HD testing in a later chapter.
PredispositionaI testing is done when having a gene variant increases the likelihood that a person will
develop a genetic disease, but that does nor mean that the person is certain to get it. Testing for rhe breast
cancer risk alleles (mutations in BRCAI and BRCA2) is predispositional. Testing positive for a documented
mutation confers an 85% risk of getting breast cancer over a person's lifetime. Alrhough this risk is high, it is

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 Chapter 16 Genetic and Genomiclesting 327

not 100%, so something else must be happening (environment or additional gene variants) in those men and
women who develop the cancers associated with mutations in these genes. These genes were formerly tested
one at a time. Now that next-generation sequencing is available, multiple genes can be tested at the same
time. Some laboratories can sequence as many as 80 genes at the same time.

Inconclusive Results
Although most results are positive or negative, unfortunately, another result is possible. If the person tested is
found to have a gene variant, but it has not yet been linked to the disease in question, the results are consid-
ered "inconclusive." For example, if your patient is at risk for breast cancer and has a variation in BRCA 1 or
BRCA2 that has not been documented as increasing the risk of breast cancer but has also not been identified
as a benign common variation, the results would be reported as inconclusive. When a patient has risk factors
that elevate the chance of developing a malignancy, this genetic test result can cause confusion. We expect
that persons with inconclusive results would continue high-risk monitoring according to recommendations,
but they should receive appropriate counseling to help them understand what their results actually mean and
when they could receive a definitive negative or positive answer. Mutation databases, such as ClinVar, are
used to determine if a change in DNA sequence is pathogenic and associated with a disease or benign and not
associated with a disease or family trait. ClinVar is contributed to and is accessible by the public, with all
information reviewed, substantiated, and referenced (National Center for Biotechnology Information lNCB!],
2016). Some laboratories maintain their own databases and do not allow contributions or access by outside
clinicians or researchers.

Carrier Testing
Carrier testing is done when persons have family members affected by a heritable disease, but they themselves
are not affected. Carrier testing can also be done for persons who are at high risk of a genetic disease based
on their ethniciry, Table 16-2 shows carrier frequencies of some genetic diseases in particular ethnicities. Most
-

Carrier Frequencies in Selected Genetic Conditions

Disease Population Carrier Frequency
-
Cystic fibrosis European American 1 in 25
Ashkenazi Jewish 1 in 27
Hispanic 1 in 45
African American 1 in 92
Asian 1 in 90
Sickle cell disease African American 1 in 10
Mediterranean 1 in 40
lay-Sachs disease Ashkenazi Jewish 1 in 30
French Canadian/Cajun 1 in 30
l3-lhalassemia Mediterranean in 25
African American 1 in 75

Data from JScreen. tn.d). Ethnicity and genetic disease: Genetic disease risk assessment
Retrieved from https:!/jscreen_org/reasons-for-genetic-testing!; Jorde. L 8.. Carey. J_ C. &
Bamshad. M_ J_ (20101_Medical generics (4th ed.), Philadelphia. PA: Elsevier.

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328 Unit V Genomics and Disease Management

Ashkenazi Jewish Genetic Panel

Bloom syndrome
Canavan disease
Cystic fibrosis
Familial dysautonomia
Fanconi anemia group C
Gaucher disease
Niemann-Pick disease types A and B
Tay-Sachs disease
Torsion dystonia

Adapted from Cigna.(20171.Ashkenazi Jewish generic panel

(AJGPJ. hnps:/twww.cigna.comlhealthwellnesslhw/medical-topcsl
ashkenazi-iewis~enetic-panel4v7879
I

carrier testing is done for couples considering having children. For example, when two people of Ashkenazi
Jewish (Eastern European) background plan to have children, they are often counseled to have carrier testing
for diseases with risk alleles common in this population. Because these diseases are autosomal recessive or
X-linked recessive, finding out if one or both persons in the couple carries the risk allele can be helpful in
deciding whether to have children, to use technologically assisted reproduction (see the "Preimplanrarion
Genetic Diagnosis" section), or to prepare for the possibility of having a sick child. Table 16-3 lists diseases
that are common in people with Ashkenazi background. Carrier resting for this group of diseases can be done
at the same time and is called an "Ashkenazi Panel" by some clinical laboratories.
Some genetic testing panels are targeted to people of specific ethnicities. For example, more than
1,700 different mutations have been identified in the CFTR gene. Mutations in this gene can cause cystic
fibrosis (CF), which is discussed in Chapter II. The American Congress of Obstetricians and Gynecologists
(ACOG) and the American College of Medical Genetics have developed a panel of 23 common mutations
that can be used to screen for CF, but many of these mutations are more common among people of some
ethniciries than others. For example, if this recommended mutation panel is used for a European American
patients, the detection rate will be about 95% (i.e., about 95% of the time, the mutation causing the patient's
CF will be found), but if the same panel is used for African American patients, the detection rate will be only
about 71 % (i.e., about 71% of the time, the patient's mutation will be found). Thus, including information
about erhniciry is important when requesting some tests (ACOG, 2017a).

Prenatal Testing
Once a woman is pregnant, prenatal testing can be done to determine if the fetus carries a specific gene variant
or a chromosomal disorder. Numerous kinds of prenatal genetic tests exist. These tests vary by when they can
be done, the disorders tested for, and the invasiveness of the procedure. Chromosomal microarray analysis
and next-generation sequencing have greatly improved the ability of prenatal tests to detect genetic disorders.
Prenatal genetic tests can be either screening or diagnostic. Screening tests determine the likelihood that a

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 Chapter 16 Genetic and GenomicTesting 329

fetus has a genetic disorder such as Down syndrome. During the first trimester (about the first 10-13 weeks
of pregnancy), a pregnant woman's blood is screened, and an ultrasound test is done. The ultrasound measures
the thickness of an area toward the back of the ferus's neck. This is called nuchal translucency (NT) screening.
The availability of noninvasive prenatal screening (NIPS) using cell-free fetal DNA (eff DNA), as discussed
earlier in this chapter, has greatly improved the accuracy of prenatal blood test results. These screening tests
use the small amount of circulating DNA from the placenta (about 10% of maternal blood volume). This fetal
DNA can be tested for disorders. including Down syndrome, trisomy 13, trisomy 18, and sex chromosome
problems. cff DNA screening can be done beginning at 10 weeks, and it is particularly helpful for women
who have an increased risk of carrying a baby with a chromosomal disorder.
Second-trimester screening is usually done between 15 and 20 weeks. It typically includes the "quad" screen
testing for aneuploidy. open neural rube defects, Down syndrome, and trisomy 18. (ACOG, 20 17b). Of course,
it is important that parents understand that these tests are for screening only, and therefore accuracy is limited.
A diagnostic test is done to determine whether or not the fetus actually has a particular disorder. If
a screening test is positive, a diagnostic test often follows. The increased use of cff DNA screening has
reduced the number of diagnostic tests done during pregnancy. For diagnostic testing, fetal cells can be
obtained via amniocentesis or chorionic villi sampling. These cells can then be analyzed by a variety of
different rests, including karyotyping, fluorescence in situ hybridization (FISH), chromosome rnicroarray
analysis, or DNA testing for specific mutations. If a diagnostic test is positive, it is important that the
results are explained to the family by a genetics professional and that resources for suppOrt are available
(ACOG, 2016).

Preimplantation Genetic Diagnosis

Preimplantation genetic diagnosis (PGD) is a process done in conjunction with in vitro fertilization. A group
of embryos is tested prior to implantation when one or two cells are removed from the eight-cell blastocyst.
Cells from each embryo can be tested to find gene variants causing single-gene disorders or chromosomal
problems, or to determine sex. One or twO"healthy" embryos are then selected for implantation. If the parents
are concerned about an X-linked recessive disorder, which primarily affects boys, they may choose to implant
only female embryos. Persons using PGD may also be older and concerned about the impact of advanced
maternal or paternal age on the health of their baby. In addition, PGD may nor be ethically acceptable [0 all
families, because unwanted embryos are often discarded, but it offers an alternative to prenatal testing and
pregnancy termination for couples willing and able to have the procedure.

Newborn Screening
Newborn screening is done to identify those infants at high risk of a variety of disorders for which immediate
treatment or intervention is available. The tests are usually biochemical rather than gene based, but results
can indicate the likelihood of a genetic disorder being present. Newborn screening has been done since the
I960s, when Dr. Robert Guthrie developed the test to screen for phenylketonuria (PKU). Screening programs
vary somewhat ftom state to state in the United States. The Advisory Committee on Heritable Disorders in
Newborns and Children of the U.s. Department of Health and Human Services (2016) provides a Recom-
mended Uniform Screening Panel that lists disorders for which states should screen. Disorders on the panel
are chosen based on three criteria: the current evidence supporting the benefit of doing the screening, a state's
ability to actually do the screening. and whether or not treatment is available for the disorder. Hearing loss,
metabolic disorders. cystic fibrosis, and sickle cell anemia are examples of disorders on the recommended list.
A complete list of Core and Secondary disorders on the recommended screening panel can be found at https:11
www.hrsa.gov/advisorycommitteeslmchbadvisory/heritabledisorders/recommendedpanel/.

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Other Types of Genetic Testing

Several other types of genetic testing are used by consumers to answer questions unrelated to disease risk.
Zygosity testing is used to determine if twins are monozygotic (identical) or dizygotic (fraternal). Sometimes
dizygotic twins look so similar that it is difficult to tell without testing their genotypes! Parentage testing has
become very popular on daytime talk shows and is used to determine whether family relationships are biologi-
cal in nature. Knowing a person's biological parents allows him or her to report an accurate medical family
history. Table 16-4 lists some types of genetic testing, interpretation, and follow-up.

TABLE 16-4:
Tvpes of GeneticTesting, Interpretation, and Follow-Up
For Positive Test Results

If the test The interpretation is ... And follow-up includes genetic

purpose was ... counseling- and ...
Diagnostic Clinical diagnosis is confirmed. Medical management and treatment
testing Preventive surgeries or medical
management
Surveillance for future cancers if
this was for a germ line mutation
associated with multiple cancer
types
Predictive The likelihood of showing disease Counseling for life planning; medical
testing symptoms is increased. management if available
Carrier testing The patient is a carrier. Testing offered to partner; prenatal
testing offered if indicated
Prenatal testing A fetus is diagnosed with a specific Pregnancy treatment/management
condition. or termination
Newborn Disease in a newborn is suggested; carrier Confirmatory testing-if positive,
screening status in a newborn may be identified. medical management and
treatment; carrier testing offered
to parents
For Negative Test Results

If the test The interpretation is ... And follow-up may include ...
purpose was ...
Diagnostic Clinical symptoms are unexplained. Further testing and/or follow-up
testing genetic consultation
If negative for a familial mutation,
cancer risk returns to that of
general population

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 Chapter 16 Genetic and GenomicTesting 331

Types of Genetic Testing, Interpretation, and Follow-Up-cont'd

Predictive The likelihood of showing symptoms is Counseling for survivor guilt and
testing decreased. long-range life planning; no high-
risk surveillance needed
Carrier testing The likelihood is high that the individual is Testing offered to other family
not a carrier; the risk of having a child members if indicated
affected with the condition in question
is low
Prenatal testing If the fetus was symptomatic (e.g., by If fetus was symptomatic, further
ultrasound findings). clinical symptoms testing and/or pregnancy
remain unexplained and may need management; if fetus was not
further investigation. If the fetus was symptomatic, no follow-up
not symptomatic, the chance of the
condition tested for is very small.
Newborn The newborn is not expected to have the No follow-up
screening condition tested for.

"Genetic counseling includes discussion of expected course of the disorder.possible imerventions, underlyingcause. risks to family
members, reproductiveoptions, and support
Adapted from University of Washington. Seanle.(2009. March 4). GeneTesls. Retrievedfrom hnp:/Mrww.genelesls.org
'--

OVERSIGHT OF GENETIC TESTING

The stakes are high when considering genetic testing. False negatives from a prenatal test could result in
the unexpected birth of a critically ill child, whereas false positives could result in the termination of a
normal pregnancy. All laboratories performing such tests must be certified under the Clinical Labora-
tory Improvement Act (CLlA). Sometimes families choose to participate in research studies that incor-
porate genetic testing. They should find OUt if they will receive their genetic test results and if the
laboratory doing the testing is CLlA certified. If a research laboratory is not CLlA certified, the results it
provides should not be used to make health-care decisions (National Human Genome Research Institute
[NHGRI], 2016).
Genetic testing in the United States is overseen by three different federal agencies: the Centers for Medicare
and Medicaid Services (CMS), the Food and Drug Administration (FDA), and the Federal Trade Commission
(FTC). The FDA is responsible for the regulation of all laboratory tests sold as kits. Kits include all the reagents
needed for a genetic test packaged together and sold to laboratories. There are also laboratory-developed
tests (LDTs), which have been developed by a specific laboratory. Specimens tested using LOTs are typically
shipped to the lab that developed the test for analysis.
The quality of a genetic test is evaluated in three ways. We must know that a test is both accurate and
reliable (analytical validity), we must be sure that the information provided from the test will be medically
meaningful (clinical validity), and we must know that using this test will improve health care (clinical
utility) (NHGRI, 2016).

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LABORATORY METHODS USED

FOR GENETIC TESTING
DNA Sequencing
DNA sequencing refers to the analysis of the bases in a length of DNA. Laboratories most commonly look
at the sequence of nucleorides in the regions that code for protein (exons) and the intron/exon boundaries, or
splice sites. Now, the introns (non-protein-coding regions) and the regions between genes (intergenic regions)
are sometimes being considered because they may contain sequence variations in regulatory sequences like
promoters or silencers. DNA sequencing is the most accurate and most specific test used in identifying gene
variants.
To evaluate a sequence, a DNA sample is extracted from some body fluid or tissue. Laboratories usually
use leukocytes from blood or epithelial cells from saliva or buccal samples. Any cell with a true nucleus can
be used (as any fan of television procedural crime dramas knows). The process of polymerase chain reaction
(PCR) is used to amplify (greatly increase the quantity of) tiny amounts of DNA for examination. Although
the process is not complex, it does take some time.
An elecrropherogram is a graphic illustration of the nucleotide sequence in a stretch of DNA amplified by
PCR. Different colored spikes correspond to one of the four DNA bases (A is green, T is red, C is blue, and
G is black). The lab technician can read the electropherogram and report any variations between the sequence
found in the patient sample and the order that is reponed to be the common sequence (or wild type).

Cytogenetic Testing
Cytogenetic testing involves the evaluation of whole chromosomes for variations in structure or number.
Cytogenetic testing is done in a variety of situations. For example, a chromosome study is commonly done
when evaluating a possible genetic cause of infertility or developmental disability. Cancer tumor cells can also
be evaluated by cytogenetic testing. For example, if a person has chronic myelogenous leukemia, finding a
9:22 translocation (Philadelphia chromosome) can help clinicians choose a targeted therapy. Cytogenetic testing
is also used if a prenatal screen shows that a fetus may have Down syndrome. In such a case, the Auid from
amniocentesis can be tested to determine if cells have an extra chromosome 21.
In order to observe and identify individual chromosomes, cells must first be cultured and arrested during
the stage of metaphase in cell division. During metaphase, chromosomes are condensed making them easier
to identify individually. The condensed chromosomes are spread out on a slide and are stained for better vis-
ibility under a microscope. Persons trained in cyrogenerics can look at the banding pattern, placement of the
centromere and the size of the chromosomes (including the "p" [petite] and "q" [follows "p" in the alphabet]
arms) from large to small. The result is a karyotype, such as those you saw in Chapter 6, Figures 6-1 and 6-3.

Fluorescence in Situ Hybridization

Fluorescence in situ hybridization (FISH) is a laboratory test that uses a string of fluorescencly labeled nucleic
acids (DNA bases) that are complementary to the bases in an area of interest on a section of a chromosome or
on a strand of DNA or messenger RNA (mRNA). The string of bases is called a probe and is designed to glow
(or fluoresce) in the presence of a specific dye. The probe is attached or hybridized to the sequence of interest,
which is most commonly a string of single-stranded DNA. When a cell containing the probe hybridized to the
complementary strand of DNA is examined under a fluorescence microscope, the region of interest will glow.
For example, a laboratory technician can use FISH to determine whether a cell taken from the amniotic
fluid COntains two or three copies of chromosome 21. To do this, a fluorescent probe that is complementary

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 Chapter 16 Genetic and GenomicTesting 333

to a region on chromosome 21 would be designed and allowed ro hybridize (bind) with the patient's chro-
mosomes. The number of chromosomes glowing would be counted. Three chromosomes glowing in each cell
indicates that the test is positive for trisomy 21, Down syndrome.
FISH can be used to determine whether a person carries a translocacion. Probes for each chromosome are
dyed with different colors of fluorescent dye. If chromosome 9 shows a region with the color of chromosome
22, and chromosome 22 shows a region with the color of chromosome 9, a 9:22 translocation has occurred.
FISH is also used to detect deletions, microdeletions, and duplications of chromosomal material.

Genome-Wide Association Studies

Genome-wide association studies (GWASs) are used by researchers to find areas of the genome that are
associated with disease. The process involves the use of genetic markers or, more commonly, single-nucleotide
polymorph isms (SNPs). The genomes of large numbers of people (often about 1,000) with a given disease
are compared with the genornes of people (also about 1,000) without the disease, to look for gene variations
that are more common in the people who have the disease. Once regions of interest are identified, they are
said to be "associated" with the disease, and the genes located in those regions can be examined further. This
technique is possible because of contributions from the Human Genome Project, completed in 2003, and
phase I of the Human HapMap Project, published in 2005.
GWASs are most useful in studying genecic variations that contribute to complex or multifactorial dis-
eases such as diabetes mellitus type 2, Parkinson disease, heart disease, obesity, and asthma. Establishing the
genetic risk factors for complex diseases is very difficult because they usually involve many genes that each
contribute a small amount of risk combined with environmental risk factOrs. Studies are ongoing, and some
have produced exciting results.
In 2005, scientists used GWASs to find a genetic risk factor that contributed to age-related macular
degeneration (AMD), the most common vision disorder in older people. AMD initially blurs "straight-ahead
vision," making reading difficult and driving unsafe. Three separate studies found a variation in the gene for
complement factor H, which produces a protein that regulates inflammation. The idea that inflammation
played an important part in the onset of macular degeneration was new to people investigating this disease
(NHGRI,2015).

Whole-Exome Sequencing (WES)

Whole-exome sequencing (WES) focuses on the protein-coding parts of the genes (exons) and the areas that
are right next to the exons (splice junctions). This accounts for only about 1% to 2% of the human genome.
The goal is to identify genetic changes that affect the order of base sequences in the proteins. Because this is
a much smaller number of variants to test, WES is more efficient and less expensive. WES is most useful with
rare Mendelian diseases with a few genetic changes presenr in a small number of people. GWASs, by contrast,
measure shared genetic sequence changes in many individuals in the larger population. Especially important,
the disease-causing variants in rare diseases are more likely to be found in the protein-coding regions of the
genome (Lewis, 2012).
Whole-genome sequencing (WGS) is just what the name implies it is: the sequencing of the whole human
genome. As you might imagine, this should be pretty expensive. When WGS was firsr done in 2003, it COSt
about $2.7 billion! Now Illumina, a company offering the service, has a machine that promises to be able to
sequence the entire human genome for $100. Illumina has been able to do WGS for $1,000 since 2014 (Buhr,
2017). Of course, sequencing an entire genome produces lots and lots of informacion. The challenge becomes
how to make sense of all that data and how to determine what effect (if any) the variants uncovered have on

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334 Unit V Genomics and Disease Management

the person's health. It may be quite some time before \VGS is used clinically. Currently, WGS is being used
to identify pathogens in food or in the environment.

DIRECT-TO-CONSUMER GENETIC TESTING

During the last few years, many companies have begun to offer direct-to-consumer (DTC) genetic testing,
most commonly online. Many tests are available, including tests for single-gene disorders, such as heritable
breast cancer, and some for multifactorial diseases. Some companies offer limited COntact with a genetic
counselor, whereas others do not, Making genetic testing available without extensive counseling by genetic
professionals raises some interesting concerns. Although some people believe they have the right to learn about
their genetic risk on their own, whether they have enough information to properly understand their results
is another matter entirely.
The American Society of Human Genetics (ASHG) and the American College of Medical Genetics and
Genomics (ACMG) issued statements on DTC genetic testing in 2007 and 2008, respectively. Both organiza-
tions were adamant that a knowledgeable professional be involved in ordering and interpreting genetic tests.
The ACMG (2015) continues to be concerned because genetic rests require technical expertise, and inter-
pretation of those tests can be difficult. A genetics expert must be available, and the consumer must be fully
informed about the test and its implications. Other concerns include the strength of the scientific evidence on
which the tests are based and whether the companies sufficiently protect their customers' privacy. Clinicians
fear that inaccurate or misunderstood results could lead people to take health and lifestyle risks by continuing
behaviors, such as smoking, because they believe their risk of cardiovascular disease is low or choosing not to
have screening mammograms because they believe that having no sequence variations in BRCAJ 12 means they
have no risk of developing breast cancer. DTC genetic testing is not cheap, with COStsranging from around
a hundred to a few thousand dollars, depending on the number of genes included in the test, In some cases,
products, such as nutritional supplements, can be purchased from a DTC company with the genetic testes)
included for free (FTC, 2014).
Guiding your patients to genetics professionals rather than to the Internet when they are considering genetic
testing is very important. Most genetic tests are not regulated even though three federal agencies have a role in
the regulation of genetic tests. As noted earlier, the CMS regulates clinical laboratories and the performance
of genetic tests. The FDA has the authority to regulate genetic tests but has chosen to control only a small
number of kits sold to laboratories, and the FTC focuses only on addressing false and misleading advertising.
The FTC has primarily addressed DTC companies that were misleading the public about testing for genetic
mutations in regions of the DNA that do not code for protein so results would be meaningless to consumers.
The companies that offer these tests commonly state that they are being offered for recreational use and that
they should not be used for clinical decision making, but how consumers themselves view these test results
and what actions they might take based on them is unclear. An individual considering DNA testing through
a DTC company should collect information regarding whether the test is accurate and reliable, whether the
test result will provide medically meaningful information, and whether the test result can improve his or her
personal health or the health of relatives (NHGRl, 2016). Very few States require consumers to sign a consent
form about the purpose and use of the test.

RISKS AND BENEFITS OF GENETIC TESTING

Genetic testing carries both potential risks and benefits. For example, knowing that you do not carry the fam-
ily's gene variant for colon cancer means that you can adhere to the general recommendations for colonoscopy

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 Chapter 16 Genetic and GenomicTesting 335

screening rather than the more frequent screenings recommended for those who have a genetic risk. Being
tested can reduce uncertainty. A positive predictive test can allow the patient time to prepare for the likeli-
hood of becoming ill or the need for prophylactic surgeries, and a negative test can relieve his or her worry.
Table 16-5 shows a sample laboratory report for a genetic test. Reports similar to this one would be provided
to the health-care practitioner ordering the tests with a copy for the patient.

"'~:t~•.~~ ~ __
Sample Laboratory Report
Doesn't Really Exist Genetics Laboratory
Los Alamos, New Mexico
Patient Name: PP
DOB: 8-10-2009
Patient Name: Patty Patient
Date of Birth: 8-10-2009
Sex: Female
MRN: 000 000 001
Clinical Team: Suzie Helpful and Carlos Cares-a-Lot
Sample Type: Saliva
Test Perfonned: Sequence analysis and deletion/duplication testing of the 6 genes listed in the results
section below.
Loeys-Dietz syndrome panel
2 individual genes
Summary:
Negative results. No Pathogenic sequence variants or deletions/duplication were identified.
Clinical Summary:
• The fact that this is a negative test result does not eliminate the possibility that there is a genetic
contribution to this patient's condition. It is still important that the patient and her/his family members
be followed up as determined by their clinician(s).
• It is important that these laboratory results be considered in combination with other test results, family
history, and clinical signs and symptoms.
• Clinical genetic counseling is strongly recommended for mutation carriers or if you have any questions
about these results. You can arrange for genetic counseling by calling this number: 555-555-5555.
Complete Results:
The following genes were evaluated for sequence changes and exonic deletions/duplications:
CBS. FBN1. SMAD3.TGTB2. TGFNR1. TGFBR2
Results are negative
Any sequence changes determined to be benign. likely benign. silent, or intronic variants with no current
evidence indicating that they are disease-causing changes are not included. This information is available
upon request.
Detailed methods, including specific sequence, flanking sequences, reference sequences, and microarray
techniques used, are available upon request.
Continued

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336 Unit V Genomics and Disease Management

.. ,~:t~~~ ~

Sample laboratory Report-cont'd

References:
LaDuca, H., Farwell, K. D., Vuong, H., I,u. H.-M., Mu, W., Shahmirzadi, L., ... Chao, E. C. (2017). Exome
sequencing covers >98% of mutations identified on targeted next generation sequencing panels. PLOS
One, 12(2), e0170843.
Zastrow, D. B., Zornio, P A., Dries, A., Kohler, J., Fernandez, L., Waggott, D., ... Wheeler, M. 1 Exome
sequencing identifies de novo pathogenic variants in FBNl and TRPSl in a patient with a complex
connective tissue phenotype. Cold Spring Harbor Molecular Case Studies, 3(1), a001388.
Disclaimer:
DNA sequencing does not provide a definitive test for the selected condition in all persons. There are
possible sources of error that could provide incorrect results. These could include trace contamination,
technical errors, and recent scientific developments. This test is not diagnostic and should be used by
the health-care provider in conjunction with clinical and other laboratory data. This test has not been
approved by the U.S. Food and Drug Administration (FDA). The FDA has determined that approval of this
test is not necessary.
This laboratory is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLlA) as
qualified to perform high-complexity clinical laboratory testing. This test is used for clinical purposes.

Counseling is essential before undergoing any generic resr. The meaning of positive, negative, and incon-
clusive results should be discussed with a genetics professional prior to resting. Genetics professionals include
generic counselors. genetic nurses, or medical geneticists. Currently only 1.200 generic counselors practice in
the United States, so having access ro quality genetic counseling may be difficulr, bur its importance cannot
be overemphasized. Patients and their families should be led through a discussion of options for managing
the range of possible results. Generic counselors have training that allows them to explain the many different
types of genetic tests and what tests are appropriate given the family history. Most importantly. they can guide
a family through the difficult decisions both before and after genetic testing is done.
Genetics services are usually provided through major medical centers or private clinics that specialize in
genetics. They are often organized by specialty, so you may find genetic counselors or genetics nurses that
specialize in rare diseases in prenatal, pediatrics, adult, or cancer genetics. You can help your patients locate
generics professionals in your area by consulting the Clinic Directory at generests.org or the Generic Tesring
Regisrry (NCBI, 2017). More information about the types of services offered by genetics professionals can
be found in Chapter 18.
Important issues such as the right to privacy. informed consent. and confidentiality are crucial when con-
sidering generic testing. These topics are discussed in Chapter 19.

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 Chapter 16 Genetic and GenomicTesting 337

SUMMARY
Genetic testing is becoming much more common. It is being used clinically to help predict or diagnose genetic
disease. Advanced reproductive technologies are being used to screen embryos for sex or genetic traits in the
process of preimplanration genetic diagnosis. Genetic tests are even being sold directly to consumers online.
Many genetics professionals are concerned that people will choose to have genetic tests without receiving
counseling from health-care professionals who have genetic expertise. This could result in people taking tests
they do not need or in misinterpretation of the results causing early or unnecessary surgeries. It could have
negative implications for family dynamics because genetic tests often tell us something about the family as
well as the person being tested. Advances in genetic testing have brought with them many new and challeng-
ing ethical dilemmas.

GENE GEMS

• Genetic testing includes the testing of DNA, RNA, chromosomes, protein products, and protein metabolites.
• Clinical genetic testing is available for more than 2,000 different diseases.
• Some gene variants may be found in many people with a disease, while not necessarily being the cause
of the disease.
• Updated information about genetic testing can be found at www.genetests.org.
• A sample for genetic testing can be taken from many body fluids or tissues, but the most common
sources are buccal swabs, saliva, and blood.
• Predictive genetic testing is used to determine the likelihood that an asymptomatic person will develop
a genetic disease.
• Carrier testing is used to find out if a person who has a genetic disease in his or her family can pass
the disease on to his or her children.
• Carrier frequencies for genetic diseases vary in populations.
• Preimplanrarion genetic diagnosis can be used to screen and select unaffected embryos for implantation.
• cf DNA testing is safer and offers the potential for moniroring real-time clinical changes in oncology
settings.
• cff DNA provides a noninvasive prenatal screening method that can be done beginning at 10 weeks'
gestation.
• Direct-to-consumer genetic testing is controversial.
• Genetic testing carries both potential risks and benefits.
• Genetic counseling is essential before having a generic test.

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338 Unit V Genomics and Disease Management

Self-Assessment uestions ....

1. An asymptomatic 28-year-old woman with a three-generation family history of breast cancer diagnosed
at early ages comes [Q the clinic [Q see if she has a murarionts) that could increase her susceptibility [Q
this malignancy. Her diagnosed relatives are no longer living and did not have germline testing before
their deaths. What type of testing could be appropriate?
a. Diagnostic testing
b. Predisposirional testing
c. Presympromatic testing
d. Cytogenetic testing
2. A healthy couple with an Ashkenazi Jewish background comes to the genetics clinic and would like
co know if they could pass on a recessive condition CO their baby. Which type of genetic testing would
be appropriate for this couple?
a. Carrier genetic screening
b. Prenatal screening via chorionic villus sampling
c. Prenatal screening via amniocentesis
d. Multiple marker screening
3. Presymptomatic genetic testing would be appropriate for which of the following disorders?
a. Breast cancer
b. Cystic fibrosis
c. Hemochromatosis
d. Huntington disease
e. Marfan syndrome
4. A woman with a family history of a breast cancer gene mutation is tested for the known variant. How
would you explain her results?
a. If she has a negative result, she will not develop breast cancer in her lifetime.
b. Ifshe has a negative result, she has a lower risk ofdeveloping breast cancer than the general population.
c. If she has a positive result, she will definitely develop breast cancer in her lifetime.
d. If she has a positive result, she has a much greater risk of developing breast cancer than does the
general population.
5. Which type of genetic testing has high reliability and a low risk of complications?
a. Prenatal screening via chorionic villus sampling
b. Direct-co-consumer testing
c. cfDNA testing
d. Preimplantation testing in conjunction with in vitro fertilization
6. Which of the following groups has the authority to regulate all laboratory testing?
a. Centers for Disease Control
b. Cen ters for Medicare and Medicaid Services
c. Food and Drug Administration
d. Office for Human Research Protections

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 Chapter 16 Genetic and GenomicTesting 339

CASE STUDY

Your patient Harry was diagnosed with colon cancer and an identified variant in the APC gene at the age of
24. He and his wife met with you to talk about testing their 4-month-old son for this mutation. They want
to have more children but are afraid of having a child who will be diagnosed with familial adenomatous
polyposis. They ask you what you think about testing their son now and preimplantation genetic diagnosis
(PGD) for any future children.
1. Should the 4-month-old son be tested now or later? If later, at what age?
2. Is PGD an appropriate test for them?
3. Should they incorporate testing into a plan for in vitro fertilization to ensure a "healthy" baby?

References

Advisory Committee on Heritable Disorders in Newborns and Children, U.S. Deparrmenr of Heald, and Human Services.
(2016). Recommmded uniform screening ptlllel. Retrieved from hrrps:llwww.hrs3.gov/advisorycommirrees/mchbadvisoryl
herirabledisorders/ recommendedpanell
American College of Medical Generics and Genomics. (2015). Direct-to-consumer generic resting: A revised posicion statement
of the American College of Medical Generics and Genomics. Gmetics ill Medicin«; 1-2.
American Congress of Obstetricians and Gynecologists. (2016). Prmllftllgmetic ditlgnosticIt'Sts.Retrieved from hrrps:llwww.acog.org/
Patien ist FAQs/Prenata l-Generic- D iagnostic-Tests
American Congress of Obstetricians and Gynecologists. (20 17a). Ctlrrier scrullillgjor gmuic conditions (Cornrnirrce Opinion
No. 691). Retrieved from https:llwww.acog.orgiResources-And-Publicarions/Committee-OpinionsICommirree-on-Geneticsl
Carrier-Screening-for-Generic-Condirions
American Congress of Obsrerricians and Gynecologists. (2017b). Prel/tlfIllgmericsCI'wlingteu« Retrieved from hrrps:llwww.acog.org/
Patien [.1FAQs/Prenatal-Genetic-Screeni ng-Tesrs
Buhr, S. (2017). Illumlna umnts to sequmu Jour II/holegmollle for $100. Retrieved from Imps:/lrechcrunch.com/2017/01/101
illumina-wams-tQ-sequence-your-whole-genome-for-l001
FederalTrade Commission. (2014). FTC Consumtr inforlllllf·ioll--dilrCf-lD-mIlSlIIllel"ltSts. Retrievedfrom https:llwww.collSumer.ftc.gov/
articles/O16G-direct-consumer-genetic-tesrs
GeneTesrs. (2017). Statistics. Retrieved from hrrp:llwww.generests.org
Jiang, E, & Lo, Y. M. D. (2016). Circularing cell-free DNA and the ins and outs of molecular diagnostics. Trendsill Cenetia,
32(6), 360-371.
Lewis, R. (2012). 10 things exorne sequencing can nor do-Bur why ir'sstill powerful. Scimtific American. Retrieved from https:1I
blogs.scienriflcamerican.com/guesr-blogfl O-things-exome-sequencing-canr-do-bur-why-its-still-powerfull
McPherson, R, & Tybjaerg-Hansen, A. (2016). Genetics of coronary anery disease. Circulation Research, 118,564-578.
National Center for Biotechnology Informacion. (2016). ClillVtir. Retrieved from hrtps:llwww.ncbi.nlm.nih.gov/dinvar/imro/
National Center for Biotechnology Informacion. (2017). Genetic restil1grt'gisrry. Retrieved from hrrps:flwww.ncbi.nLm.nih.gov/gtr/
National Human Genome Research Institute. (2015). Gmoll1t'-widt associationstudie«. Retrieved from hrrps:flwww.genome
.gov/200 195231

ERRNVPHGLFRVRUJ
340 Unit V Genomics and Disease Management

National Human Genome Research Institute. (2016). Rtgllwtioll ofgml'tic tests. Retrieved from https:llwww.genome.govII0002335/
regulation-of-genetic-tests/
Salirnerrics. (2015). Sfllivtl collection find hflndling ndoice (3rd ed.). Retrieved from https://www.salimerrics.com/as..ers/documems/
Saliva_Collecrion_Handbook.pdf

Self-Assessment Answers
I. b 2. a 3. d 4. d 5. c 6. c

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 Assessing Genomic Variation
in Drug Response
Learning Outcomes
1. Identify the goals of pharmacogenetics.
2. Explain the variation in drug responses when an agonist drug binds to the receptor and when an antago-
nistic drug binds to the receptor.
3. Compare the expected outcomes for drug responses among poor rnerabolizers, extensive rnetabolizers, and
uIrrametabo Iizers.
4. Describe the known effects of specific ethnicities as a factor in drug effectiveness.
5. Explain why some individuals experience no pain relief from high doses of codeine but do obtain relief
with lower doses of morphine.
6. Explain why genoryping is nor always accurate in predicting drug responses.
7. Describe variation in response to specific drugs related to differing levels of metabolizing enzymes.

Key Terms
Absorption Metabolism Precision medicine
Agonist Minimum effective Prodrug
Antagonist concentration (MEC) Receptors
Bioavailability Personalized medicine Side effects
Elimination Pharmacodynamics Targets
Enterohepatic circulation Pharmacogenetics Therapeutic effect
First-pass loss Pharmacoge nomics

Intended action Pharmacokinetics

INTRODUCTION
When you look at the ways in which people respond to different drugs and dosages, you can see enormous
variation. Sometimes this is based on age, weight, or liver function, but sometimes no obvious clinical reason
exists to explain why people respond the way they do. Pharmacogenomics (or pharmacogenetics) is the study

341

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342 Unit V Genomics and Disease Management

of how inherited variations in DNA affect the ways people respond to medications. Technically, pharmacoge-
nomics refers to the genome-wide effects, which include the impact of sequence variations, translocarions,
epigenetics, and gene expression. Pharmacogenetics is more specific and refers to the impact of inherited or
acquired DNA sequence variations on a person's response to a drug. Although many people use the terms
interchangeably, we are learning more and more about the complex pathways that lead to protein production
and use, so pharmacogenomics (PGx) is usually the preferred term.
Sometimes people refer to pharmacogenomics as an important component of personalized medicine,
which typically means tailoring the therapy to an individual patient's needs. When all things are considered,
this could be a very expensive proposition, although we have been practicing personalized medicine in some
forms for quite some time. For example, before giving a blood transfusion, we test the recipient's blood in
order to give him or her compatible blood. The term personalized medicine should nor be misinterpreted to
mean that medical devices would be invented or drugs would be synthesized specifically for a given patient.
A newer term is precision medicine. Sometimes precision medicine is used interchangeably with personalized
medicine because people think they mean the same thing. The term precision carries with it ideas of accuracy,
but it is used to mean that therapies could be tailored to treat people with subgroups of diseases that would be
determined by genomics (Ashley, 2016; Valdes & Yin, 2016). You will probably see the term precision medi-
cine used much more frequently. For example, we will discuss cystic fibrosis (CF) later in this chapter. Drugs
are being developed to target specific mutations that can cause CF, with the hope that these therapies will
be more effective than generic treatments for individuals whose disease is caused by these specific mutations.
Pharmacogenetics is not a new idea. In facr, the term was first used in the 1950s after a German geneticist
named Frederich Vogel discovered that people responded differently to medications because they had varying
levels of metabolic enzymes. Variations in drug response were first written about by Pythagoras more than
2,000 years ago. He noticed that some people became sick after eating fava beans, whereas others did not.
Now we know that he had identified people with the X-linked disorder glucose-6-phosphate dehydrogenase

All patients with the same diagnosis

GCCCACCTC GCCCGCCTC
Treat responders and patients Remove nonresponders and
not predisposed to ADRs responders with ADRs

GQQlQQQQQ QQQQQQ QoQQQQOQQQ0Q QQQQ

IIIGGGQQ
GQGGGGGQQQGQQQQQ
Figure 17-1 The effects of gene polymorphisms on drug activity and metabolism.

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 Chapter 17 Assessing Genomic Variation in Drug Response 343

deficiency (G6PD). Eating fava beans causes them to develop hemolytic anemia. So, although PGx seems like
a new and exciting field, the ideas that form its basis have been around for a very long time.
The pharmacogenetic variations in individual drug response are based on polymorphisms in genes coding
for metabolizing enzymes, transporters, and receptors (Fig. 17-1). The clinical responses to these differences
can range from life-threatening adverse reactions (ADRs) to a complete lack of therapeutic effect. About
20% of drugs produce adverse reactions that were unknown when the drugs first came to market, and adverse
drug reactions are considered one of the leading causes of death. One of the main goals of pharmacogenomics
is the reduction of adverse reactions to medications.
Many things alter the way our bodies use the drugs we take. Some examples are age, body mass index
(BMI), tobacco or alcohol use, comorbid conditions, and alterations in organ function. Polymorphisms in
genes involved in the drug response account for the largest portion of variation from person to person
(Table 17-1). Genetic polymorphisms may lead to nonfunctional, superfunctional, or absent proteins. Typically,

.'!~:t
lII::ar.4:llt

Personal Factors Affecting Drug Metabolism

Category Factor

Physiological Genetic polymorphisms in enzymes responsible for drug metabolism and elimination*
Age
Albumin and prealbumin blood levels
Cardiovascular function
Circadian rhythm variation
Disease
Fever
Gender
Gastrointestinal activity
Immunological activity
Infection
Kidney function
Lactation
Liver function
Pregnancy
Psychological status
Environmental Alcohol intake
Barometric pressure variation
Behavior
Dietary intake
Drugs (therapeutic, recreational. illicit)
Exercise level
Occupational exposures
Season variation
Sunlight exposure
Stress
Tobacco use
Weight and fat-to-lean ratio

• Degree of influence on personal variation in drug responses.

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344 Unit V Genomics and Disease Management

the phenorype is recognized before the genetic basis responsible for the drug response variation is known.
If a patient develops a toxic reaction to a drug when the standard dose is given, he or she likely has some
variation in the way his or her body is using that drug or has a true allergy to it. Review the physiological
processes that lead to drug responses to understand how genomics affects the ways in which people respond
differently.
A drug is prescribed to produce a patient response, a desired and expected change in the function of one
or more tissues or organs, known as its intended action or therapeutic effect. Although the intended action
of a drug is expected to occur in any patient who receives it, nor all patients respond to the drug as intended
or to the same degree. This variation in patient response results from personal genetic differences that inRu-
ence both the target of the drug and the drug's metabolism (how long the active drug remains in the body
in Contact with its target).

PHARMACODYNAMICS
Phannacodynamics refers to the body responses induced by a drug. These responses include both the intended
action and side effects of the drug. A person's genetic differences can influence a drug's pharmacodynamics by
changing the way that individual person responds to that drug.
All cells have specific individual functions or actions that contribute to proper whole-body function. Drugs
induce their responses by changing the acrivity level of different cellular processes. The function of any tissue
or organ can be decreased, halted, or increased by exposure to a specific drug. The mechanism of action for
any drug is how, at the cellular level, it acts to change cell and tissue function. For many drugs, the mecha-
nism of action involves the interaction of the drug with cellular receptors that normally control cell function.
Although not all drugs exert their inrended actions through a receptor, many do.

Receptors and Intended Actions

Receptors are sites on a cell surface or within a cell where naturally occurring substances can bind and control
cell function. For example, binding of epinephrine or norepinephrine to beca.vadrenergic receptors on smooth
muscle cells in blood vessels causes internal celJ responses that result in smooth muscle contraction (an increase
in this cellular functional activity) and blood vessel constriction. When more norepinephrine is bound, the
vessel constricts to a greater degree; when less norepinephrine is bound, the vessel is more relaxed. In this
case, when the receptor is properly activated, ceUuJar function (smooth muscle constriction) is increased. This
response continues as long as norepinephrine remains bound to the receptor. Any drug that binds to a cell's
receptor sites and causes the same response as the naturally occurring hormone or substance is known as an
agonist (Fig. 17-2).
Remember that different cell rypes may respond differencly to the same substance. This difference is related
to the receptOr type. For example, when epinephrine or norepinephrine bind to Pradrenergic receptors in
bronchiolar smooth muscle, the internal cell responses cause smooth muscle relaxation and dilation of the
airways. The drug is stiU acting as an agonist in this case because the celluJar function of bronchiolar smooth
muscle is to help maintain a patent airway through muscle relaxation. The substance is the same, but the
celluJar response is different because the receptors are different.
For a drug to stimulate a cell's function, it must bind correctly and tighcly to the cell's receptors. This is
known as afunctional fit or fimctional binding. Some drugs bind incorreccly to a cell's receptors, blocking the
cell's function (a nonfunctional fit). These drugs are known as antagonists because they cause the opposite
responses of an agonist and inhibit the expected cell function by preventing receptor interaction with agonist
substances. Thus, when a p-adrenergic antagonist drug (beta blocker), such as propranolol (Inderal), binds to

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 Chapter 17 Assessing Genomic Variation in Drug Response 345

Cell

i-:
Receptorsites Drug Drugbound to cell receptorsites

The rate of cetl activity without The rate of cell activity with the
A the drug bound to the receptor B agonist drug bound to the receptor
Figure 17-2 Receptors that control cell activity. (A) The rate of cell activity
without the drug bound to the receptor. (8) The rate of cell activity with the
agonist drug bound to the receptor.

PI receptors in the heart, cardiac muscle contraction is less vigorous. When this drug binds to ~2 receptors in
the bronchiolar smooth muscle, the muscle constricts and the airways narrow. Most cells have more than one
type of receptor, allowing different drugs to affect the same cell in different ways.
Cells with receptors that can bind with a drug (functionally or nonfunctionally) are the targets of the
drug. For example, the targets of insulin are those ceUs that have insulin receptors. When insulin binds [Q
insulin receptors, the membranes of those cells become more permeable (open) to glucose, allowing glucose
in the blood [Q enter the cells. This action leads to reduced blood glucose levels. The targets of morphine, an
opioid, are the receptors of neurons in the brain responsible for pain perception. These cells have opioid recep-
tors, and when morphine binds [Q these receptors, the person's perception of pain is reduced. This response
is enhanced when more opioid receptors are presenr and when the drug remains tightly bound to them. For
example, hydromorphone (Dilaudid), an opioid for pain control, is an opioid agonist that binds more tightly
to the opioid receptors and remains bound longer than morphine. As a result, hydromorphone can provide
greater pain relief at lower doses than morphine.
The number of receptors cells have can vary from person to person, which affects the intended drug action.
For example, a person may have 5,000 p-adrenergic receptors per cardiac muscle cell, whereas another person
may have as many as 100,000 p-adrenergic receptors per cardiac muscle cell. The person with higher receptor
numbers will have a grearer response to an agonisr for those receptors and a lesser response to an antagonist
for those receptors. Variation in the gene or genes coding for the receptors is one facror responsible for the
differences in recepror numbers from one person to another.

Receptors and Side Effects

A perfect drug would affect only irs target and resulr in the intended drug action. No drug is perfect, and all
drugs have side effects in addirion to their intended actions. Side effects are drug effects rhar are nor rhe main
purpose of the intended action. They are expected patient responses to the drug's mechanism of acrion and

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346 Unit V Genomics and Disease Management

are usually mild, although not every person taking a drug experiences all expected side effects. For example,
a person who uses an inhaled ~-adrenergic agonist for asthma, such as albuterol (Proventil), should have the
intended action of bronchiolar smooth muscle dilation, resulting in reduced asthma symptoms. This person
may experience side effects of the drug because ~-adrenergic recepcors also are present on other tissues. Expected
side effects include an increased heart rate and increased blood pressure, and these occur in nearly everyone
taking this drug. Such side effects may be uncomfortable and may result in the patient choosing to avoid a
specific drug. Additional side effects of alburerol can include feeling faint; developing a skin rash; swelling of
the face, lips, or tOngue; developing an irregular heartbeat; and experiencing chest pain. These side effects are
less common, and when they occur with usual drug dosages, they may be related to a genetic variation that
increases personal sensitivity to the drug.
When a known side effect is present to an exaggerated degree in a patient, or an unusual response occurs,
the reaction is called an idiosyncratic response. Genetic differences can result in increased personal sensitivity
to the drug and in idiosyncratic responses. For example, nearly everyone who takes an opioid pain reliever for
2 days or longer becomes constipated to some degree. People who develop more severe constipation tend to be
those who become constipated easily; however, very few people develop a paralytic ileus as a result of taking or
receiving opioid pain medications. Some idiosyncratic reactions are unexpected effects that are unique to the
patient and may not be related to the drug's mechanism of action. For example, people who have a variation
that results in a glucose-S-phosphare dehydrogenase (G6PD) enz.yme deficiency develop hemolytic anemia
when they take primaquine to prevent malaria or when they eat fava beans.

PHARMACOKINETICS
Most drugs must enter the body to produce their intended actions. Once inside the human body, the drug
is distributed to different body fluid compartments. As a result of a drug coming into contact with a variety
of cells, it is changed or processed by some of these cells. Thus, at the same time a drug is exerting one or
more effects on the body, body cells are affecting the drug's chemistry. The actions of the body that change
the physical and chemical properties of a drug are known as the process of pharmacokinetics. Because drugs
are "foreign" substances in the body, most of the processes involved in pharmacokinetics focus on prepar-
ing the drug for eventual elimination. These processes include drug absorption, drug metabolism, and drug
elimination.
Because most drugs exert their effects on body tissues and organs, drugs first have to enter the body and
then enter the bloodstream so they can reach their targets. For the intended action to occur, the drug must
reach and maintain a high enough constant level in the blood or target tissue to produce the action. The lowest
blood or tissue level required to cause the intended action is known as the minimum effective concentra-
tion (MEC), as shown in Figure 17-3. If the drug is eliminated faster than it is absorbed, the blood or tissue
drug level will nor be sufficient to produce the intended action. If the drug is eliminated more slowly than it
is absorbed, the drug blood or tissue level may reach toxic concentrations and result in serious adverse reac-
tions. For drugs to produce intended actions without becoming toxic, blood drug levels must be maintained
at the MEC by balancing drug absorption with drug elimination, a condition known as a steady-state drug
level (Fig. 17-4).
Although an average MEC has been calculated for every approved drug, genetic variation in drug absorp-
tion, drug metabolism, and drug elimination may make the MEC for a specific drug in one person very
different from the "average MEC." (In addition to genetic difference, other factors that change drug MEC
include age; general health; organ health; and the ingestion of additional drugs, food, alcohol, and herbal
substances.)

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 Chapter 17 Assessing Genomic Variation in Drug Response 347

TOXIC DRUG LEVEL

Range 01 drug concentrationin blood/tissue

I
that causes serious adverse reactions

Range01 drug concentration

in blood/tissuethat allows
the intendedaction
r--+/~~~~~~~~~~~~'~~ ~ -;~MEC

Figure 17-3 The minimum effective concentra-

tion (MEC) of drug in the blood or tissue needed
"\ Dose administered Time
for the intended action.

Extensive Poor Intermediate unrarapto

metabolizer metabolizer metabolizer metaboiizer
(balanced) (unbalanced) (unbalanced) (unbalanced)

"Steady state": After MEG Low enzyme activity: Drug Low enzyme activity: Drug Greatly increased enzyme
is first achieved, drug elimination is slower than elimination is much slower activity. Blood/tissue drug
absorption is equal to drug absorpaoo. Blood! than drug absorption. Blood! level is too high, and toxic
drug elimination. Patient tissue drug level is too high, tissue drug level is too high, effects may occur. MEG is
tends to respond in the and toxic effects may occur. and toxic effects may occur. greatly exceeded.
expected way to standard MEG is greatly exceeded. MEG is greaUy exceeded.
drug dosages.

= Drug
Figure 17-4 Comparison of blood/tissue drug levels affected by the activity of the enzymes respon-
sible for drug metabolism and elimination.

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348 Unit V Genomics and Disease Management

Drug Absorption
Drug absorption is the entrance of a drug from its route of administration into the bloodstream. The amount
of an administered drug dose that reaches the bloodstream, regardless of the method of administration, is
its bioavailability. When the entire drug dose administered reaches the bloodstream, the bioavailability is
100%. When only part of the drug dose administered reaches the bloodstream, drug bioavailability is less
than 100%. Drugs can be administered by the percutaneous route (through skin or mucous membranes),
the enteral route (through the gastrointestinal [GIl system), and the parenteral route (through injection into
the bloodstream, subcutaneous tissue, or muscle). Only when a drug is administered intravenously or intra-
arterially is its immediate bioavailabiliry always 100%. For most other methods of drug delivery, less than the
administered dose is absorbed into the bloodstream, resulting in lower percentages of bioavailabiliry, The drug
administration method with the least predictable bioavailability and the one that is most highly influenced by
genetic variation is the enteral route, which is also the most common route for drug entry.
Enteral drugs are swallowed as liquids, tablets, or capsules (the enteral route does not include drugs that
are absorbed through oral mucous membranes directly into the bloodstream) and are absorbed elsewhere in
the GI tract into the bloodstream. After a drug is swallowed, it is acted on by stomach acids, enzymes, and
other secretions. Only a few drugs are absorbed into the bloodstream directly from the stomach. Each person's
stomach secretions are unique in amount, which means that each person's stomach processing of a drug is
unique. After leaving the stomach, most enteral drugs enter the small intestine, where they undergo further
processing, especially dissolving, before the drugs can be absorbed into the bloodstream. This processing is
the result of mechanical mixing and the action of various enzymes on the drug. Again, each person's intes-
tinal enzyme concentration is unique. The innermost lining of the small intestinal is the major site of drug
absorption. When drugs in the intestines are poorly absorbed, the drugs remain in the stool and are eliminated
without exerting their intended actions.
Drugs absorbed through the small intestine into venous blood are quickly exposed to the liver before entering
the rest of venous blood flow in the inferior vena cava back to the heart, where the drug is then distributed
throughout the circulatory system. This circulatory derour, known as enterohepatic circulation, is a result
of all the venous blood from the last half of the mouth, the esophagus, the stomach, the intestines, and the
higher part of the rectum draining first into the portal vein and circulating to the liver before entering the
systemic circulation. As a result, the liver has a chance to metabolize drugs absorbed from the GI tract before
they reach target tissues or organs. Although this demur is generally a helpful process, allowing the liver to
remove any microorganisms that remain in nutrients that enter the GI tract as food (after all, we do not
sterilize our food before we eat it), the extensive enzyme systems in the liver can and do alter drug function.
In addition to genetic differences in digestive enzyme function and anatomical variation in circulation to
the intestinal tract, nongenetic factors that alter the intestinal absorption of drugs include intestinal pathol-
ogy and the presence of additional drugs, food, and herbal substances in the tract at the same time the drug
is present.

Drug Metabolism
Drugs are considered foreign chemicals in the body, which triggers the normal response of processing the
drug for elimination through metabolism. Metabolism is a chemical reaction in the body that changes the
chemical shape, size, content, and activity of the drug. The liver enzyme systems, especially the cytochrome
P450 (CYP, pronounced "sip") systems of enzymes, are most responsible for metabolism. These enzymes also
are present in white blood cells, both those that circulate and those that are embedded within various body
tissues. A few other organs, such as the adrenal glands, lungs, kidneys, intestinal mucosa, and skin also have
enzymes that can participate in metabolizing drugs.

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 Chapter 17 Assessing Genomic Variation in Drug Response 349

Cytochrome P450 System

The cytochrome P450 system of enzymes is coded for by a gene family currently known to be composed of
57 main genes and hundreds of subfamilies. Each cytochrome P450 gene name begins with "CYP," indicating
that it is part of the cytochrome P450 gene family. The gene name also has a number indicating its assignment
into a specific group within the main gene family and a letter that represents the gene's specific subfamily.
The last number in the name indicates the gene's assignment to the specific gene within the subfamily. For
example, the cytochrome P450 gene that is in group 2, subfamily D, gene 6 is written as CYP2D6 (National
Library of Medicine, 2017). These genes are large and vary greatly in sequencing. These variations make some
genes and gene products more active and others less active than "average."
This group of enzymes is extremely important in drug metabolism. Some specific enzymes, such as CYP2D6,
metabolize thousands of different substances from within and outside of the body. Some, such as CYPI9A,
metabolize JUSta few. Although these enzymes are present in several body sites, because the liver has the great-
est concentration, it is the tissue in which drug metabolism is most active.

Stages of Metabolism
Although a drug is usually inactivated and prepared for elimination by the process of metabolism, remember
that metabolism is a multistage action and that some stages can activate drugs as well as inactivate them.
The first stage or phase of drug metabolism is one in which the enzymes add specific groups to the original
drug (parent compound, the actual chemical composition of the drug as it was when it entered the body),
which usually results in making the drug express a negative charge. These groups may include hydroxyl groups
(OH), amine or amide groups (NH), and sulfhydryl groups (SH). The reaction also can change the amount
of oxygen or hydrogen present in the drug. These changes form drug metabolites that can bind more easily co
body proteins and DNA. The metabolites may be active or inactive, or they may undergo more metabolism
to make them easier to eliminate from the body.
When a drug enters the body as an active parent compound, it is capable of exerting the intended action
in this form, and first-stage metabolism forms inactive metabolites. For example, when the lipid-lowering
drug Huvastarin (Lescol) is swallowed, the drug is already active. It is rapidly absorbed from the stomach and
enters the bloodstream at that point. When it is metabolized by one of the CYP enzymes, it becomes inactive
and ready for elimination. In contrast, the lipid-lowering drug atorvasrarin (Lipiror) is a prodrug, meaning
that it is ingested as an inactive parent compound and
cannot exert its intended action in this form. When How Would Variation in the Activity
atorvastatin is metabolized by one of the CYP enzymes, of Different Metabolizing Enzymes Affect
five separate active drug metabolites are formed, each of a Drug's Intended Action and a Patient's
which can help lower blood lipid levels. So, in this case, Response to That Drug?
first-phase metabolism activates this drug rather than If a person had higher-than-normal levels of the
prepares it for elimination. For these active metabolites enzyme that prepared morphine for elimination (or
to be eliminated, they must then undergo second-stage a more active version of this enzyme), the patient
metabolism, which then alters the chemical structure would need higher or more frequent doses of mor-
further co add substances to the now-active drug metabo- phine to maintain a good level of pain relief On the
lites that enhance their excretion through the intestinal other hand, if a person had lower-than-normallevels
tract or in the urine by the kidney. (These substances of the enzyme that prepared morphine for elimi-
include glucuronic acid, sulfuric acid, acetic acids, amide nation, any morphine administered would remain
active in the system longer. Although this would
groups, and methyl groups.)
enhance the pain relief effect of morphine, it could
Because various CYP enzymes exist, and their activities
also increase the side effects of the drug.
are affected by their gene sequences, people commonly

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350 Unit V Genomics and Disease Management

CYP2D6
~

Figure 17-5 Enzymatic conversion (biotransfor-

Codeine Morphine mation) of codeine to morphine.

differ in how well a drug works for them. For example, the opioid drug codeine is often given for pain relief.
Codeine is a prodrug, and for it to alter a person's perception of pain, it must undergo first-stage metabolism
by the specific enzyme CYP2D6. This action converts codeine co morphine, which then can bind CO opioid
receptors and reduce the perception of pain. For a person who has a deficiency of CYP2D6 or a gene muta-
tion that makes it less active, codeine is not converted to morphine, and the person does not have any pain
relief from the drug (however, if he or she receives morphine, the pain is relieved). A different enzyme (not
CYP2D6) is responsible for second-stage morphine metabolism, preparation for drug elimination (Fig. 17-5).

Elimination
Elimination is the inactivation and final removal of drugs from the body. Although many tissues and organs
eliminate drugs to some degree after they have been prepared for elimination by metabolism, the most active
elimination routes are the GI tract, the kidneys, and the lungs. Drugs can be eliminated in the feces, urine,
exhaled air, sweat, tears, saliva, breast milk, and semen.
Drugs that were metabolized by the liver for elimination are either sent to the GI tract or to the blood and
then to the kidney for elimination. As a result, even parenteral drugs can be eliminated through the GI tract.
When a drug is given orally, some of the drug is metabolized very quickly by the liver and rapidly eliminated
from the body. This rapid inactivation and elimination of enteral drugs is called first-pass loss. For some
drugs, first-pass loss can be so great that the enteral form of the drug has practically no intended action.
For example, the drug nitroglycerin has a first-pass loss of 95%. This means that if the drug is administered
orally, only 5% of it is bioavailable and able to exert its intended action (dilation of the coronary arteries). To
avoid first-pass loss with this drug, it is administered as a sublingual (under the tongue) spray or tablet. This
works because blood vessels under the front of the tongue are not part of the enterohepatic circulation, and
the venous blood drains from here without going through the liver before entering the systemic circulation.
Drugs that are small and dissolved in the blood may leave the body in the urine. The drugs may change
the color or smell of the urine. (This is why urine tests are accurate in determining the presence of some
illegal drugs.)
Drugs that are small and easily vaporized (become gaseous) are metabolized and eliminated by the lungs
with exhaled air. (This is why a breathalyzer test is accurate in determining a blood-alcohol level).

GENETIC/GENOMIC VARIATIONS
Genomics influences the way drugs work in four ways: (1) altering a drug's pharmacodynamics, (2) altering
a drug's pharmacokinetics, (3) creating unique reactions such as hypersensitivity to a drug, and (4) targeting
specific factors in the pathogenesis of disease [0 alter disease severity.

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 Chapter 17 Assessing Genomic Variation in Drug Response 351

More than 40% of drug labels that contain genetic informacion have information about the CYP genes, so
understanding about how people vary in the enzymes coded for by these genes is very important (Fujikura,
Ingelman-Sundberg, & Lauschke, 2015). People can be grouped according to variations in CYP450 metabolic
enzyme activity (see Fig. 17-4). Some people are considered "poor metabolizers." They have little if any of
a specific enzyme activity and would have difficulty clearing an active drug that requires processing by this
specific enzyme. They would be likely to have high blood levels of a drug given at a standard dose and might
have adverse reactions or toxicity. Some people are considered "intermediate rnerabolizers." They have low
enzyme activity and have a difficult time clearing a drug. Most people are "extensive rnerabolizers," and they
tend to respond in the expected way to drugs given at standard doses.
People who are "ultrarapid merabolizers" often have duplications of the gene coding for the enzyme respon-
sible for metabolism. They have greatly increased enzyme activity and will clear an active drug very quickly.
This can result in little or no therapeutic effect when standard doses are given (see Fig. 17-4). For example,
tricyclic antidepressants (active drugs) are metabolized by the CYP2D6 enzyme. A person who has a varia-
tion in the gene coding for the enzyme CYP2D6 that makes him or her a poor metabolizer could have toxic
plasma concentrations and side effects such as dry mouth, hypotension, sedation, tremor, or even cardiotoxicity,
Someone who has a variation that makes him or her an ulrrarapid merabolizer would experience neither the
expected therapeutic effect nor side effects.
When you are giving a prodrug that requires biotransformation before it can be used (e.g., codeine, which
must be converted to morphine to have a therapeutic effect), things are quite different. A CYP2D6 enzyme
poor rnerabolizer who rakes codeine would not be able to efficiently convert the drug to morphine and so he
or she would have little or no plasma concentration of morphine; no analgesia; and, of course, no constipa-
tion. An ultrarapid metabolizer would be rapidly and efficiently converting codeine to morphine and so might
experience adverse reactions such as severe abdominal pain, constipation, and possibly respiratory depression.

Drug Interactions
Remember that many enzymes may be involved in the metabolism of a given drug, and that drugs are rarely
given in isolation. The list of drugs that are metabolized by the CYP2D6 enzyme (e.g., quinidine, Huoxetine,
propanolol, etc.) is quite long. With a set amount of enzyme present, giving two drugs that are both metabo-
lized by it means that the activity is spread over two drugs, which then reduces the rate of metabolism for both
drugs (inhibition). The normal amount of the enzyme would be insufficient to fully metabolize either drug.
Thus, giving these drugs together increases the effects of both drugs because neither drug is fully metabolized
and remains active in the system longer or to a higher concentration.
Not all drugs that are metabolized by CYP2D6 work as inhibitors when they are given together. Taking an
inhibitor along with another drug metabolized by CYP2D6 could result in adverse reactions in someone who
was genetically an extensive rnerabolizer, Although many drugs inhibit the activity of CYP2D6, no drug induces
or increases its activity. Up-to-date information about CYP450 enzyme substrates, inhibitors, and inducers is
available from the "Clinical Pharmacology" section of the Indiana University Department of Medicine's (2016)
website. Tables 17-2, 17-3, and 17-4 provide a shortened version of this reference.

CYP Enzyme Variability

The CYP450 enzymes are responsible for the metabolism of many drugs. The CYP2 family contains 16 genes
that code for the enzymes needed to metabolize approximately 50% of currently available prescription drugs.
The CYP3 family contains only 4 genes, but CYP3 enzymes metabolize 120 frequently prescribed drugs.
The CYP2D6 enzyme alone is responsible for the metabolism of25% to 30% of prescribed drugs, includ-
ing many beta blockers, antiarrhyrhmics, antidepressants, anripsychorics, and opioids. The percentages of

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352 Unit V Genomics and Disease Management

Selected Clinically Relevant CYP450 Substrates

CYP2C9 CYP2C19 CYP2D6 CYP3A4,5,7

NSAIDs: PPls: Beta Blockers: Macrolide Antibiotics:

Diclofenac Lansoprazole S-metoprolol Clarithromycin
Ibuprofen Omeprazole2 Propafenone Erythromycin2 (not 3A5)
Piroxicam Pantoprazole Timolol Antiarrhythmics:
Oral Hypoglycemics: Antiepileptics: Antidepressants: Quinidine->3-0H (not 3A5)
Glipizide Diazepam Amitriptyline Benzodiazepines:
Tolbutamide Phenobarbitone Clomipramine Alprazolam
Angiotensin II Phenytoin duloxetine Diazepam-730H
Blockers: Others: fluoxetine Midazolaml
Losartan Amitriptyline Imipramine Triazolam2
Irbesartan Clomipramine Paroxetine
Immune Modulators:
Others: Clopidogrel Antipsychotics: Cyclosporine
Celecoxib Cyclophosphamide Haloperidol Tacrolimus (FK506)
Fluvastatin Risperidone
HIV Antivirals:
Phenytoin Thioridazine
Indinavir
Rosiglitazone Others: Ritonavir
Tamoxifen Aripiprazole Saquinavir
Torsemide Codeine
Prokinetics:
Warfarin Dextromethorphan 1
Cisapride
Flecainide
Mexiletine Antihistamines:
Ondansetron Astemizole
Tamoxifen Chlorpheniramine
Tramadol Calcium Channel Blockers:
Amlodipine
Diltiazem
Felodipine
Nifedipine2
Nisoldipine
Nitrendipine
Verapamil
HMG CoA Reductase Inhibitors:
Atorvastatin
Lovastatin
NOT pravastatin
NOT rosuvastatin
Simvastatin
Others:
Aripiprazole
Buspirone
Gleevec
Haloperidol
Methadone

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 Chapter 17 Assessing Genomic Variation in Drug Response 353

.J!1:1-m;:
Selected Clinically Relevant CYP450 Substrates-cont'd
CYP2C9 CYP2C19 CYP2D6 CYP3A4,5,7

Pimozide
Quinine
Tamoxifen
Trazodone
Vincristine

Adapted from IndianaUniversity, Department of Medicine. (2016).Flod:han lable: P450 dllJginteractions. Retrievedfrom hnp://medicine
.iupuLedu/CLINPHARM/ddis/clinical-table

.'!':tlll:arCCf
Some Inhibitors of CYP450 Enzymes
CYP2C9 CYP2C19 CYP2D6 CYP3A4,5,7

Fluconazole Cimetidine Bupropion Indinavir

Amiodarone Ketoconazole Fluoxetine Nelfinavir
Omeprazole Fluoxetine Paroxetine Ritonavir
Quinidine Clarithromycin
Duloxetine Amiodarone Itraconazole
Cimetidine Ketoconazole
Nefazodone
Erythromycin
Grapefruit juice
Verapamil
Diltiazem

Adapted from IndianaUniversity, Depanment of Medicine. (2016).Flod:han lable: P450 dllJg imersctions. Retrievedfrom hnp://medicine
.iupui.edu/CLINPHAAM/ddis/clinical-table

TABLE 17-4
Some Inducers of CYP450 Enzymes
CYP2C9 CYP2C19 CYP2D6 CYP3A4,5,7

Rifampin Rifampin Carbamazepine

Phenobarbital Ritonavir Phenobarbital
St John's wort St. John's wort Phenytoin
Pioglitazone
Rifabutin
Rifampin
St. John's wort
Troglitazone 1

Adapted from IndianaUniversity, Depanment of Medicine. (2016).Flod:han tsble: P450 dllJginteractions. Retrievedfrom hnp://medicine
.iupui.edu/CLINPHARM/ddis/clinical-table

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354 Unit V Genomics and Disease Management

Estimated Ethnic Distribution of CYP2D6 Phenotype

Phenotype CYP2D6 Estimated Ethnic Distribution

Poor metabolizers None Caucasians, 6%-10%

Mexican Americans, 3%-6%
African Americans, 2%-5%
Asians, 1 %
Intermediate metabolizers Low Not established
Extensive metabolizers Normal Most people
Ultrarapid metabolizers High Finns and Danes, 1%
European Americans, 4 %
Greeks, 10%
Portuguese, 10%
Saudis, 20%
Ethiopians, 30%

Adapted from Horn, JR & Hanson, po, (2008), Pharmacy limes, Get to know an enzyme CVP2D6, hnp:/twww.pharmacylimes.com/
pub Iications/issue/20OS/2008.Q7/200a.07-8624
-
poor, extensive, and ultrarapid rnetabolizers can vary with the geographical origin of a person's ancestors as
well as by personal gene changes, For example, poor CVP2D6 enzyme metabolism is seen in 5% co LO%of
European Americans but in only 2% to 4% of African Americans. Differences are even greater when we look
at other ethniciries. About 0,7% of Chinese are poor merabolizers, compared to 19% of South Africans. The
percentages of ultrarapid metabolizers also vary widely. About 2% of both African Americans and European
Americans are ultrarapid rnerabolizers, but 20% of Saudi Arabians and 30% of people from geographically
nearby Ethiopia are as well (Table 17-5), Remember that the United States is an ethnically diverse country
with considerable reproductive mixing of races and ethnicicies. Although the numbers given may apply to
people whose ancestors came from one geographic area, they cannot be relied upon to select an appropriate
dose for a particular patient (see the "Genetic Tescing for Drug Response" section). They are provided only
so that you can see that there is a wide range of variability in me world's populacion.

CLINICAL APPLICATIONS
OF PHARMACOGENOMICS
Pharmacogenomics (PGx) is being used clinically in a variety of ways, including helping to predict the most
appropriate dose for a given patient, Dose alterarions in the chemotherapeutic agent 6-mercaptopurine (6MP)
can be made based on genetic test results; however, more than the patient's genome can be tested. For example,
some clinical applications of PGx testing are based on genomic variation in tumors or viruses. Genetic testing
of tumor cells has resulted in the development of targeted therapies designed to treat subsets of disease. This
is precision medicine. Examples include imarinib (Gleevec) for chronic myeloid leukemia, erlorinib (Tarceva)
for lung cancer, and trastuzurnab (Herceprin) for Her2-neu-positive breast cancers. Testing of viral genomes
has been used to help select the best treatments for HIY infection based on the drug resistance of the
virus itself.

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 Chapter 17 Assessing Genomic Variation in Drug Response 355

Cystic fibrosis (CF) is a disease caused by mutation in the CFTR (cystic fibrosis transmembrane con-
ductance regulator) gene, which codes for a transmembrane protein. You can read about this disease in
Chapter 11. About 2,000 different mutations have been identified in CFTR, and most of them cause disease.
These mutations keep the protein from working in a few different ways. Some of these mutations result in the
production of a defective protein; some cause a problem with protein folding, and others reduce the amount
of normally functioning protein. Traditionally CF treatment has focused on the end result of these problems
such as frequent respiratory infections and replacing pancreatic enzyme. Now researchers are working on drugs
to target the specific mutarion and treat the problem at its source. For example, the most common mutation
causing CF is F508del. It results in a misfolding of the protein in the Golgi apparatus, which prevents the
protein from getting to the cell membrane. The drug lumacafror is thought to improve both protein folding
and chloride transport. It is currently being tested in clinical trials and has shown some promising results
(Carter & McKone, 2016).

Pharmacogenomics and Anticoagulants

PGx may have its greatest impact when drug doses are highly individualized, and life-threatening adverse
reactions are a common concern. The anticoagulant drug warfarin (Coumadin) is such a drug. People who
have a polymorphism in the gene coding for the enzyme CYP2C9 take longer to stabilize the dose, have an
increased risk of above-range international normalized ratio (INR), bleed earlier, and have more serious or
life-threatening bleeding, but other proteins playa parr in the way people use warfarin.
Vitamin K epoxide reductase complex 1 (VKORCl) is a warfarin target gene, and variations in the genetic
sequence coding for this gene product have resulted in resistance to warfarin. The VKORCI enzyme recy-
cles endogenous vitamin K, which aids in the synrhesis of coagulation factors that depend on vitamin K.
Common polymorphisms in VKORC1, the gene coding for the VKORCI enzymes, have been found [Q
affect the dose response to vitamin K antagonists, Likewarfarin. Warfarin dosage genetic tests (testing both
CYP2C9 and VKORC1) is available from major medical centers or from online companies that offer genetic
testing.
In 2007, the Food and Drug Administration (FDA) placed precautions on the warfarin label, reminding
physicians and health-care providers that people with genetic variations require a lower starting dose. In 2010,
the FDA added a suggested dosing schedule that incorporates pharmacogenetics to guide the selection of a
starting warfarin dose. Medicare has refused to pay for warfarin-response genetic testing, citing scant evidence
that having a genetic test results in better outcomes for patients compared to the way in which warfarin is
currently prescribed. Standard procedures of starting with a dose based on factors such as the patient's age,
weight, and organ function and then adjusting that dose based on INR test results is thought to be more
cost-effective. Currently, Medicare will pay for genetic testing if a patient is enrolled in a clinical trial, has not
been tested before, and has received fewer than 5 days of warfarin therapy (Centers for Medicare and Medicaid
Services [CMS], 2016; Maier, Duncan, & Hill, 2016).
Warfarin is a vitamin K antagonist, but other types of anticoagulant drugs work differently. Direct oral
anticoagulants, such as direct thrombin inhibitors (e.g., dabigauan) and factor Xa inhibitors (e.g., apixaban)
are now commonly used. Because they are relatively new, Limited information on the impact of pharmacoge-
nomics on the function of these types of drugs is so far available.
Clopidogrel is another drug that is used for anticoagulation. Because it is less effective for people with
polymorph isms in the CYP2C19 gene, the FDA added a warning on the drug label in 2010. Genetic testing
for CYP219 variations before taking clopidogrel has been suggested for patients with acute coronary syndromes
or those undergoing percutaneous coronary interventions, but some expertS do not support routine testing
(Maier et al., 2016).

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356 Unit V Genomics and Disease Management

CYP3
The CYP3A family is responsible for the metabolism of about 50% of drugs, including most calcium-channel
blockers, most benzodiazepines, most statins, and acetaminophen. Inhibitors of the CYP3A enzyme include
grapefruit juice, keroconazole, cirnetidine, and erythromycin. Drugs that speed up metabolism by the CYP3A
enzyme include St. John's WOrt,rifarnpin, and ritonavir, One of the challenges in the application ofPGx is that
for some enzyme families (e.g., CYP3A), studies have not shown consistent genotype/phenotype concordance;
in other words, we have not been able to accurately predict clinical response based on genetic tests.

Other Metabolic Enzymes

The phase II liver enzyme Nvacerylcransferase (NAT) is needed for the metabolism of some drugs. NAT adds
an acetyl group to drugs in the process of acetylation. Sulfamechoxazole, hydralazine, procainamide, isoniazid,
and caffeine all require acetylation to facilitate elimination. People can be grouped into twO categories according
to their ability to perform acetylation. Fast acerylarors are similar (0 ulrrarapid rnerabolizers in the CYP450
enzyme system. They tend to need larger and more frequent doses of drugs that require acetylation, but they
can efficiently detoxify carcinogenic compounds in tobacco smoke. Slow acerylators may need a 10% to
15% reduction in dose and are at increased risk of side effects, including hepatotoxicity.
Drugs such as azathioprine (lmuran), mercaptopurine, and thioguanine used to treat childhood leukemias,
rheumatoid arthritis, or inAammatory bowel disease require metabolism by the enzyme thiopurine methyl-
transferase (TPMT). The activity ofTPMT is rrirnodal, meaning three different levels of enzyme activity exist
among groups of people. About 90% of people have high TPMT activity. They have faster drug metabolism,
which results in lower exposure of leukemic ceUs to active thiopurines. About 100/0of people have intermedi-
ate activity, and a very small fraction of people (about 0.3%) have low activity. Those who have low TPMT
activity are homozygous for variations in the gene coding for TPMT, so they produce nonfunctional protein.
People with low TPMT activity risk myelosuppression, secondary cancers, and possibly fatal toxicity when
they are given chemotherapeutic agents requiring metabolism by TPMT. They may need to have the dose of
their chemotherapeutic agents reduced 8- to lO-fold. Fortunately, testing for TPMT levels is available.

Beyond Metabolic Enzymes

Glucose-ti-phosphate dehydrogenase (G6PD) deficiency was one of the first pharmacogenomic variations
discovered. This Xvlinked recessive disorder is common in the Middle East, Africa, and Southeast Asia and
found in about lO% of black males (in the United States). Affected people risk hemolytic anemia when they
are given antimalarials, aspirin, probenecid, or vitamin K or if they eat fava beans (favism). G6PD is necessary
for erythrocytes to maintain cyroskeleral integrity in the presence of oxidative stress. Unfortunately, the correla-
tion between genotype and phenotype is imperfect, so genetic testing does not always predict clinical response.
Less is known about genetic variations in drug transporters. One example is the gene ABCBl coding
for P-glycoprotein-MDRl, which is a membrane effiux transporter responsible for moving drugs, including
such drugs as pacliraxel (Taxol) and digoxin (Lanoxin), from the intestine into the blood. When duodenal
expression of ABCBl results in low levels of P-glycoprotein-MDRl, less drug can be transported across the
intestinal ceU membrane.

GENETIC TESTING FOR DRUG RESPONSE

Laboratories at major medical centers offer genetic testing for drug response, and many provide excellent
patient education materials on what PGx testing is, what it means, and how the results could improve patient

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 Chapter 17 Assessing Genomic Variation in Drug Response 357

care. But genetic testing for drug response can also be purchased online from direct-to-consumer companies.
(Chapter 16 provides more information about direct-to-consumer genetic resting.)
Health-care professionals treating people with mental health disorders have been particularly interested in
PGx, largely because finding the right drug and dose for each patient is so difficult. Only 35% to 45% of
patients respond sufficiently to their psychotropic drugs to return to a desired functional level. Although the
base of studies involving psychotropic medications is expanding, the Evaluation of Genomic Applications in
Practice and Prevention (EGAPP) panel decided that insufficient evidence exists to suppOrt the link between
testing for CYP450 polymorphisrns and improved clinical outcomes (EGAPp, 2007).

SUMMARY
Drug response is a complex trait influenced by many genes and the environment. You have seen examples of
increased or decreased drug metabolism in the CYP450s, acetylation, and TPMT enzyme systems. We have
also seen genetic variants cause unexpected responses such as the hemolytic anemia seen when a person with
GGPD deficiency takes an antimalarial drug. Despite some very promising studies, little improvement in clinical
outcomes using PGx testing for drug administration has been reported. That means that our understanding of
the impact genetic variations have on the way we use drugs is incomplete. Polyrnorphisrns in modifier genes
or major genes that have not been identified probably have an as-yet-undiscovered impact on the ways that
our patients process drugs such as warfarin. Much must be learned before pharmacogenomics will be in use
at every bedside, but that day will come.

GENE GEMS

• Pharmacogenetics and pharmacogenomics are similar concepts, but pharmacogenomlcs has a more
in-depth scope.
• Precision medicine includes the idea that we can develop medications tailored to specific subgroups
of disease.
• We know most about genetic/genomic differences in the way people metabolize drugs as compared to
drug absorption or transport.
• Drugs often work in the same way the body hormones, enzymes, and other proteins do.
• Most drugs exert their effects by binding to a ceU recepror.
• At the same time that a drug is changing the body's activity, the body is processing the drug fur elimination.
• Drugs have to reach a high enough level in the blood ro exert their effects.
• Taking more than one drug at the same time can change the effectiveness of each drug.
• Drug metabolism reduces its bioavailabiliry.
• The most important organs for drug metabolism and elimination are the liver, kidneys, and white
blood cells.
• The CYP450 enzyme system is responsible for the metabolism of many of the most commonly pre-
scribed drugs.
• People can be classified as slow, intermediate, extensive, or ulrrarapid metabolizers, depending on
CYP450 enzyme activity.
• Nsaceryltransferase (NAT) is required for phase II metabolism of many drugs.
Continued

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358 Unit V Genomics and Disease Management

• People can be classified as slow or fast acerylators.

• Genetic testing is available for some variations in the way people respond to drugs.
• The clinical efficacy of drug response genetic testing is controversial, but PGx testing is currently being
used clinically.

Self-Assessment Questions .....

1. What drugs block a cell's function by binding incorrectly (a nonfunctional fit) to a cell's receptor?
a. Antagonists
b. Sympathetic drugs
c. Agonises
d. Colony-stimulating factors
2. Which provides the best explanation of pharmacodynamics?
a. Distribution of a drug into the body's compartments
b. How the body responds co drugs, including the drug's mechanism of action
c. Drug metabolism by the body
d. Drug bioavailabiliry
3. Your patient has had direct-to-consumer genetic testing [Q determine her CYP2D6 status before she

begins taking Aecainide (formulated as an active compound) for her paroxysmal aerial fibrillation.
What might she expect if she is found to be a poor rnetabolizer?
a. High enzyme activity
b. Drug elimination that is faster than drug absorption
c. Poor clinical efficacy
d. Possible [Oxic levels of drug when it is given at standard doses
4. You find Out that your patient will be taking cimetidine (a CYP2D6 inhibitor) along with her
Hecainide. What might you expect from adding this drug?
a. It is likely to increase enzyme activity, making her drug metabolism more normal.
b. It may worsen her poor metabolism of the Aecainide.
c. It would increase first-pass loss.
d. It will have no clinical effect, due to CYP2C19 activiry.
5. What might a drug that is a "targeted therapy" do?
a. Attack specific rumor cells
b. Be given along with another drug to counteract any CYP450 inhibition
c. Increase acetylation
d. Promote effective drug elimination
6. Genoryping consistently and accurately predicts whether a patient will have a therapeutic response
to a drug.
a. True
b. False

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 Chapter 17 Assessing Genomic Variation in Drug Response 359

7. Your patient is a "fast acerylator." What might happen when she takes procainamide, a drug that
requires acetylation for phase II metabolism?
a. Higher blood level of the drug at a standard dose
b. Lower blood level of the drug at a standard dose
c. Tenfold increase in TPMT activity, resulting in toxicity
d. Eightfold decrease in TPMT activity, resulting in lack of therapeutic result

1. What is different about the drugs that are being developed based on CTFR mutations that cause
cystic fibrosis?
2. How do you think PGx will affect your nursing practice now and 5 years from now?
3. Why is the concept of precision medicine important, and how does it vary from the concept of
personalized medicine?

References
Ashley, E. A. (2016). Towards precision medicine. Nature &vi~1IJ$ Cmu;cs, 17,507-522.
Carter, S. C, & McKone, E. F. (2016). Pharmacogenetics of cynic fibrosis rrearmenr. Pharmacogenomics, 17(13), 1453-1463.
Centers for Medicare and Medicaid Services. (2016). Pharmacogenetic usfillg to pr~dicr wlllforill responsioene«. Retrieved from
https:llwww.cms.gov/Medicare/Covernge/Coverage-with-Evidence-DeveiopmenuPharmacogenomic-Tesring-[O-Predict-Wru'farin
-Responsiveness.hrml
EGAPP (Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group). (2007). Recommendations
from the EGAPP Working Group: testing for cytochrome P450 polymorphisms in adults with non psychotic depression
treated with selective serotonin reuprake inhibitors. Cm~fia ill Medicine, 9(12), 819-825.
Fujikura, K., Ingelman-Sundberg, M., & Lauschke, V. M. (2015). Ceneric variation in the human cytochrome P450 supergene
family. Pharmacoguutics alld Genomics, 25, 584-594.
Indiana UniversityDepartment of Medicine. (2016). FlockIH1rllllb/~:
P450 drug intemctlons.RerrievedITomhttp://medicinc.iupui.edu/
CLiNPHARM/ddis/clinical-table
Maier, C L., Duncan, A., & Hill, C E. (2016). Pharmacogenetics in oral anrirhrornbotic therapy. Clinicnl Laboratory Medicine,
36, 461-472.
National Library of Medicine. (2017). Cytochrome P450. Retrieved &omhnps://ghr. nlrn, nih.gov/primer!geneF.uniIyl cyrochromep-i50
Valdes, R., & Yin, D. (2016). Fundamentals of pharmacogenetics in personalized, precision medicine. Clinica] Laboratory
Medicine, 36, 447-459.

Self-Assessment Answers
1. a 2. b 3. d 4. b 5. a 6. b 7. b

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 Ch a p1er ] 8------'
Health Professionals
and Genomic Care

Learning Outcomes
1. Describe the educational preparation and general roles of various genetics professionals.
2. Explain the role of general registered nurses in providing genomic care.
3. Identify interdisciplinary health-care professionals who provide supportive roles in genomic care.

Key Terms
Advanced-practice nurse in Clinical geneticist Genomic care
genetics (APNG) Clinical laboratory geneticist Medical geneticist
Certified genetic counselor Genetic counseling Nondirective
(CGC)
Genetics clinical nurse (GCN) Research geneticist

INTRODUCTION
Professionals with special or extended education have been caring for patients with genetic disorders for decades.
Since completion of the human genome sequencing in 2003, interest in genetics education and entrepreneurial
opportunities is growing. More individuals are idenrifying diverse roles to enhance the detection, diagnosis,
and precision treatment of genetic disorders while altering the lives of patients and families. As new tech-
nologies are revealing more information about genetic diseases, the need increases for more detailed patient!
family education and careful dialogue about the impact of testing results on other relatives, even children
not previously included in the discussions. Genetics professionals are necessary to ensure that genomic care
addresses the influences of a person's genetic history on health and disease and is considered as parr of general
assessment information for all ages of patients and families. This information must be put into perspective
for health status as much as personal environmental considerations of disease development and for responses
to therapy. This does not mean that all patients should have some SOrt of genetic testing. Rather, it means

360

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 Chapter 18 Health Professionals and Genomic Care 361

that all health-care professionals are obligated to avoid

What Makes Someone a Genetics
overlooking genetic issues that may affect an individual's Professional?
health or risk for health problems.
Does taking a course on the topic of genetics or dis-
cussing genetic issues in one of your clinical courses
make you a genetics professional? How about a
GENETICS PROFESSIONALS genetics focus in your college biology course? Is
your family physician or nurse practitioner a qenetics
The title genetics professionaL implies that the individual professional? \.t\Ihohas the responsibility for working
has extensive education and, often, special credenrialing with families and individuals at increased genetic
in some aspect of the broad genetics field. Such a pro- risk for a health problem or problems? lMlat is your
fessional is an expert in one or more areas of genetics. role as a direct-care provider in the era of "genomic
By this criterion, a person with an entry-level degree medicine"? Does any of the new information, like
in a health-care profession, such as a registered nurse, epigenetics, affect the importance of other interdis-
ciplinary partners in the dissemination of genomic
registered dietitian, physical therapist, pharmacist, or
care? This chapter addresses these issues.
physician, is not a genetics professional because genetics
was not the focus of her or his professional education.
However, all health-care professionals are expected to have at least a basic understanding of the general pat-
terns of inheritance and genetic terminology as well as to be able to construct an accurate three-generation
pedigree from assessment information (see Figure 8-6). This is not to say that, for example, a registered
nurse who works within a specialty area that deals with one type of genetic problem, such as cystic fibrosis or
phenylketonuria, is not very informed about the genetic issues associated with the disorder, but this on-the-job
acquired knowledge is limited in scope. That person is still nor a genetics professional. However, new genetic
information, such as epigenetics, is suggesting new directions in prevention, management, or alleviation of
symptoms associated with some of the diseases, offering the potential for altered specialties and expansions
of some of the conventional roles.
Genetic counseling is defined as "the process of helping people understand and adapt to the medical,
psychological and familial implications of genetic contributions to disease" (National Society of Genetic Coun-
selors, 2017). Various genetics professionals are credentialed co perform genetic counseling to varying levels.
Regardless of education level and credentiali ng, any level of genetic counseling must be performed in
a nondirective manner. Nondirective means that the person providing genetic information and coun-
seling presents all facts and available options in a way that neither promotes nor excludes any decision
or action (within legal boundaries). Remaining nondirective can sometimes be very difficult because
patients and families may feel overwhelmed and want someone else to make decisions. They want ro do
the "right thing," which may not be the same for everyone. Often, they ask the genetics professional pre-
senting information, "What would you do?" Regardless of the specific genetic issue and the condition at
hand, the patient and family members directly involved must ultimately make decisions that feel right
for them.

Certified Genetic Counselor

The most familiar genetics professional who performs genetic counseling is a certified genetic counselor. A
certified genetic counselor (CGC) is a professional in genetics who has a master's degree in genetic counsel-
ing from a graduate program accredited by the American Board of Genetic Counselors (ABGC), which is
part of the National Society of Genetic Counselors. This profession was first recognized in 1969. Currently,
the United States has 37 accredited genetic counseling programs, Canada has 4, and countries throughout
the world have additional programs.

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362 Unit V Genomics and Disease Management

The preparation for becoming a genetic counselor starts with a baccalaureate degree from an accredited
undergraduate institution. Although the degree can be in any undergraduate major, most genetic counsel-
ing graduate programs have admission requirements that include prerequisites of specific biological sciences,
advanced mathematics, basic genetics, and behavioral sciences. Graduate courses for the specialty commonly
include all aspects of genetics (population and quantitative genetics, molecular genetics, cytogenetics, bio-
chemical genetics), embryology and human development, psychosocial development, counseling, ethics,
assessment, crisis counseling, social and legal issues, and case management techniques. Most programs also
include extensive laboratory methods courses, not because a CGC is expected to perform these tests as part
of his or her role but to ensure that the counselor has adequate background to help clients understand
testing procedures and results. Students are engaged in supervised counseling sessions throughout the graduate
program.
After successful completion of a master's degree in genetic counseling from a program accredited by the
ABGC, the person must pass the certification examination to become a certified genetic counselor (CGC),
who is both professionally and legally qualified to perform genetic counseling. In addition to the initial cer-
tification, genetic counselors must recertify every 5 years, either by taking the certification examination or by
participating in appropriate continuing education activities.
The scope of practice for a CGC focuses on three general areas: providing expertise in genetics, communi-
cating directly with and counseling patients and families at potential risk for genetic problems, and ensuring
that counseling services are delivered in a manner that is consistent with professional ethics and values. States
vary on the extent of CGC practice regarding ordering tests and performing physical assessments. At all times,
a CGC is a client advocate and performs his or her professional duties in a nondirective manner.
Genetic counselors are members of the health-care team who together provide information and suppOrt to
individuals and families who have an identified genetic problem or are at increased genetic risk for a variety
of genetic disorders. Some genetic counselors specialize within the profession. For example, One genetic
counselor may work exclusively in prenatal counseling, whereas another might specialize in oncology and
cancer risk. Regardless of the area of specialization, the genetic counselor provides information about spe-
cific disorders, testing, inheritance patterns, the risk for recurrence, management options, and appropriate
referrals.

Clinical Geneticist
To become a clinical geneticist, a person holding a Doctor of Medicine (MD) or Doctor of Osteopathic
Medicine (DO) degree must complete a I-year residency of at least 12 months of direct patient care experi-
ence. An additional 2 years of training is required for the individual to gain the competence to provide com-
prehensive genetic diagnostic, management, therapeutic, and counseling services. The next level is a 2-year
dual-board-approved residency ptogram in one of the specialty areas; these include Pediauics/Medical Genetics
and Genomics, Internal Medicine/Medical Genetics and Genomics, Reproductive Endocrinology and Infertil-
ity/Medical Genetics and Genomics, and Maternal Fetal Medicine/Medical Genetics and Genomics. Once
the combined training is completed, the trainee can apply for certification by the American Board of Medical
Genetics and Genomics (ABMGG) in that discipline. Board certification in the specialty is not necessary to
practice in clinical genetics and genomics. Other board certifications are available in clinical cytogenetics and
genomics, clinical biochemical genetics, and clinical molecular genetics and genomics. Each of these requires
basic education as an MD, DO, or Doctor of Philosophy (PhD) with 12 months' additional residency after
the first certification. Multiple specialty certifications can be obtained in any order.
Responsibilities of clinical geneticists include diagnosing, clinically managing, and counseling patients
with a wide variety of genetic disorders. They may work in a specialty sercing or as part of a referral center

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for genetic disorders. Many clinical geneticists also choose to take additional training and become certified in
another aspect of genetics, such as cytogenetics, molecular genetics, or biochemical genetics. For example, a
clinical geneticist who specializes in working with patients and families affected by lysosomal srorage disorders
(see Chapter 10) commonly also certifies in biochemical genetics.
Initial certification for clinical genetics is valid for 10 years. Clinical geneticists can recertify by examination
during the 8th, 9th, or 10th year, and they must demonstrate that they have maintained competence in the
field by completing a minimum of 250 hours of continuing education credits in the specialty that has been
approved by the ABMGG. Most often, these professionals use the online review modules every 2 to 3 years
that have been developed by the ABMGG.

Clinical Laboratory Geneticist

A clinical laboratory geneticist is either a physician with a medical degree (i.e., an MD or DO) or is a sci-
entist with a PhD degree in genetics or biological science. Some clinical laboratory geneticists may have both
a medical degree and a PhD. Specialty training for certification is an additional 24-month fellowship in an
ABMGG-approved program. These individuals can then be certified by examination through the ABMGG
in at least one of three subspecialties: cytogenetics, molecular genetics, or biochemical genetics. JUSt as for a
clinical geneticist, initial certification for clinical laboratory geneticists is valid for 10 years. Clinical laboratory
geneticists can recertify by examination during the Bth, 9th, or IOrh year and must demonstrate that they
have maintained competence in the field by completing a minimum of 250 hours of continuing education
credits in the specialty that has been approved by the ABMGG. Most often, these professionals use the online
review modules every 2 to 3 years that have been developed by the ABMGG.
The primary role of a clinical laboratory geneticist is to oversee and work in laboratories that perform diag-
nostic genetic tests. They develop and implement new tests, provide quality assurance of routine cests, interpret
test results, and communicate these results to health-care professionals and other genetics professionals. L1
genera), the clinical laboratory geneticist does not participate in the direct care or counseling of patients and
families but assists other professionals ro provide accurate information and explanations.

Medical Geneticist
Despite the term medical in the title of medical geneticist, this individual is not a physician. A medical
geneticist has a doctorate (PhD), most commonly in population genetics or epidemiology. As of 2008, this
genetic specialty is no longer regulated by the ABMGG, although some medical geneticists still have valid
certification. These individuals commonly work along with certified genetic counselors to provide accurate
recurrence risk information for affected families. In addition, medical geneticists commonly teach in academic
institutions.

Research Geneticist
A research geneticist has a doctorate (PhD) in genetics or relevant biological science and has completed at
least one 2- to 4-year postdoctoral program of specialized laboratory training in genetics. The focus of this
career is in laboratory or "bench" research to identify exact pathological mechanisms that result from various
genetic disorders and to develop possible therapeutic approaches, including gene therapy, to reduce the effects
of the pathological mechanisms.
Generally, research geneticists have a minimal role in the genetic counseling process. They may work with
a clinical geneticist or a certified genetic counselor to provide the scientific details associated with a specific
disorder or explain how a new or experimental therapy may affect the disorder.

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Nurse Genetics Professionals

Two levels of genetics professional specialty training and recertification have been available for licensed registered
nurses: the Advanced Genetics Nursing (AGN) credential renewal is available through the American Nurses
Credentialing Center (ANCC), and renewal for the genetics clinical nurse (GCN) certification is also avail-
able. Currently, new certifications for either credential are not available. Maintenance of existing credentials
is offered for individuals who continue to meet criteria through the ANCC.

Advanced-Practice Nurse in Genetics

The minimum requirements for the advanced-practice nurse in genetics (APNG) include practicing the
equivalent of at least 2 years full time as a registered nurse, a master's degree in nursing from an accredited
program, completion of 30 continuing education hours in advanced generics/genomics applicable to nursing
within the past 3 years, and accrual of 1,500 hours of practice hours in the specialty area of advanced genet-
ics nursing in the past 3 years. The person must be currently licensed to practice in at least one state with
evaluation by a supervisor or peer. The narrative required in the portfolio must address the four domains of
professional development, professional and ethical nursing practice. teamwork and collaboration, and quality
and safety.
The AGN may work in conjunction with other genetics professionals or, in some states, may maintain an
independent practice and caseload for genetic counseling. Other specific functions include facilitating genetic
testing and interpreting genetic test resulrs and laboratory reporrs (International Society of Nurses in Genetics
[ISONG], 2016). Most APNGs specialize within an area of genetics. such as oncology, specific inborn errors
of metabolism, or cystic fibrosis. In addition to counseling, the APNG performs physical assessments and
may assist in clinical management. In some States, he or she may order tests and prescribe pharmacological
therapy or medical foods.

Genetics Clinical Nurse

As noted, new certification as a genetics clinical nurse (GCN) is not currently available. However, renewal
is performed through a professional portfolio review process by the ANCC rather than by examination.

ROLE OF GENERAL NURSES IN GENOMIC CARE

Although registered nurses who have not undergone additional education and credenrialing in genetics are not
genetics professionals, they nevertheless have important roles in genomic care. They are usually the health-
care professional who has the most interaction with patients. In addition, most patients feel comfortable with
nurses and may be willing to share more information or ask more questions of nurses than other health-care
professionals. As a result, nurses are in positions to identify patient or families who may have an increased
genetic risk for a health problem. Whenever a nurse performs a patient assessment, the "red flags" of genetic
risk and the potential need for genetic referral discussed in Chapter 8 should be kept in mind.
The nurse may be the health-care professional who first verifies information to bring a genetic problem to
light. For example, during an assessment, a 48-year-old patient reveals that his 55-year-old brother has severe
emphysema even though he has never smoked. The patient indicates that he is worried that he, toO, might
develop the disease. Not only should the nurse know that emphysema in a nonsmoker is rare, but the nurse
should also recognize that this patient's expression of concern is a perfect opportunity to obtain specific assess-
ment information. The nurse might then ask, "Did either of your parents, aunts or uncles, or grandparents
have emphysema or any other respiratory problems?" Be aware of other cues that may indicate the patient

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 Chapter 18 Health Professionals and Genomic Care 365

is interested in or concerned about a possible increased genetic risk for any health problem. Such cues may
include statements or questions like these:
• Do you think I could have passed this problem on to my children?
• Could I pass this problem on to my children?
• Because there are other people in my family with this disease, is something wrong with my genes?
• I have heard that all diseases are genetic. Is this true?
• Can we test my genes?
For this patient who is concerned about a possible genetic issue with his family and emphysema, in addition
to asking more about his family history, what other responsibilities do you have? Is this considered "genetic
counseling"? What major responsibilities for genomic care by a registered nurse should be addressed? Is it
possible the individual responsibilities would need to be performed simultaneously? The following sections
address the issues identified above concerning the role of the nurse in a setting of non-specialized genomic care.

Providing Accurate Information

Provide as much accurate information as you can in any situation while remembering that you are not a
genetics expert and are not expected to be the final or definitive source of information for the patient about
the issue of concern. Work with the patient to develop his or her family history as a pedigree that includes
at least three generations (see Chapter 8). Using the patient JUStdescribed as an example, you might respond
to him by saying, "Yes, emphysema can have a genetic influence, and more informacion about your family is
needed before anyone can determine whether this is a possibility for you." Another question to ask is, "Have
you mentioned your brother's health to your physician?" Although most physicians are not also genetics pro-
fessionals, leering him or her know about a patient's concerns and any information that supportS the concern
is always helpful. Remind the patient that you are not a geneticist but that you can help him find accurate
and helpful information about the specific topic in the form of written materials and legitimate websites.

Ensuring Appropriate Referral

Providing genomic care is a team effort. By bringing the physician into the picture, you are already beginning
the referral process. However, your responsibility may not end there. Many physicians, although nor genetic
experts, may have clinical knowledge of genetic risks for common disorders within their specialty. In the
case of the patient concerned about his brother's emphysema, his physician may have been unaware of the
brother's health status and, with your communication of this information, may then investigate the problem
more deeply, keeping the possibility of genetic testing or referral in mind.
But what about a situation in which the physician either disregards your information or says that it is not
important? For example, a 31-year-old woman who is being seen for infertility tells you that her mother, her
sister, and her older brother have aU had breast cancer by the rime they were 40 years old. She then asks, "Do you
think I should have genetic testing?" When you report this information to the patient's physician, the response
is, "She worries about everything. Don't put anything else inro her head." What is your responsibility here?
First, express to the physician that although the patient may have other unfounded concerns, this issue
is a well-documented genetic "red Bag" with health and practice (and legal) implications. If the physician is
not inreresred in making a referral, be sure to document the patient's concerns in the medical record. If you
have generated a pedigree in conjunction with the patient, also place that in the medical record, and make
a copy for the patient. Even if you are not comfortable with creating a pedigree, be sure to document the
pedigree in the medical record. One approach could be patient and siblings; maternal lineage with aunts,
uncles, cousins, and grandparents; and then the paternal lineage with the information about aunts, uncles,

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cousins, and grandparents. Tell the patient that you are not a genetics professional but that you will help her
find someone who can provide more information about this special issue. Possible resources include the hos-
pital's breast center (which may have a genetic counselor), a breast or gynecological advanced-practice nurse,
or the local unit of the American Cancer Society. Providing this type of information is within your scope of
practice as a registered nurse.

Serving as a Patient Advocate

The situation described in the previous section demonstrates an aspect of advocating for a patient. Other ways
to advocate for the patient as part of genomic care is to make certain that the patient understands any provided
genetic information. Communication between the patient and whoever is providing the genetic information
must be clear. Determine the patient's cognitive ability and education level. Also check whether the patient
is under the influence of any drugs that could interfere with comprehension. Work with the genetics profes-
sional to provide information in terms the patient understands. Determine whether the patient can see and
hear clearly and understands the language being used. At times, having a family member present, especially
if the patient is older, can be very helpful in assuring understanding.
If possible, and if the patient desires, be present with the patient during any discussion with a genetics
professional. Look for patient cues to indicate understanding, and ask the patient to describe what has been
said in his or her own words. If you cannot be present, encourage a family member or close friend to also
attend the genetic referral.
An important issue to consider is whether the patient is being coerced to have genetic testing by a relative
or even another health-care professional. Remind the patient that he or she has the right to refuse to undergo
genetic testing and must make the decision based on his or her belief about whether such testing would be
beneficial or harmful.

Maintaining Confidentiality
JUStas with all other patient information, genetic information must be kept confidential, even the decision of
whether to have a specific genetic test. This is even more important because genetic information reveals issues
that affect not only the patient but also his or her family members. Ensure that any conversations you have
with the patient about his or her health problem and family history take place privately (unless the patient
requem otherwise). The patient has the right ro determine who may be a part of the discussion and can
decide to keep the information from his or her physician, family members, or anyone else. If you are present
during a discussion between the patient and a genetics professional, do not disclose information, formally or
informally, without the patient's permission.
If genetic testing is performed, results are usually received by the genetics professional involved with the
patient's case. Even at this point in the process, the patient has the right to choose not to be told the results
of the test and can decide not to share the information. Chapters 14 and 16 present more information on
the legal, social, and ethical issues surrounding genetic testing.

INTERDISCIPLINARY HEALTH-CARE
PROFESSIONALS
Various other health-care professionals from multiple disciplines support the genetics professionals providing
direct care to patients and families with a genetic disorder. Table 18-1 gives a list of different types of careers
and role descriptions for non-health-care providers who work in generics.

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 Chapter 18 Health Professionals and Genomic Care 367

Careers as an Interdisciplinary Professional in Human Genetics

Undergraduate Degree (Bachelor of ArtslBachelor of Science)

Biotech sales/marketing Apply scientific background to educate clients to understand biological or

clinical products applicable to their work
Clinical research associate Assist investigators and clinical researchers to run clinical trials required
for Food and Drug Administration approval of new drugs and medical
devices
Work for companies sponsoring the drug, device, or technology
Dietitian/nutritionist* Provide nutritional guidance for disease prevention or management
Work with a medical team (e.g., metabolic genetic diseases)
Forensic scientist Use modern science to analyze evidence from crime scenes and match
evidence to suspects
High school science teacher Teach one or several related subjects
May require state certification in public school
Laboratory technician Work in clinical or basic research labs
Responsible for ordering supplies, maintaining equipment, and getting
biological specimens or samples ready for experiments
Patent agent Assess the patentability of new technologies, processes, and treatments
and help researchers write and obtain patents
Must register with the U.S. Patent and Trademark Office by passing a bar
exam
Law degree not required, but agent cannot represent clients in court cases
Quality control specialists Evaluate whether a product meets quality standards and specifications
Review each step in the production process with detailed and careful
notes
Research compliance officer Ensure that research is done ethically and in accordance with laws and
regulations
Expert in federal and state regulations plus industry standards
May develop educational training materials
May require research or health compliance certification
Science outreach Use expertise to connect the scientific community and general public
Help the public grasp the nature of science and contributions of science
to modern society Translate cutting--edge scientific discoveries to the lay
public
Science writer Make newest scientific research available and understandable through
publications such as the New York Times or Scientific American
May maintain personal blogs
Scientific/medical illustrator Communicate scientific concepts and subjects through drawings and
diagrams that appear in scientific journals, textbooks, and exhibits and in
other online or interactive mediums
Continued

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368 Unit V Genomics and Disease Management

Careers as an Interdisciplinary Professional in Human Genetics-cont'd

Master's Degree (Master of Arts/Master of Science)
Bioinformatician Manage and analyze genetic data
Community college professor Prepare students to complete their associate's degrees or transfer into
a bachelor's degree program
Graduate and postdoctoral Responsible for creating and implementing professional development
affairs administrator programs that strengthen trainees' (undergraduate/graduate students
or individuals completing post-baccalaureate training) scientific and
career skills
Physician assistant Licensed to practice medicine under the supervision of a physician
National certification exam required
Program officers Implement manage, and review grant programs
Work closely with organizations or individuals seeking funding and may
assist with the entire proposal submission process
Provide decision makers with analyses and recommendations to
ensure that specific grant initiatives are promoting research that
aligns with the organization's goals
Public health researcher Study health and disease, including social, behavioral, and economic
factors, at the population level instead of the individual level
Centered on prevention and management of factors that cause disease
Public health worker Assist in the design, implementation, and evaluation of public health
programs related to general or specific issues
Evaluate various characteristics, including compliance and operational
standards, and create presentations to give recommendations to
management for program modifications
Analyst/Evaluator Focus on changes in genetics and genomics that have social, political,
economic, and health-care implications; consider all angles of
new developments; and evaluate their impact on business and
government policies and plans
Speech-language pathologist Specialize in diagnosing and treating communication disorders, some
with a genetic basis
Technical/medical writer Write about complex scientific or medical ideas for specialized
audiences (versus the general public)
Produce publications such as instruction manuals or textbooks
Technology transfer associate Help with licensing and commercialization of patented technology after
patent agents have identified and obtained patents

Law Degree (Juris Doctor [JOn

Bioethicist Focus on the societal. ethical, and philosophical issues surrounding
both research and clinical advances in modern life sciences
Interact with the scientific community as well as the broader public to
research the impacts of scientific or medical advances from several
different points of view

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 Chapter 18 Health Professionals and Genomic Care 369

..r~:1~_;~~ __
Careers as an Interdisciplinary Professional in Human Genetics-cont'd
Intellectual property/patent Help clients obtain patents
attorney May also represent clients in patent cases
Requires JD degree and passing of state bar exam

Medical Degree (Doctor of Medicine/Doctor of Osteopathic Medicine)

Independent clinical researcher Conduct research on mechanisms of and therapeutic interventions for
human disease. including clinical trials for new drugs or treatments
Interact with patients
Doctoral Degree (Doctor of Philosophy)
Audiologist Diagnose. study. and treat hearing and balance disorders. including
those with genetic basis
Biocurator Collect and annotate the scientific community's data in publicly
accessible databases
Requires strong science background to understand data sets and
determine which data, annotations. and user tools are most
important to the community they serve
Need strong technical computer skills
Academics with genetics Professors at small or liberal arts institutions with focus on teaching
teaching focus Minimal research focus
Field application scientist Respond to customers' technical inquiries and frequently travel to
customers to assist with troubleshooting or to provide product
training and demonstrations
Provide education about company's products; includes biotech sales/
marketing
Independent basic researcher Study genetic mechanisms in humans or model organisms to
understand biological processes
No patient interaction
Management consulting Tackle scientific issues identified by corporate clients
Science museum director Build collections and design exhibits and programming on interesting
topics in science for the general public
Scientific editor Manage and edit scientific texts and academic journals based
on strong scientific background Identify manuscripts that are
scientifically sound and novel
Either Doctor of Medicine/Osteopathy (MD/DO) or Doctor of Philosophy (PhD)
Clinical laboratory scientist: Certified to perform and interpret genetic tests that are important for
1. Clinical biochemical geneticist diagnosing and managing genetic diseases. Can include forensic
2. Clinical cytogeneticist uses.
3. Clinical molecular geneticist
Continued

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370 Unit V Genomics and Disease Management

TABLE 18-1
Careers as an Interdisciplinary Professional in Human Genetics-cont'd
Medical science liaison Collaborate with the medical and scientific community to provide
consumer-safety and marketing information about the company's
products
Frequently travel to speak with health-care professionals regarding the
educational needs of consumers and attend scientific conferences to
gather the newest scientific information relevant to the company and
products
May also provide internal clinical support and respond to medical
information inquiries from health-care professionals
Science/health policy Infuse public policy with the most current scientific knowledge
Develop policy to guide scientific enterprise
Work can include producing commissioned scientific reports to aid
lawmakers in making policy decisions. lobbying politicians on behalf
of scientific organizations. and working with regulatory agencies to
develop regulations for new technologies

Based on information from National Human Genome ResearchInstitute. (n.d.l. Genomic Careers-Find your furure. Retrievedtrom
https://www.genome.gov/genomiccareers/

SUMMARY
Generic counseling is a process that commonly involves many ream members and occurs in multiple sessions.
Most health-care professionals have Iirtle, if any, formal education in genetics and are not genetic experts. Thus,
they are not generics professionals and are not qualified to provide final, definitive information to patients and
families at increased genetic risk for health problems. All health-care professionals have the responsibility to
assess genetic facrors mar influence me health status of any patient within their care. Orner interdisciplinary
health-care professionals also work with genetic diseases, and although they are nor genetic counselors, their
roles much me patient in different ways to provide accurate generic resting results.

GENE GEMS

• AJI health-care professionals are expected to have basic competencies in genetics, bur without additional
education and credentialing, rhey are not considered "genetics professionals."
• AJI health-care professionals have me responsibility to assess genetic factors that influence the health
status of an)' patient within their care.
• To be a genetics professional, an individual must have an advanced degree in a genetics field from a
program that has been accredited by either the American Board of Medical Genetics and Genomics
or the American Board of Genetic Counselors or have completed a residency program accredited by
the American Society of Medical Genetics. The person must also have current certification by one of
these twO accrediting bodies.

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 Chapter 18 Health Professionals and Genomic Care 371

• Providing information or performing genetic counseling, regardless of the title or level of the genetics
or health-care professional, should always be done in a nondirective manner.
• An advanced-practice nurse nurse in genetics (APNG) can perform independent nursing and counsel-
ing practice.
• Insurance companies require counseling at the level of a certified expert prior to testing.
• Determine whether any information obtained during patient assessment constitutes a "red Rag" for
genetic risk.
• Organize data obtained by patient history assessment into a three-generation family pedigree.
• Be sure to check the accuracy of any genetic information you provide to a patient or family.
• Maintain confidentiality regarding any patient data, testing, or decisions.
• Work with other members of the health-care team to determine what type of genetics professional or
level of genetic counseling may be most appropriate for a specific patient or family thought to have an
increased genetic risk for a health problem.
• Keep in mind that the patient has the right to choose or refuse to have genetic testing and that he or
she alone determines whether any of the information is shared with anyone.
• Determine whether the patient understands the genetic information provided to him or her .

...
Self-Assessment Questions .
1. Which statement made by a genetics professional to a woman who does not want to know the results
of her BRCAll2 genetic test best demonstrates a nondirective approach?
a. "The results will be available in the future should you change your mind."
b. "It is important that you know these results before you decide to have children."
c. "By choosing not to know the results, you will derive no benefit from this test."
d. "You have a right to make that decision, but it is not being fair to your family."
2. A I-rnonth-old infant has JUStbeen diagnosed with Gaucher disease, an inherited lysosomal srorage
disorder. Which genetics professional, together with a pediatrician, can best direct this infant's care?
a. Medical geneticist
b. Certified genetic counselor
c. Clinical geneticist
d. Research geneticist
3. Which activity would a cytogeneticist be expected to perform as part of genomic care?
a. Calculating recurrence risk for parents who have JUSthad a child with nondisjunction Down syndrome
b. Informing a patient that his test results are positive for a genetic disorder
c. Requesting a consultation visit from a clinical geneticist
d. Detecting and interpreting chromosome abnormalities
4. Which of the following positions for interdisciplinary professionals in genetics interacts with the
scientific community and public to identify the impacts of scientific/medical advances from different
points of view?
a. Intellectual property or patent attorney
b. Bioerhicisr
c. Medical science liaison
d. Quality control specialist

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372 Unit V Genomics and Disease Management

References
American Board of Medical Genetics and Genomics. (2017). Tminil1g options. Retrieved from hrtp://abmgg.org/pagesl
training_options.shtml
American Nurses Credential Center. (2017). Adoanced gmnies in nllNil1g. Retrieved from http://www.nursecredentialing.org/
CertificationlNurseSpecialtiesiAdvancedGenetics
American Society of Clinical Pathologists. (2017). Retrieved from hrtps:l!www.ascp.orgicontent!pathologists
American Society of Human Genetics. (20IS). Education: Careen in buman gm"tics. Retrieved February 2017 from Imp://ww\V
·ashg.org!education! career_Aowcharr.shrmI
International Society of Nurses in Genetics (ISONG). (2016). Gmuics/gl'l1omies IIIlNing: Seop" and standards of practice
(2nd ed.). Retrieved from http://www.isong.orgiISONG_professional_practice.php
National Human Genome Research Insriture. (n.d.) Gmuie careers-Find JOlir fitN1r". Retrieved from https:!lwww.genome
·gov!genom iccareers!
National Society of Genetic Counselors. (2017). Abolll gmnic counselors: \'(fllO( is gmnic eOllns,,/ing? Retrieved from http://www
·nsgc.org!index. ph p?mo=cm&op=ld&fid=477#counsel ing

Self-Assessment Answers
1. a 2. c 3. d 4. b

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 UNIT VI -
Global Genomic Issues

373

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 Chapter 19
Financial, Ethical, Legal,
and Social Considerations
Learning Outcomes
1. Discuss the interaction of genomics and society.
2. Describe the history of genetic discrimination.
3. Explain how the Genetic Information and Nondiscrimination Act protects consumers from genetic dis-
crimination in employment and insurance coverage.
4. Compare the professional's "duty to warn" with the consumer's "right to privacy."
5. Discuss the implications of gene patenting for future research and genetic testing.
6. Explain the ethical implications of gene therapy.
7. Describe three ways in which financial, ethical, legal, and social issues affect the genetic health of patients.

Key Terms
Autonomy Eugenics Genetic Information and
Beneficence Financial, ethical, legal, and Nondiscrimination Act (GINA)

Duty to warn social issues (FELSI) Intellectual property

Ethical, legal, and social issues Gene therapy Patents

(ELSl) Genetic information Right to privacy

INTRODUCTION
The impact and interaction of genomics and society are important as science moves forward with genomic
investigation and knowledge generation. Psychosocial issues are dearly related to genomics research and genomic
medicine, such as how patients react to finding Out that they are or are not at genetic risk or whether to test
a child for an adult-onset genetic condition. Legal and policy issues are also factors, such as intellectual prop-
erty rights, regulation of genetic testing, and protection from genetic discrimination. Additional issues relate
to the ways in which we define health and disease and how we release genetic information about individuals
and groups.

374

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 Chapter 19 Financial, Ethical, Legal, and Social Considerations 375

Genetic information is different from other kinds of health information. Of course, all health information
should be protected and remain confidential. However, genetic information is even more sensitive. It is typi-
cally shared within families, and it provides information about the person being tested and often about his
or her family members as well. For example, let's say you are caring for a patient named Jim whose paternal
grandfather has Huntington disease (HD). Remember that HD is transmitted in an autosomal-dominant
fashion. Jim's father does not want to be tested; he would rather not know whether HD lies in his future.
Jim chooses to have predictive genetic testing to see if
Was It Ethical for Jim to Be Tested When he carries the allele for HD, and he tests positive. Now
Genetic Testing Could Reveal Information we know something not only about Jim but also about
His Father Did Not Want to Know? his father.
What happens when Jim's "right to know" interferes Jim's father is almost certainly positive for the allele
with his father's "right not to know"? As you can that causes HD. This devastating disease awaits him
see, the ethical dilemmas that surround genetics (unless he dies from something else first). Even if Jim
can be very challenging. We will discuss some of plans nor to tell his father about the genetic test results,
these issues and circle back to this hypothetical
the knowledge that his father is also positive could put
case later in the chapter.
a significant strain on their relationship.

ETHICAL GOALS OF CLINICAL GENETICS

Genetics professionals are trained to provide genetic information in a nondirective and supportive way
that allows patients and their families to make informed decisions that are best suited to their needs and
values. Respecting patient autonomy is an important guiding principle. Counselors provide informa-
tion to patients and their families that will help them identify their own perspectives on any issue. For
example, counselors may have strong personal feelings about the wisdom of bringing a disabled child into
the world. However, when they are working with couples who have JUStreceived the results of a prenatal
test indicating their child will have a significant disability, counselors must put aside their personal feel-
ings. They are obligated to provide the couple with all the information and support they need to make
their own decision (Wilson, 2000). More information about the role of the genetics professional is given in
Chapter 18.

GENETIC DISCRIMINATION
Advances in genetic testing and generic health care promise to make things better for most people seeking
treatment for many diseases. However, many Americans report that they are afraid of having genetic testing
done because they do not want to be victims of genetic discrimination. They are afraid that they will lose
their health insurance or have [Q pay much higher premiums if their insurance companies find out that they
are at increased genetic risk for a major health problem. They are also afraid that they might lose their jobs
and not be hirable if their genetic risk is documented in their health records. Fortunately, we now have legisla-
tion designed to protect people from discrimination in employment and/or insurance coverage based on their
genetic information. We will discuss the Genetic Information and Nondiscrimination Act in a later section.
This law is important both in fighting existing genetic discrimination and reducing the public's fear that they
might become victims of genetic discrimination.
Advances in genetic knowledge have brought with them new ethical concerns and puzzles. Fortu-
nately, when the Human Genome Project began, the U.S. Department of Energy (DOE) and the National
Institutes of Health (NIH) designated 3% to 5% of their annual budget toward studying the ethical,

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376 Unit VI Global Genomic Issues

legal, and social issues (ELSI) of the newly available genetic knowledge. This funded the largest bio-
ethics program in the world. The acronym ELSJ was used to designate this program. More recently,
some people have added financial concerns to the list to better reRect the societal issues involved. Now,
the acronym FELSI reflects the financial, ethical, legal, and social issues confronting patients and their
families.

Eugenics and Preimplantation Genetic Diagnosis

One fear that genetics advances bring to mind surrounds the technological ability to produce "designer babies."
Much of this fear probably comes from memories of Nazi Germany's effortS to "purify" the human popula-
tion, which was an appalling chapter in human history. However, efforrs (Q breed superior human beings
were not limited to the actions of Nazi Germany. Between the years of 1910 and 1940, the eugenics move-
ment in both the United States and the United Kingdom gained strong suppOrt. Eugenics can be defined as
working to improve humankind by selectively breeding people who have genes that society would consider
"good" and not allowing reproduction of people with genes that society would consider "bad." Some people
during that time supported euthanasia, and others suggested genocide, but sterilization of people considered
"socially inadequate" had widespread suppOrt beginning in the 1920s. By 1924, more than 3,000 people had
been involuntarily sterilized (Allen er al., n.d.). Read more about the American eugenics movement at http://
eugenicsarchive.org/eugenics/list3.pl. You will find many disturbing images and much unsettling information.
The fear of something like this movement happening again makes people wary of the new abil iry to choose to
implant selected embryos and reject embryos that do not meet specifications. We must remember our history
and guard against making decisions that affect the moral structure of our culture.
Preirnplantarion genetic diagnosis (PGD), discussed in Chapter 16, has been around for some time. The
first successful use of PGD took place in 1988. In this process, genetic testing is done on an embryo produced
through the process of in vitro fertilization. The fertilized egg is allowed co divide until it gets to the 6- or
to-cell stage (blastomere). At this point, one or twO cells can be removed without damaging the embryo.
Those cells can be tested to see if they contain a genetic abnormality of concern to the parents. The parents
can then choose to have any unaffected embryos transferred to the uterus in the hope that it will become
implanted and mature into a healthy baby (Basille er aI., 2009).
This is a very exciting technology that promises to reduce inherited genetic disease. However, it is very
expensive and brings with it major concerns about the ethical use of such a technology. For example, finding
our if an embryo is male or female makes sense if the mother is a carrier of an X-linked recessive disease
because every male child this mother conceives has a 50% risk of being affected. These parents may prefer to
have a female child, with only a 50% risk of being a carrier and virtually no risk of being affected. Testing the
embryo for sex determination may be less expensive than testing for particular gene mutations that cause disease.
But is it ethical to test embryos for sex determination if a couple has four girls and JUStwants to have a boy?
An additional concern about this procedure regards what happens to the "unsuitable" embryos. These may
be considered "defective" and simply discarded. Many people are concerned with the message this action sends
to people living with a disability. What is the value of their lives ro society when embryos carrying similar traits
are thrown away? As you might imagine, people within the disabilities community are very concerned about
this process and its ability to reinforce social biases regarding disability. Although precise data are not avail-
able, an estimated 60% ro 80% of fetuses diagnosed with Down syndrome are selectively aborted (Stainron,
2007). Some see the use of technology to eliminate or reduce the number of people with disabilities as the
ultimate expression of prejudice and point out that many people with disabilities are productive members of
society. The debate is ongoing and will no doubt continue to grow as reproductive technologies advance. We
might consider PGD a very early form of genetic discrimination.

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 Chapter 19 Financial,Ethical, Legal, and Social Considerations 377

History of Genetic Discrimination

We discussed the fear that many people have of being discriminated against based on their genetic informa-
tion. A brief look at the history of genetic discrimination can provide a sense of how this problem affects the
decisions patients make and how these decisions might be protected.
Several landmark cases set the stage for the development of legislation that addresses genetic discrimination.
One case involved the Burlington Northern Santa Fe (BNSF) Railroad. In 2001, the U.S. Equal Employ-
ment Opportunity Commission (EEOC) filed a lawsuit against the BNSF for testing its employees for a
genetic predisposition to hereditary neuropathy with liability to pressure palsies (HNLPP)-without their
consent. HNLPP is a rare condition that causes several symptoms, including carpal tunnel syndrome. The
railroad wanted to find out if the employees, who were claiming disability from repetitive stress injuries, were
genetically predisposed to having carpal tunnel syndrome. The hope was to demonstrate that some claims
of work-related carpal tunnel syndrome were not occupational injuries at all but the result of an underlying
genetic problem. The doctors employed by the BNSF were also cold to screen workers for medical conditions
such as diabetes and alcoholism, also without their consent. No mention of genetic testing was made, and
an employee who refused to be examined was told he could be terminated. The lawsuit filed by the EEOC
was based on the Americans with Disabilities Act because federal legislation that directly protected people
from genetic discrimination did not exist at that time. The EEOC claimed that the medical and genetic tests
being done were not related to the employee's ability to do the work. Decisions about employment that were
based on the results of these tests would be evidence of illegal discrimination based on alleged disability. The
EEOC won the case without any difficulty (National Human Genome Research Institute [NHGRI], 2012).
Many more examples of genetic discrimination are presented by the Council for Responsible Genetics
(CRG, 2010). One woman who was diagnosed with hereditary hemochromatosis lost her health insurance,
even though she showed no clinical signs of the disease. In another case, a family lost health insurance for
their son with fragile X syndrome because the insurance company said that fragile X was a preexisting condi-
tion. One man was denied employment for a position with the government based on genetic test results that
indicated he carried one copy of the gene variant that causes Gaucher disease. He had no clinical signs of
the disease; he was an unaffected carrier for this recessive trait. Hundreds of similar cases that have not been
publicized likely exist. However, uncovering these cases is difficult because many people do not want others
to know about the genetic risk factors in their families. Having actual numbers of cases would be very useful.
Unfortunately, much of the information we have now is anecdotal and highly subjective.

Legislation to Prevent Genetic Discrimination

On May 21, 2008, the Genetic Information and Nondiscrimination Act (GINA; Pub. L. No. 110-233)
was signed into law by then-president George W. Bush. This was the result of a 13-year-long effort on the
part of the genetics community to establish federal legislation protecting genetic information. The bill was
passed unanimously by the Senate and by a vote of 414 to 1 in the House of Representatives. Prior to the
passage of this law, some protection against discrimination was provided by state laws (some states had laws
providing more protection than others) and by the Health Insurance Portability and Accountability Act. The
passage of GINA provided federal protection against genetic discrimination in employment and insurance to
almost all Americans. The exceptions are people serving in the military, veterans receiving their health care
through the Veteran's Administration, and people receiving their health care from the Indian Health Service.
These groups are protected by other mechanisms (NHGRI, 2016).
GINA contains two parts. Tide I of GINA went into effect on May 21,2009. This provision makes it illegal
for health insurers to use clients' genetic information to make decisions about their eligibility for insurance,
the size of their premiums, or the extent of their coverage. Health insurers also cannot use genetic information

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378 Unit VI Global Genomic Issues

as evidence of a preexisting condition, and they cannot require that a client have genetic testing. The final
regulations for Tide II went into effect in January 2011. Title II makes it illegal for employers to use genetic
information to make decisions about hiring, promoting, or terminating employees (NHGRI, 2016).
GINA clearly explains what is meant by genetic information. Genetic information includes the results
of one's own genetic tests and those of his or her family members all the way Out to fourth-degree relatives
(e.g., your great-great-grandparents or your grandnephews and grandnieces). Any clinical signs of a disease
in a family member are also protected, so your employer has no legal right to know if you have a parent or
grandparent who has Huntington disease, for example. Information about whether you or any of your family
members have requested genetic services, such as participating in a research study that included genetic testing,
seeking genetic counseling, or attending genetic education programs, is also protected (NHGRI, 2016).
Abundant excellentinformation on GINA isavailablefrom reputablewebsiressuch as www.genome.govl10002077.
All health-care professionals should become familiar with the provisions of this law. Patients worry about their
insurance and employment risks should their genetic information be disclosed. As mentioned earlier, many
people choose not to have genetic tests that will benefit them or their family members because of the fear of
genetic discrimination. You cannot assure them that they will not be discriminated against; however, federal
legislation is now in place that protectS the use of their genetic information in health insurance and employ-
ment decisions.

DUTY TO WARN VERSUS

THE RIGHT TO PRIVACY
As health-care professionals, we commonly have access to genetic information that could benefit or harm a
patient or his or her family members. Sometimes that information has been found incidentally. For example,
suppose a female patient is being tested for cardiovascular risk, and the clinician finds out that she has the
A POE genotype that places her at high risk not only for cardiovascular disease but also for Alzheimer disease.
Should she be told that she has an increased risk of getting Alzheimer disease, which could cause her psycho-
logical harm? Does she have the right to know? Do you have the duty to warn her about this risk? In other
words, is it the responsibiliry of the health-care provider to tell a patient or a patient's family members about
their genetic risk?
What would you do if your patient tested positive for a mutation that greatly increased his risk of hereditary
nonpolyposis colon cancer (HNPCC)? He learned about this from his primary care physician and was told that
his children should also be tested because they are at risk as well. What if he tells you that he has no intention
of informing his daughter that she is also at risk, and the reason why is "none of your business"? Which is
more important, his right to privacy or your duty to warn his daughter of her risk? If the daughter knows of
her risk, she can get the recommended screening and/or choose [Q have genetic testing herself. What happens
if the daughter develops colon cancer and then takes legal action against her father's health-care providers for
not warning her? Will she be successful?
Your dury to keep your patient's genetic information confidential is usually seen as stronger than the
right of his or her family members to be warned that they are at risk. You are familiar with the importance
of maintaining the confidentiality of health-care information, which is protected by the privacy rule of the
Health Insurance Portability and Accounrabiliry Act (HIPAA) of 1996 (Pub. L.I04-191). However, as a
health-care professional, you also have a dury to abide by the ethical principle of beneficence. You want [Q do
good for others. You want to make decisions based on what will benefit your patients and their families. You
also need to adhere to the ethical principle of patient autonomy. You need to respect the rights and wishes of
your patients. An ethical problem arises when these cwo important ethical principles contradict each other.

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 Chapter 19 Financial, Ethical, Legal, and Social Considerations 379

Figure 19-1 Balancing duty to warn with right

to privacy.

Knowing that she is at genetic risk is best for the patient's daughter. However, respecting her father's right
to privacy requires that she not be told. The duty to warn and the right to privacy (autonomy) can be seen
as two sides of a balance scale, weighing the importance of one against the importance of the other in each
individual case (Fig. 19-1).

Related Court Cases

Some experts say that clinicians have a professional relationship only with their patients and not with their
family members, so there is no duty to warn family members of genetic risk. The courts have disagreed on
this. Each of these cases has involved the actions (or inactions) of physicians rather than those of other health-
care professionals. However, you can still learn much about the complexity of this issue by reviewing these
legal decisions.
In the case of Pate v. Threlkel, a physician was sued because he had not warned his patient's daughter that
she was at genetic risk for thyroid cancer. The daughter developed advanced thyroid cancer 3 years after her
mother was diagnosed. The daughter claimed that she would have been diagnosed sooner if she had been warned
that she was at risk. The Supreme Court of Florida agreed that the daughter should have been warned and
that the physician was obligated to inform the mother that her family members should be warned. The court's
decision did recognize that warning the family members directly would be difficult for the physician and that
his duty to warn would have been satisfied by telling his patient to warn her family members (Weaver, 2015).
In another case (Safer v. Estate of Pack), a New Jersey court made a different decision. Thirty years after her
father died, a woman sued the estate of her father's physician for failing to warn her that she was at genetic
risk for her father's disease. The father died of familial adenomatous polyposis, a condition that results in
hundreds or thousands of colon polyps developing in childhood. Cancer usually results by age 40 years.
The treatment was previously removal of the colon (prophylactic colectomy) during the teen years, although
current disease management may include treatment with anti-inflammatory drugs. The daughter was diag-
nosed with both polyposis and metastatic colon cancer and claimed that if she had known of her genetic risk,
she could have benefited from careful monitoring and early diagnosis. This court decided that simply telling

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380 Unit VI Global Genomic Issues

the patient that his family is at risk does not meet the requirements of the duty to warn and that the physi-
cian must take "reasonable steps" to ensure that the risk is communicated to all immediate family members
(Weaver, 2015).
Another important case focused on the need to inform families of the genetic risk to future pregnan-
cies. In Molloy v. Meier, the Minnesota Supreme Court ruled that a physician should have performed a
diagnostic genetic test on a child with cognitive impairment to see if that child had a genetic condition.
After a sibling was born who clearly had fragile X syndrome, this family came to understand that their first
child had fragile X also. The parents claimed that they would have chosen not ro have another child if they
had known their first child had fragile X and that other children would be at risk for the same condition.
They claimed the physician should have tested their first child so that they would have had this information
(Weaver, 2015).
Numerous professional organizations have put forward statements on disclosure of genetic information. In
the United Kingdom, the General Medical Council recommended that physicians disclose genetic informa-
tion without a patient's consent when it will benefit a family member. This disclosure should occur only after
the patient has been rold of the importance of warning his or her family members and has refused to do so.
The council's decision was based on the need to protect families and the need for physicians to have guidance
about what to do if a family member is at genetic risk for something treatable, such as breast or colon cancer.
However, it is still controversial (Dyer, 2009).

Professional and Governmental

Organization Recommendations
Most recommendations of professional and govemmental organizations try to balance the principles of maximiz-
ing benefit and minimizing harm, even if the harm is only psychological. Some organizations recommend that
a physician disclose protected genetic information to family members directly if the patient agrees. However,
most recommendations do not support direct contact between the physician and the family members. When
the patient is the one telling his or her relatives, no private information is being disclosed by the health-care
provider. One problem arises when the patient says he or she will tell the family members but never does so
(Godard, Hurlimann, Letendre, & Egalire, 2006). This can be a problem for the family members but is not
typically considered the responsibility of the health-care provider. We hope that with new federal legislation
in place to protect consumers from genetic discrimination, family members will be more willing to share their
relevant genetic information with at-risk family members.
In the mid- to late 1990s, the Institute of Medicine and a Presidential Commission provided guidance to
health-care providers in the United States about when disclosing otherwise private health-care information
is acceptable. These times include when harm will very likely result if the information is not disclosed and
when the harm from not disclosing the information would be greater than the harm of disclosing it. Most
organizations recommend that each case should be looked at individually and that decisions about whether
to disclose genetic information should be made by considering the unique aspects of each case (American
Society of Human Genetics [ASHG], 1998).
Discussing what will happen to the results of any genetic testing during the consent process is essential
for providers. Patients must make informed decisions about how and when vulnerable family members will
be told of results that impact their personal health or that of their children. In addition, patients need to be
told that our knowledge of genetic risk is growing and changing. A result that showed little or no genetic risk
today may later be found to have great risk as new knowledge is obtained. Of course, the reverse could also
be true. Therefore, also very important is that patients and providers discuss the process for contacting the
patient in the future if new and relevant genetic information is found.

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 Chapter 19 Financial, Ethical, Legal, and Social Considerations 381

INTELLECTUAL PROPERTY
RIGHTS AND GENE PATENTS
The commercialization of genetic resting has brought with it controversy about who owns human genetic
information. Protecting their intellectual property, the creative products that they develop using their intel-
lects, is certainly important for scientists. The government permits people to patent the output of their
creative work as long as the invention is new, useful, and nor obvious to others working in the same area.
Physical phenomena, such as gravity or changes in the weather, cannot be patented. This becomes a bit more
complicated when we look at scientific advances. For example, a particular microorganism that exists in nature
cannot be patented. However, if a scientist genetically alters that microorganism to make it disease resistant,
the newly developed microorganism can be patented (Chuang & Lau, 20 10).
Now it becomes even more complicated. The U.S.
Patent and Trademark Office (pTa) has agreed to patent What Does This Mean for Those of Us Caring
isolated sequences of the human genome. The PTa for Patients?
reasoned that isolating a sequence of DNA from the It turns out that it means a lot. When genes are
genome requires considerable human intervention and is patented, genetic testing for specific gene variants
therefore patentable, but is it really a new thing? Almost then becomes proprietary: It becomes something
20% of the human genome has been patented, and that is the intellectual property of the company or
scientist who holds the patent. They have the right
approximately 40,000 DNA-related patents have been
to exclude other people from using it or marketing
filed (Chuang & Lau, 2010).
it without their permission, and they have the right
The case that has brought this issue to the forefront to charge whatever they want to grant permission
involves the company Myriad Generics. Myriad is a bio- for its use by others.
technology company that held the gene patent for the
gene variants that predispose people to familial breast cancer. Myriad held the patents on isolated forms of
the genes BRCAl and BRCA2. Remember, we all have copies of BRCAl and BRCA2. People are genetically
predisposed to breast and ovarian cancer when they carry disease-causing mutations in these genes. Because
Myriad held the patent for these two genes, the company had control over how and when they were used for
research, and Myriad could control the COStof generic testing for gene mutations. This was highly controversial.
A lawsuit was filed by the American Civil Liberties Union and the Public Patent Foundation claiming that
these gene patents held by Myriad were not valid. In March of 2010, a U.S. Federal district court decided
that patenting isolated human gene sequences should not be perrnirred. The court stated that the isolated
DNA sequences were not patentable because they did not differ significantly from the gene sequences that
exist by nature in the human genome. In July 2011, the U.S. Court of Appeals for the Federal Circuit ruled
that Myriad did, in fact. have the right to patem these two isolated human genes (Chuang & Lau, 2010).
In June of 2013, the U.S. Supreme Court issued a landmark decision when it unanimously concluded that
no one could patem isolated pieces of DNA in its natural, unmodified form (NHGRI, 2014). Up until that
time 4,300 genes had actually been patented (NLM. 2017). Importantly, the Supreme Court did allow for
patenting of modified segments of DNA. The justices felt that modification, such as isolating JUStthe exons,
constitutes an "inventive" step, which is required for parenting to be permitted.

GENE THERAPY
The use of gene therapy in the treatment of cystic fibrosis was mentioned in Chapter 11. It is exciting and
holds great promise for treating challenging disease, bur the use of gene therapy has significant legal and
ethical implications as well. Let's discuss just what we mean when we say "gene therapy" and where the ethical

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382 Unit VI Global Genomic Issues

concerns come from. Gene therapy occurs when a provider inserts a gene or a modified gene into a patient's
cell(s) to treat or prevent a disease in one of three major ways: Physicians can (1) insert a normal gene copy
into the cell, hoping to replace a copy that carries a disease-causing mutation; (2) "tum off" a gene that is
not working correctly, or (3) add a gene that will improve the patient's disease resistance.
Genes are introduced into cells by using a carrier, such as a virus. (When viruses are used, they are modified
so that they do nor cause an infecrion.) These carrier molecules are called vectors, and they are genetically engi-
neered to carry the gene of inreresr. Viruses are experts at getting into cells, which makes them effective carriers.
The vector carrying the desired gene is then injected into the tissue direccly or given intravenously, Sometimes
a small group of cells is removed from the patient and exposed to the vector in a laboratory. Then the cells are
given back to the patient. This can be a difficult process, with considerable technical challenges to overcome
when providing gene therapy to a patient. See Figure 19-2 for a depiction of the process of gene therapy.
Currently in the United States, gene therapy is only being used experimentally for diseases with no cure,
such as cystic fibrosis, sickle cell anemia, hemophilia, muscular dystrophy, and some cancers. Hundreds of
ongoing research studies are evaluating gene therapy, and the Food and Drug Administration oversees gene-
therapy products to make sure that they are safe to use in these research studies. The National Institutes of
Health has issued specific guidelines to direct the use of gene therapy in dinical trials,

Virll N~.... Viral

DNA GeM OIIA
I I I I
~
Modified DNA Injected
Inoo

Vector binds to
cell membrane

VHIde breaks
down,releasing
veclOf

therapy using
adenovirus vector

Figure 19-2 The process of gene therapy. (U.S. National Library of Medicine. (2017). Genetics home
reference: How does gene therapy work? Retrieved from httpsl/ghr.nlm.nih.gov/primer/therapy/procedures.

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 Chapter 19 Financial, Ethical, Legal, and Social Considerations 383

Many ethical questions surround the use of gene therapy, similar to questions we have considered before
related to genetic testing and its availability and accessibility. These include the COStof the therapy and whether
gene therapy could be made available to more than JUStthe wealthy. Another concern is how we decide what
is "normal" and what is a "disability." If gene therapy becomes common, will people who do not fit a certain
view of what is "normal" be rejected by society? As we noted with preimplanration genetic diagnosis, what
will happen if people choose to use gene therapy to make their children smarter, or taller, or more athletic?
Remember that the kind of gene therapy currently being tested involves altering genetics in the somatic,
or body, cells (not the germline). These would include the bone marrow or blood cells. One major ethical
issue arises when people consider using gene therapy to alter the germline cells (eggs and sperm). This kind of
genetic change would alter nor only the person being treated but also his or her offspring. The U.S. government
does not currently permit federal funds to be used in studies of germline gene therapy in people (National
Human Genome Research Institute, 2017). Many countries outlaw the use of gene therapy for germline cells.

SUMMARY
Many legal and ethical issues have surfaced along with advancements in our knowledge of genetics and genom-
ics. We are confronted with conflicts and controversies that no one anticipated, and even more controversies
will likely emerge in the future that we cannot foresee. Options for reproductive decision making have changed
with the development of advanced reproductive technologies such as preimplantarion genetic diagnosis. Legisla-
tion to prevent genetic discrimination in employment and insurance is now in place in the United States; we
will see how well it protects our patients and their families. The advances in biotechnology have resulted in
controversial decisions about whether genes can be patented. Gene therapy is a new and promising treatment
for some genetic diseases, but much work remains to be done before it will be widely available. All of these
issues have an important impact on the patients for whom we provide care. Importantly, research into the
financial, legal, ethical, and social implications of genetic advances is continuing and will help us understand
the best ways to manage these problems.
And what about Jim, who tested positive for the HD disease gene mutation, which means that his father,
who did not want to know his mutation status, is also positive for the gene mutation? This situation presents
a major problem for genetics professionals and underscores the importance of families receiving good genetic
counseling prior to the completion of any genetic test. The best-case scenario would be for Jim and his father
to sit down with a genetic counselor and discuss all the possible outcomes of Jim's generic test before Jim gets
tested. The family can then decide what is best for them and what actions Jim should take after he learns his
results. Genetic counselors are skilled in helping families work through such dilemmas about sharing genetic
information. As with so many issues, advanced planning and open communication can help to reduce the
risk of problems for all family members.

GENE GEMS

• Genetic information is different from other kinds of health information because it involves family
members as well as patients.
• Respecting autonomy is an important guiding principle in caring for a patient's or family's genetic health.
• Many Americans report that they are afraid of having genetic testing done because they do not want
to be victims of genetic discrimination.

Continued

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384 Unit VI Global Genomic Issues

• Between 3% and 5% of the annual budget of the Human Genome Project was designated for studying
the ethical, legal, and social implications of genetic knowledge.
• The American eugenics movement sought to eliminate "defective" people from the reproducing population.
• Fear of the widespread resurgence of eugenics makes some people wary of using advanced reproductive
technologies.
• Preimplanration genetic diagnosis allows parents to screen in vitro fertilized embryos for specific genetic
traits (or sex) and implant those that are less likely to carry the disease.
• On May 21, 2008, the Genetic Information and Nondiscrimination Act (GINA) was signed into law
by then-president George W. Bush.
• GINA provides protection against genetic discrimination in employment and health insurance.
• Sometimes the health-care professional's duty to warn family members of genetic risk conflicts with the
obligation to maintain the privacy of a patient's health-care information.
• Although the legal cases presented involved only physicians. the recommendations from governmen-
tal agencies and professional organizations that resulted from them are important for all health-care
professionals.
• Some companies have patented sections of the human genome, claiming this was their intellectual
property.
• When genes are patented, the company that holds the patent can restrict research using those genes
and can charge excessively high rates for genetic tests.
• In June of 2013, the U.S. Supreme Court unanimously concluded that no one could patent isolated
pieces of DNA in its natural, unmodified form.
• Most gene therapy is still experimental and has both promise and challenges.

Self-Assessment Questions. . ...

1. Why can the "duty to warn" be complicated in considering the genetic care of your patients?
a. The provider'S duty to warn can sometimes conflict with a patient'S right to privacy.
b. The duty to warn is clearly more important than a patient's autonomy.
c. The ethical principles of beneficence always take precedence over other concerns.
d. HIPAA confirms that health-care providers have a duty to warn.
2. What area(s) are covered under the Genetic Information Nondiscrimination Act (GINA)?
a. Establishing legal guidelines for disclosure of genetic information
b. Providing free medical care to persons with genetic diseases
c. Preventing discrimination in employment and insurance based on a genetic condition
d. Ensuring that all health-care providers receive education in genetics
3. Why is learning about and understanding the history of eugenics important for health-care providers?
a. Eugenics describes the impact of genetically modified organisms in our food supply.
b. Reproductive technologies could function similarly to selective breeding and lead to "designer babies."
c. Eugenics provides a way to improve genetic health and deter genetic discrimination.
d. Aborting fetuses with disabilities strengthens our society.

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 Chapter 19 Financial, Ethical, Legal, and Social Considerations 385

4. Gene therapy has used several approaches. Identify the selection that is a gene-therapy approach.
a. Inserting a "super" gene in place of a normal one
b. Turning on a gene that carries a dangerous mutation
c. Adding a group of genes that will prevent all diseases
d. Inactivating a gene that is not functioning as it should
5. Can genes be patented?
a. No, they are naturally occurring and nor the result of an invention.
b. Genes that have been modified cannor be patented.
c. Whether genes can be patented is unclear.
d. Gene patents are the intellectual property of the laboratory rhat isolated them.

CASE STUDY

Yourneighbors Mary and Nathanhave three children. Ethan, their son, has cystic fibrosis (CF).Their other
three children are healthy. Mary has applied for a new job, and during her pre-employment physical,she
mentions that her son has CF.The providerconducting the physicalmakesa note of this. Three days later,
Mary gets a call from the Human ResourcesDepartment at the company to which she had applied.They
tell her that they cannot hire her based on the finding that her son has CF.They note that CF is a genetic
disease. Mary knocks on your door and complains about how ignorant her prospective employer is and
frets that she can do nothing about it.
1. Is Mary at risk of havingCF even though she has no symptoms?
2. Is Marya carrier of a mutation that could cause CF in her offspring?What about Nathan?
3. How would the Genetic Information and DiscriminationAct (GINA)affect the outcome of this
case?
4. What information is the Human ResourcesDepartment missing?

References

Allen, G., Carlson, E., Lombardo, P., Micklos, D., Selden, S., & Witkowski, J. (n.d.). Imagr archive on the American cugenics
movement: Retrieved from http://eugenicsarchive.org/eugenicsllist3.pl
American Society of Human Genetics. (1998). ASHG statement. Professional disclosure of familial genetic information. The
American Society of Human Genetics Social Issues Subcommittee on Familial Disclosure. American [ournal of Human
Ceneiics, 62(2), 474-483.
Basille, C, Frydman, R., EI Aly,A, Hesrers, L., Fanchin, R., Tachdjian, G., ... Achour-Frydman N. (2009). Preimplancarion
genetic diagnosis: State of the art. Europeanjournal ofObsturics, GYIlt!CO!ogy, and &producrive Biology, 145(1),9-13.
Chuang, C S., & Lau, D. T (2010). Patenting human genes:The Myriad controversy. Clinical Therapeutics, 32(12), 2054-2056.
Council for Responsible Genetics. (2010). Genetic (ming, privacy and discrimination. Retrieved from http://www
.councilforresponsiblegenetics.orgl
Dyer, C. (2009). Doctors may share genetic information to help patients' relatives. British Medica/journal, 339, b4031.

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386 Unit VI Global Genomic Issues

Genetic Information Nondiscrimination Act of 2008. Pub. L. No. 110-233. 122 Stat. 881 (2008).
Godard. B.• Hurlimann, T. Letendre. M .• & Egalire, N. (2006). Guidelines for disclosing genetic information to family members:
From development to use. Familial Canur. 5(1). 103-116.
Health Insurance Portability and Accountability Act of 1996. Pub. L. No. 104-191. 110 Stat. 1936 (1996).
National Genome Research Institute. (2017). Retrieved from hrrps:llwww.genome.govI27569225/what-are-the-ethical-concerns
-about-genome-editingl
National Human Genome Research Institute. (2012). Cas~sofg~l1uic discrimination. Retrieved from hrtp:llwww.genome.gov/
pfv.cfm?pageID=125 13976
National Human Genome Research Institute. (2014). Intelleaua! property and genomirs. Retrieved from Imps:1I
www.genome.gov/19016590/
National Human Genome Research Institute. (2016). Gmnicdiscrimination. Retrieved from Imp:llwww.genome.govII0002077
National Library of Medicine. (2017). Generia bome 1'f'ftrmc~:Call gml'J b~pnrmud? hrrps:lIghr.nlm.nih.gov/primer/testingl
genepatent.~. Retrieved August 6. 2017.
Stainton. T (2007). Missing the forest for rhe trees? A disability rights take on genetics. Journal on Developmental Disabilities.
13(2). 89-92.
U.S. National Library of Medicine. (20 17). Gm~ticsbom« yo/rmu: W'hat is gm~ I/~rnpy. Retrieved from hrtps:lIghr.nlm.nih.govl
p rimer/ therapyl gcnetherapy
Weaver. M. (2015). The double helix: Applying an erhic of care to rhe duty to warn generic relatives of genetic information.
Bionhics.30(3).181-187.
Wilson. G. N. (2000). Clinical genetia, New York, NY: Wiley & Sons.

Self-Assessment Answers
I. a 2. c 3. b 4. d 5. a

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 Chapter 20
Genetic and Genomic Variation
Learning Outcomes
1. Distinguish between genetic drift and founder effects.
2. Describe what happens in a population bottleneck.
3. Apply aspects of population genetics to explain genetic variation in human populations.
4. Explain how geography can have an impact on the transmission of heritable traits.
5. Describe current ideas about the biological basis of "race" and "ethniciry."

Key Terms
Assortative mating Genetic anthropology Human genetic variation
Ethnicity Genetic drift Natural selection
Evolution Haplotypes Population bottleneck
Founder effect Hardy-Weinberg principle Population genetics
Gene pool Heterozygosity Race

INTRODUCTION
Genetic and genomic variation describe naturally occurring differences between and among individuals (both
human and nonhuman) of the same species. These variations are the result of genetic mutations that develop
over time. (Remember, all mutations are not bad! Some improve adaptation.) Population genetics principles
such as genetic drift, population bottlenecks, and the founder effect also play an important role. These will
be discussed later in this chapter.
Despite the fact that we have some differences on the surface, humans are a very homogenous group.
We are 99.5% genetically alike. When you think about the entire genome (remember that the human
genome contains approximately 3 billion base pairs), it is amazing that people are so similar. However, that
0.5% difference is important. It has both health-related and social-cultural consequences. People vary in their
individual DNA sequences by copy numbers, polymorph isms, and the presence or absence of chemical additions
that result in differing levels of gene expression (epigmetics). Human variation exists in more than 80 million
places in the genome. These include single-nucleotide polymorphisms (SNPs), insertions, and deletions as

387

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388 Unit VI Global Genomic Issues

well as structural variation (National Human Genome Research Institute fNHGRI], 2015). That is a lot of
variation for only a 0.5% difference.
Scientists believe that humans have so little genetic diversity because all women are descended from the
same female African ancestor, who lived about 140,000 to 200,000 years ago, and all men are descended
from the same male ancestor, who lived in Africa about 60,000 years ago. Humans appear to have migrated
out of Africa to southern Asia, China, and Europe about 65,000 years ago, but they left genetic tracks behind
(National Genographic Project, 2016; Tishkoff & Verrelli, 2003). Analyzing the genetic markers of people all
over the world has allowed scientists to document the path of this human migration.
When we pass DNA down through the generations, a lot of mixing of genetic information occurs. Earlier
in this text, you read about some factors that increase our genetic diversity, including Mendel's principle of
independent assortment of alleles during meiosis and crossing over of segmentS of homologous chromosomes,
which also occurs during meiosis (Chapter 3). However, some pieces of genetic material are passed from gen-
eration to generation with very little change. These include the mitochondrial DNA, which is passed from a
mother to all her children, and the Y chromosome, which is passed from father to son. Small changes to these
genetic materials are inherited, and eventually, people from the same region end up with common markers
that allow us to determine the geographical origin of people's ancestors.
Many people are interested in learning about their very distant relatives. The study of genetic anthropol-
ogy uses a combination of genetic information and physical evidence, such as the fossil record, to learn more
about our history as a species. In 2006, the National Geographic Society began the Genographic Project with
the goal of assembling DNA from more than 100,000 people and creating the largest DNA database in the
world. They wanted to get samples from all major populations living on the earth and catalogue genetic simi-
larities and differences. Human genetic variation is the phrase used to describe the genetic differences that
can be found within and between groups of people. This database is considered "open source," meaning that
it is available to interested people everywhere. Another way that scientists are working to document human
genetic variation is by assembling a map of human haplorypes.

Haplotypes
We all have groups of genes (or SNPs or markers) that tend to be inherited together. These are called haplo-
types, and one way to think about them is as genetic "neighborhoods." A gene does not exist in isolation-it
is always on a chromosome near other genes and intergenic regions. The International HapMap Project was
completed in 2005 and provides a catalogue, or map, of common patterns of human genetic variation. This
project makes it easier for scientists to study the differences in the risk of disease and the response [Q drugs
found in different human populations. The HapMap Project is an international collaboration of scientists
from the United States, Japan, the United Kingdom, Canada, China, and Nigeria (NHGRI, 2012).

POPULATION GENETICS
In most of this text, we discuss the impact of genetics on the health of individuals and their families. But
remember that people and families exist as partS of larger groups, or populations. Those groups share com-
monalities, such as culture, heritage, customs, and often a higher risk for certain diseases.
The field of population genetics examines the ways in which allele frequencies change in human popula-
tions over time, including those events that keep the frequencies the same and those events that change them.
A species with many different alleles (versions of a gene) will have far more genetic diversity than a species
with a small number of alleles for each gene.

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 Chapter 20 Genetic and Genomic Variation 389

Disease Risk and the Geographic Origin of Ancestors

We also see rates of disease risk that vary by the geographical origin of ancestors, For example, why is
hemophilia A rare and sickle cell disease so common among people of African descent? Why do Afri-
kaners, the descendants of Dutch settlers from South Africa, have a higher-than-average risk of Hun-
tington disease? These apparent mysteries have simple genetic explanations, and we have to look at
more than individuals and families to answer them. We need to look more broadly at large populations,
migration patterns, and the results of foundational ideas, such as natural selection (the notion that
organisms that are best suited to the environment will survive to reproduce and pass on their genetic
characteristics). Scientists are very interested in how and why the frequencies of different traits change in
populations.
When we look at disease risk, some different versions of a gene can be helpful, and some can be harmful.
For example, we discussed sickle cell disease (SCD) in the chapter on childhood diseases (Chapter 11).
Remember that being homozygous for the mutation that causes SCD means you will have the signs and
symptoms of SCD. However, being heterozygous confers protection against malaria without most of the prob-
lematic manifestations of SCD. If we look at this trait
from a population level, the mutation is helpful. Of What Do YouThink Will Happen to the
course, when we are working with an individual patient Frequency of the SCDAllele in Future
affected by SCD, it does not seem so helpful. Looking Generations of African Americans?
at risk or benefit from a population-wide perspective is Current generations of African Americans are rarely
very different from looking at risk or benefit for one exposed to malaria. In addition, interbreeding among
individual. people whose ancestors came from Africa and those
Unlike the situation with carriers of SCD, as fur as whose ancestors came from other regions of the
we know, people of African descent do not get any world, such as Europe or northem Asia, should also
have an impact on the persistence of the SCD allele
advantage from being heterozygous for the mutation
in the general population. The SCD carrier rate is
that causes hemophilia A, so it makes sense that the
much lower in populations that come from regions
hemophilia A mutation would be much less common where malaria is not common,
than the SCD mutation in this group.

Allele Frequencies
So, how different are we? At the DNA level, one sequence variation occurs for every 200 to 500 nucleotides.
Those stretches of DNA that do not code for proteins have even greater variation than our protein-coding
regions. These changes underlie our abiliry to adapt to extreme environments and have been essential ro our
evolution as a species (Wilson, 2000). Human genetic variation is a good thing, and it is very relevant to plan-
ning appropriate health care for our patients. For example, some couples of Ashkenazi Jewish background may
choose to have carrier testing before they conceive children because carrier rates for certain recessive diseases
are relatively high in this population (see Chapter 16).
Many laboratories offer an Ashkenazi Jewish Panel that provides individuals and couples with genetic
testing to determine whether they are carriers of diseases that are common among people of Ashkenazi Jewish
ancestry. If both partners are carriers of one copy of a mutant gene that results in a disease such as Tay-Sachs,
for example, they could choose to have preirnplanrarion genetic diagnosis in order to screen out affected
embryos. They could also choose to not have children (the risk of having an affected child if both parents
are heterozygous would be 25% with each pregnancy), or they could choose to prepare for the possible birth
of a disabled child. The abiliry to provide anticipatory guidance could improve the outcome for any couple
in this situation.

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390 Unit VI Global Genomic Issues

Changes in the Gene Pool

One way to define evolution is a change in the genetically inherited frequencies of alJeles over time. This
reflects changes in the gene pool, or the sum total of all the alleles for all the genes in a given population.
For example, on a very simple scale, we can see the evolution from one generation to another. If we say that
86% of a population has at least one copy of the "A" allele for a particular gene, then 14% of the population
has at least one copy of a different allele for that gene, which we will call "a." Now we will fast-forward a few
generations and look at the population's genotypes again. At this new point in time, 90% of the population
has at least one copy of the "A" allele and only 10% of the population has the "a" version. We can look at
these numbers and see evolution favoring the increasing frequency of the "A" allele and the decreasing fre-
quency of the "a" allele.
Maybe having more copies of the "A" allele means that you are more resistant to getting a specific disease
such as diabetes mellitus type 2. That would be a very positive change in this population's gene pool. One
thing we know is that if 95% of all alleles in a population are "A," most people will be homozygous AA.
Heterozygosity, or the proportion of a population chat is heterozygous at a particular locus, will be very low.
Very few people would be Aa at that gene location because not very many "a" alleles are available. Even fewer
people would be aa. So how do you figure out the allele frequency in a population?

Hardy-Weinberg Equilibrium
In the early 1900s, two scientists, a mathematician from England named Godfrey Hardy and a medical doctor
from Germany named Wilhelm Weinberg, independently developed ideas about how allele frequencies change
in populations. They determined that allele frequencies would remain the Same if certain criteria were met.
(Of course, these criteria are never met in human populations, so we continue to evolve!) If allele frequencies
were to remain stable, the population would be in Hardy-Weinberg equilibrium. See Table 20-1 for a list
of the criteria for maintaining Hardy-Weinberg equilibrium. They aren't much fun.
The first criterion a population must meet to remain in Hardy-Weinberg equilibrium is that everyone and
all their descendants must stay in the same geographic region. No migration is allowed. When we migrate,
we take our genetic traits with us. If only a few of us leave our native land, then future populations in this
new place will be more like the small group that migrated than they will be Likethe original population. This
is called the founder effect.
Founder effect occurs when a small group of people leave a larger population and settle somewhere else.
For example, in 1652, one shipload of Dutch settlers migrated to South Africa. It happened that one of the

Requirements for Populations to Stay in Hardy-Weinberg

Equilibrium
1. No one migrates.
2. People mate randomly.
3. The population is extremely large.
4. Everyone has children.
5. There are no mutations.

Source: Pierce. B. (2009). Transmission and population generics (2nd ed.). New York. NY:
W. H. Freeman.

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 Chapter 20 Genetic and Genomic Variation 391

immigrants carried the gene mutation that causes Huntington disease (HD), which, you will recall, is an
autosomal-dominant condition with age-related peneuance. Symptoms of HD do not usually appear before
a person is 35 to 50 years old. By that time, most people have already had children. If a parent is an affected
heterozygote, each child has a 50% risk of inheriting the disease-causing allele and developing HD. Once the
HD allele is in a population, it often continues to be transmitted. Today, the incidence of HD is much higher
in the Afrikaner people than in the original Dutch population their ancestors left behind. Most Afrikaner
people with HD today are descendants of this first Dutch immigrant (Ridley, 2003).
In order to maintain Hardy-Weinberg equilibrium, everyone in the population must mate randomly (rather
than selecting partners based on similar or different characteristics). You cannot pick your mate based on any
particular trait, You cannot mate preferentially with someone who likes the same things you like. You cannot
mate with someone who enjoys science-fiction movies if you enjoy science-fiction movies. You also cannot
choose to mate with someone who is different from you. You cannot select a person who likes to cook because
you hate to cook. Purposefully selecting a mate based on similar or dissimilar traits is called assortative mating,
and it keeps a population from achieving Hardy-Weinberg equilibrium.
If you practice random mating, which is required by the Hardy-Weinberg principle, you could not pick
your partner because she or he was attractive or intelligent or fun to be with. That is not random mating,
and choosing your partner based on particular attributes will increase the likelihood that those traits will
increase in frequency in the population. This is particularly true if lots of other people in your population
like the same traits. Of course, the terms random and assortatiuemating are usually applied to vegetables and
laboratory animals, not people.
Probably the most difficult criterion to meet of all the Hardy-Weinberg criteria is that the DNA of people
within the population must not mutate. Genetic diversity depends on changes in genotypes occurring peri-
odically. This helps us to adapt to environmenral changes. It also changes the frequency of alleles in a given
population. When you are changing the frequency of alleles, you are ruining your Hardy-Weinberg equilib-
rium. Of course, no one said that staying in Hardy-Weinberg equilibrium was a good thing for a population.
Hardy and Weinberg also developed an equation that could be used to track the genotype frequencies in a
given population and monitor changes over time. The Hardy-Weinberg equation is depicted in Table 20-2.
Knowing this may not help you care for a sick patient; however, it helps scientists keep track of how popula-
tions change, and it helps clinicians appreciate why people with ancestors from the same geographic region
share traits (and risk for certain diseases).

Genetic Drift and Population Bottlenecks

Populations can change and become less diverse from genetic drift. Genetic drift is the process by which allele
frequencies decline because of what population geneticists call sampling error. In every generation, some indi-
viduals reproduce, and others do not. Some parents have lots of children, and others have only one or rwo.
Future generations are more likely to possess the traits of people who have more children. This will happen
whether or not these traits have any survival advanrage. Figure 20-1 provides an example of genetic drift
using marbles instead of people.
In the illustration, 10 marbles are randomly drawn from a bag that contains rwo different colors of marbles,
A and B. Future marble bags are restocked in proportion to the marbles drawn from the previous bag. The
bag on the left side has been restocked with 60 marbles of color A and 40 marbles of color B, to make a bag
with a total of 100 marbles. Someone draws marbles randomly from the bag and gets eight color A marbles
and two color B marbles. The next bag is restocked with marbles in the proportion of 8:2 (80 A marbles and
20 B marbles). Now 10 marbles are randomly drawn again. This time, the sample contains 10 A marbles and
no B marbles. The next bag is restocked with 100 A marbles. Future marble "generations" will contain only

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392 Unit VI Global Genomic Issues

Development of the Hardy-Weinberg Equation

p = the fre quency of the dom inant allele.

Let's call this allele B. How many B alleles are there in a given population? Well. there are all of the alleles
in people who are homozygous dominant (BB) and half of the alleles in people who are heterozygous
(Bb); p represents all of these together.
p = BB + 1/2 Bb q = the frequency of the recessive allele.
Let's call this allele b. How many b alleles are there in a given population? Well. there are all of the alleles
in people who are homozygous recessive (bb) and half of the alleles in people who are heterozygous
(Bb); q represents all of these together.
q =bb+ 1j2Bb
p+q=l
The sum of the frequencies of all alleles must be 100%. so if there are only two alleles in the population.
we can say that:
p=l-q
Now if we do just a tiny bit of algebra. we say that the chances of all possible combinations of alleles in a
population are:
(p + q)2 = 1OR p2 + 2pq + if = 1
The frequencies of the three possible genotypes are indicated by the terms of the equation. technically
called a binomial expansion. SO ...
p2 = the predicted frequency of the homozygous dominant genotype (BB)
2pq = the predicted frequency of heterozygous genotype (Bb)
if = the predicted frequency of homozygous recessive genotype (bb)

Source: Pierce. B. (2009). Transmission and popularion generics (2nd edt. N8II\IYork. NY,W. H. Freeman.

Draw #4 Draw #5 Draw #6

~Restock
Draw ..
6:4
600:40. D~~W .. 800:20. Draw.....
10:0 ..,... 100
o.
:0

Figure 20-1 Genetic drift.

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 Chapter 20 Genetic and Genomic Variation 393

"Generation" 1 "Generation" 2 "Generation" 3 "Generation" 4

~
Draw
2:5:3
Restock

..
Draw~
.. ~:~:~
..
40.
280

320
:~

300
__,; 0:2:1 ~~

40
~ Reduced
genetic
variation

Figure 20-2 Bottlenecks and founder effects.

color A marbles. Now, let's apply this idea to human populations. If the genetic trait represented by B "drifted"
out of the population, we would have less genetic diversity. If A was a trait that protected us from a particular
disease, then our population would be less vulnerable to that disease. These genetic changes are nor influenced
by natural selection-they are simply the result of random changes in the frequency of a trait in a population.
A more dramatic way that populations change is by undergoing a population bottleneck (Fig. 20-2). In a
population bottleneck, some event happens that severely reduces the number of individuals in a population.
Only those individuals who survive this event will be able to reproduce, so only their traits will be passed on
to future generations. Population bottlenecks can greatly limit genetic diversity in the surviving populations.
In Figure 20-2, the bag on the left has three different colors of marbles: 28 of color A, 40 of color B, and
32 of color C. Someone draws 10 marbles randomly, and the draw includes 2 of color A, 5 of color B, and
3 of color C. These proportions are roughly the same as those of the original population (28:40:32). The
marbles are then restocked in the new proportions, so the generation 2 bag contains 20 marbles of color A,
50 marbles of color B, and 30 marbles of color C. If we were talking about people instead of marbles, we
would say that the smaller population reproduced.
An unusually small number of marbles (only 3) is drawn from the generation 2 bag. In this draw, we
have no marbles of color A, 2 marbles of color B, and 1 marble of color C. We have encountered a popula-
tion bottleneck. Now the entire population COntains no marbles of color A. It has been eliminated from the
population. No future generations of marbles "reproduced" from this small group will have the color A. That
"genetic trait" has been eliminated from the population. By generation 4, no marbles with this color exist
(Undemanding Evolution, 2008).
One example of a population bottleneck can be seen in the history of the northern elephant seal. During
the 1890s, these seals were hunted to near extinction. By some estimates, only 20 individuals remained.
Since that time, these seals have reproduced, and the population is currently thought to include more than
30,000 seals. What do you expect was the outcome of this population bottleneck? If we compare genetic
diversity in the northern elephant seal to genetic diversity in the southern elephant seal, a population that did
not experience a bottleneck, the difference is clear: The southern elephant seals are much more diverse geneti-
cally than the northern seals because all the northern seals surviving today are descended from the very small
population that survived the bottleneck (Seal Conservation Society, 2011; Understanding Evolution, 2008).

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394 Unit VI Global Genomic Issues

We can see similar patterns if we look at human history. Earlier in this chapter, we discussed the prevalence
of certain diseases among people of Ashkenazi Jewish ancestry. These include diseases such as breast cancer
caused by mutations in the genes BRCAl and BRCA2, as well as several lysosomal storage diseases, such as
Gaucher disease and Tay-Sachs. Although these ideas are controversial, the high prevalence of these diseases
among this population may be the result of a combination of founder effects and population bottlenecks
(Tishkoff & Verrelli, 2003). Evidence from mitochondrial DNA suggests that a population bottleneck occurred
among Ashkenazi Jews about 100 generations ago, which was followed by an increased rate of growth (Behar
et al., 2004). This could explain the prevalence of these diseases among this population.
Thus, knowing the geographic origin of a person's ancestors can be helpful because we share many traits
in common by descent, and populations that have been geographically close will be more likely to share the
impact of founder effects, genetic drift, and population bottlenecks, Things become a bit more difficult when
we try to put people in clearly bounded categories, such as racial and ethnic categories, based on the physical
traits they may share.

RACE, ETHNICITY, AND HUMAN

GENETIC VARIATION
Race and ethnicity are somewhat controversial terms with different definitions, depending on the context.
In this section, we will present some of the ideas about genetics and race and erhniciry that are of interest
to people working in health care. We are not offering a comprehensive discussion of this complicated topic.
However, those developing an understanding of genetics need to see how human genetic variation fits in with
our social and cultural ideas about population similarities and differences.
Race is commonly used to categorize people into groups that share common geographical background,
ancestry, and physical features. However, the racial categories are overlapping and do not reflect the con-
tinuous distribution of genetic variation. Although population groups share some traits in common, sharp
boundaries between groups do not exist (Royal & Dunston, 2004). Self-identified race is often associated
with the geographic origin of one's ancestors. Therefore, people who identify themselves as belonging to a
particular race are likely to share some traits in common. However, we must remember that many nongenetic
factors contribute to our ideas of what race is, and many people can trace their ancestors to several different
geographic regions (Collins, 2004).
Certainly, some genes are associated with various physical traits, such as skin color or hair texture. However,
no reliable way exists that allows us to use the genes associated with these traits to separate people into unique
groups. People whose ancestors came from the same geographic region share some alleles in common; however,
no particular allele is found in all members of a given population and not found in other populations as well.
If we look at the genetic diversity of our species, the genetic differences among individuals in the social-cultural
groups called races are much smaller than the genetic differences between each of these "races."
Ethnicity is a quality claimed by a group of people who identify with each other and believe they share a
cultural heritage. When we look at recent history, we can see variations in erhnicities that have resulted from
human migration patterns, the impact of mutations, and small subgroups settling in isolated areas. These are
some of the factors in population genetics (founder effects, genetic drift) that we previously discussed. When
we look over a much longer period of history, we can see changes that reflect natural selection and adaptation
to variations in climate and availability of food sources.
Some experts have suggested that we need a new way of thinking about human genetic variation. Results
from the Human Genome Project have made it clear that our old conceptions of race and erhniciry are
not biologically based but represenr geographical and sociocultural divisions at best (Royal & Dunston,

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 Chapter 20 Genetic and Genomic Variation 395

2004). On the other hand, knowing someone's race or ethniciry can be useful in identifying which genetic
disorders an individual is more likely to have. For example, people of Celtic background (descended from
Irish or Scottish ancestors) are more likely to carry mutations leading to the autosomal-recessive disease
hemochromatosis.
The terms race and ethnicity are used in a wide range of settings, including to categorize people in gov-
ernmental databases. Sometimes these categories can be helpful because we do nor have more accurate ways
to describe groups of people whose ancestors came from the same geographic region. We know that research
studies often compare the effect of a particular drug in one race to the effects of that drug in another race. For
example, the American Heart Association (AHA) published a facr sheet for the management of hypertension
in African Americans based on current research and the consensus of experts. The statement contains useful
information for clinicians caring for this population, even though we have no biological way to determine
the boundaries of this group (AHA, 2015).
We also know that important disparities can be described by looking at the health care available to those
classified as belonging to different races. This is greatly due to social, cultural, and political issues. However,
to be able to identify people who are more likely to experience these disparities is dearly useful, and genetics
certainly contributes co the risk of disease and response to treatment. We do not know whether genetics can
contribute much to our understanding of health disparities (Collins, 2004).
People argue about whether we should retain the ideas of race and ethnicity or even if self-identified race/
ethnicity is useful when we talk about the risk to health (Collins, 2004). More studies are clearly needed to
help scientists SOrt out these ideas. These studies must take into consideration both genetics and environment.
If we choose to continue to use the terms race and ethnicity, we must remember that they have significant
limitations when we try to apply them strictly to what we now know about human genetic variation.
Francis Collins, the director of the National Institutes of Health and the former director of me Human
Genome Project in the United States, agrees that the terms mce and etlmicity are very poorly defined. In addi-
tion, these words carry with them ideas about history, culture, and socioeconomic status that are not reflected
in genetic variation. What can be determined with some degree of accuracy from looking at sorneone's geno-
type is the likely geographical origins of his or her ancestors-that is, if those ancestors came from the same
parts of the world. People whose ancestors came from the same geographical location commonly share genetic
sequences in common and identify themselves as belonging to the same race. In that sense, a connection exists
between biology and race; however, it is a slippery one at best (Collins, 2004).

SUMMARY
The study of human genomic variation is complex. As a species, we are very similar. However, we differ from
one another in important ways, including our risk for diseases and our responses to drugs. Efforts to catalogue
human genetic diversity have produced much useful information. People have tried to categorize humans into
different groups (races and ethniciries) and have assumed that these group differences were based in biology.
With the completion of the Human Genome Project, we have learned that these racial and ethnic groups do
not have clear biological boundaries; rather, racial and ethnic groups overlap considerably.
Racial and ethnic categories may still be helpful when we look at social, cultural, and political issues, such
as health disparities. However, we must be careful not to use these words to imply that everyone in a group
is biologically like everyone else in that group. The range of genetic difference within groups is bigger than
that between groups. Understanding how human genetic variation has progressed over time and the factors
that have altered the frequencies of alleles in a given population has many benefits. There is also much more
to learn about the ways in which we, as a species, are the same and the ways in which we are different.

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396 Unit VI Global Genomic Issues

GENE GEMS

• Humans are genetically homogenous. We are 99.5% the same at the DNA level.
• The 0.5% genetic differences among humans have both health-related and sociocultural consequences.
• The National Geographic Society began the Genographic Project with the goal of assembling the largest
DNA database in the world, which will ultimately contain DNA from more than 100,000 people.
• Humans are descended from the same African ancestor.
• The International HapMap Project provides a map of human genetic variation.
• People have different risks for diseases and tend to respond differently to drugs, depending on the
geographical origin of their ancestors.
• Population genetics is the study of the changes in allele frequency in different populations over time.
• The founder effect can result in lack of genetic diversity within an isolated population.
• Genetic drift is a random change in allele frequencies nor based on natural selection.
• Population bortlenecks reduce the size of a population and limit the diversity of alleles available to
future populations.
• Many factors can cause population bottlenecks, including dramatic climate changes, famine, and socio-
political events,
• The Hardy-Weinberg equilibrium equation calculates changes in allele frequency over time.
• For a population to remain in Hardy-Weinberg equilibrium, several criteria must be met. These include
random mating, no migration, no mutations, and everyone in the population reproducing.
• People of Ashkenazi Jewish ancestry have an increased risk for breast cancer caused by mutations in
the genes BRCAl and BRCA2, as well as for lysosomal storage diseases such as Gaucher disease and
Tay-Sachs.
• Whether genetics can be of any help in explaining health disparities is unclear.
• The terms race and ethnicity are defined differently, depending on COntext.
• We can see genetic similarities in people whose ancestors came from the same geographic regions.

Self-Assessment Questions . '"

1. Which phenomenon would result in altering Hardy-Weinberg equilibrium?
a. Isolated population with no migration in or OUt
b. Frequent mutations
c. Random mating
d. Everyone in the population having children
2. A new mutation occurs that makes the fictional animal, the obalynx, run faster and get away more
easily from its predators. What do you think will happen in 500 years of obalynx evolution if no
other mutations occur?
a. Most obalynxes will run at the faster rate.
b. Fewer obalynxes will run at the faster rate.
c. Obalynxes will become extinct.
d. All obalynxes will continue to run at the current speed.

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 Chapter 20 Genetic and Genomic Variation 397

3. A group of 50 adventurers (men and women) moved to a remote area of northern Canada. They lived
there happily for many years but then noticed that their community had many people afflicted with
an uncommon autosomal-dominant disease. What might explain this?
a. They settled at a high altitude, and the community was exposed to increased levels of radiation.
b. Their lack of genetic diversity resulted in the inability to adapt to the new climate.
c. One of the founders carried a disease-causing mutation with him or her.
d. They encountered a new pathogen in the Canadian environment.
4. The first group of Mars settlers arrived on the red planet in 2164. They thrived for several years until
a catastrophic Martian storm killed 50% of the population. The survivors adapted their living spaces
so that the Storms no longer threatened them. However, they noticed that descendants of the survivors
had significantly less genetic diversity than the original sealers. What might cause this?
a. Founder effect
b. Generic drift
c. Homozygosity
d. Population bottleneck
5. What is true of people whose ancestors came from the same geographic area?
a. They belong to the same race.
b. They have similar hair and eye color.
c. They have some genetic similarities.
d. They will have nothing in common.

CASE STUDY

Sarah and her husband Ari are of Ashkenazi Jewish descent. They married 2 years ago and are now ready
to start a family. Sarah says that she wants to have genetic testing done to see if she and Ari are carri-
ers of Tay-Sachs disease. Sarah has a cousin with Tay-Sachs, and she does not want her children to be
affected. She knows that people of Ashkenazi Jewish descent are at a higher risk of getting several genetic
diseases, but she does not understand why.
1. How would you explain to Sarah why people of Ashkenazi Jewish descent are more likely to get
certain recessive diseases?
2. Which diseases are most common in this population?
3. Would you suggest that Sarah and Ari get direct-to-consumer genetic testing to see if they are
carriers?
4. What would be the role of genetics professionals in caring for this couple?

References
American Heart Association. (2015). \WJfltAbo lit AfriclIll AIIlt'TiCIIIH and high blood pr=IIIl,?Retrieved from http://www.heart.org/
idclgroups/heart-publicl@wcm/@hcm/documents/downloadable/ucm_300463.pdf
Behar, D. M., Hammer, M. E, Garrigan, D., Villerns, R., Bonne-Tamir, B., Richards, M., ... Skorecki, K. (2004). MtDNA
evidence for a genetic bottleneck in the early history of the Ashkenazi Jewish population. European JOIlr/JIII of Human Genet-
ics, 12(5),355-364.

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398 Unit VI Global Genomic Issues

Collins, F. S. (2004). What we do and don't know abour "race," "erhniciry," genecics and health at the dawn of the genome era.
Nature Genaics, 36(Suppl. II), SI3-S15.
National Genographic Project. (2016). Map ofJmman migration. Retrieved from htrps:llgenographic.nationalgeographic.coml
human-journeyl
National Human Genome Research Inscirure. (2012). About the International HapMap Project. Retrieved from Imps:1I
www.genome.gov/I1511175/about-the-international-hapmap-project-fact-sheetl
National Human Genome ResearchInsrirure, (2015). Gmetic oanationprogmm5.Retrieved ITomlmps:llwww.genome.govIl00015511
Ridley, M. (2003). Euolutian. Hoboken, NJ: Wiley-Blackwell.
Royal, C. D., & Dunston, G. M. (2004). Changing the paradigm from "race" to human genome variation. Nature Generic»,
36(Suppl. II), S5-S7
Seal Conservation Sociery. (2011). TJ~ northern elephalll seal. Retrieved from htrp:llwww.pinnipeds.org/seal-information/
species-information-pages/the-phocid-seals/norrhern-elephanr-seal
Tishkofl, S. A., & Verrelli B. C. (2003). Parrerns of human genetic diversity: Implications for human evolutionary history and
disease. Annual Reuieu:ofGmomics and Hnman Gmerics, 4, 293-340.
Understanding Evolution: Borrlenecks and founder effects. (2008). Univenity of California Museum of Paleontology.Retrieved
from http://evol urion.berkeley.edu/evolibrary/arcicle/borclenecks_OI
Wilson, G. N. (2000). Clinical gmuics. New York, NY: Wiley & Sons.

Self-Assessment Answers
I. b 2. a 3. c 4. d 5. c

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 Genetics Organizations and Support Groups

SUPPORT GROUPS

The Genetic Alliance

hnp:/ /www.geneticalliance.org/
A health advocacy organization that includes resources such as the Advocacy Atlas, which provides patients
and families with tools they can use to help their voices be heard.

Genetic Counseling, Support and Advocacy Groups Online

https://www.genome.govIl1510370/
This list is provided by the National Human Genome Research Institute (NHGRI)

National Organization for Rare Disorders (NORD)

hnps:/ / rarediseases.org!
An advocacy and resource group specializing in rare and "orphan" diseases.

PROFESSIONAL ORGANIZATIONS

American College of Medical Generics

haps:/ /www.acmg.net/

American Society of Human Genetics

http://www.ashg.org!

International Society of Nurses in Genetics

http://www.isong.org/

National Society of Generic Counselors

http://www.nsgc.org/

399

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 Selected Educational Websites

DNA from the Beginning

hrrp:1Idnafrb.org/1 I
This sire provides the basics of genetics and includes animation, images, and video interviews.

DNA Learning Center

http://www.dnai .orgl
Resources from Cold Spring Harbor Laboratory, induding activities for teaching genetics.

Gene Reviews
https:1Iwww.ncbi.nlm.nih.gov/gtr/
From the National Library of Medicine and the University of Washington, this site provides access to correct,
expert-authored reviews of educational and genetic disease resources.

Genetics Education Program for Nurses (GEPN) from Cincinnati Children's Hospital Medical Center
https:1I www.cincinnatichitdrens.orgleducation/clinical/nursinglgenetics
Continuing education modules are provided for genetics education, including self-paced instruction modules
and an l8-week online genetic institute.

Generics Home Reference

https:llghr.nlm.nih.gov/
Information about understanding genetics disorders is targeted to patients and their families.

Genetics Science Learning Center

http://iearn.genetics.utah.edu/
This site offers many resources, such as explanations of how genetic traits are passed in families and how
protein synthesis occurs.

My Family Health Portrait

h ttps:1Ifamilyhisrory.hhs.gov/FHH/htmllindex. hrrnl
This family history data-collection tool is from the Department of Health and Human Services.

Public Health Genomics

https:llwww.cdc.gov/genomlcsl
This site provides resources &om the Centers for Disease Control and Prevention that focus on public health
genomlcs.

400

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 Appendix B 401

The Genetics of Cancer

h ttpS :11 www.cancer.gov/about-cancer!causes-prevention!genetics
Tutorials on understanding a wide variety of content related to cancer genetics are offered.

The Jackson Laboratory

httpS :11 www.jax.orgl educa ti on-and -leaeninglc1inical-and-con tin uing-educa tion#
This site offers extensive educational resources, including those from the National Coalition of Healthcare
Professions in Genetics.

The National Human Genome Research Institute (NHGRI)

h ttps:llwww.genome.gov/l0000002/educationl
Offers a wide variety of educational resources, including resources for teachers.

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 G Los sa I_y __ ---'

0'.-1 Antitrypsin defi- Lack of a protein causing symptoms associated with an increased risk for Chronic
ciency (AATD) Obstructive Pulmonary Disease (COPD).

Absorption The entering of a drug from its route of administration into the bloodstream

Achondroplasia A monogenic disorder of human dwarfism that occurs as a result of a mutation

in the gene that codes for the fibroblast growth facror receptor 3 (FGFR 3)
Acquired disease A disease that did nor appear at birth. Some acquired diseases are nor present in
other family members

Adenosine triphos- The high-energy chemical that is a very common source of energy used to drive
phate (ATP) cellular actions and reactions

Advanced-practice A nurse with graduate education and experience in the specialty of advanced
nurse in genetics genetics nursing
(APNG)

Age-related macular A common disease of the eye that affects the macula, the area of the eye allowing
degeneration (AMD) persons to see fine detail. Damage to the macula, a spot close to the center of the
retina, causes blurring of the central vision needed for activities viewed straight
ahead such as reading, sewing and driving

Agonist A drug that binds tightly and functionally to a cell receptor, increasing the
expected function of the cell (tissue or organ)
Agouti (Avy) gene A gene carried by all mammals. Mice carrying tWO copies of the dominant agouti
alleles are yellow and obese, but Avy can be methylated (or turned off) to varying
degrees, resulting in variations in color and body weight

Allele An alternative or variable form of a gene at a specific chromosome locarion

Alzheimer disease The most common cause of dementia among the elderly
(AD)
Anaplastic A cellular appearance or morphology that is without a specific shape or
differentiation (usually small and round with a large nuclear-ro-cyroplasmic ratio)

Analytic validity The extent to which a generic test is accurate and reliable

Androgen insensitivity A person with the generic makeup of a man (XY chromosomes) who is resistant
syndrome (AIS) to androgens (male hormones). This causes physical traits (phenotype) of a
woman but genotype of a male

Aneuploid A cell's nucleus that COntains either more chromosomes than the normal diploid
number for the species or less chromosomes than the normal diploid number for
the species
402

ERRNVPHGLFRVRUJ
 Glossary 403

Antagonist A drug that binds incorreccly (nonfunctionally) to a cell receptor, acting in

opposition to a natural agonist and inhibiting me expected cell function by
preventing receptor interaction with agonist substances

Anticipation A genetic syndrome passed from generation to generation with me symptoms

occurring at an earlier age in the next generation. The severity of symptoms also
seems to increase. Typically caused by a trinucleotide repeat expansion

Anticodon The tRNA complementary code for an amino acid codon

Apoptosis Programmed cell death (cellular suicide)

Arrhythmogenic right A structural alteration in the heart muscle that makes the heart much more likely
ventric ular dyspla- to experience ventricular tachycardia
sia cardiomyopathy
~ARVD/C)
Association When multiple anomalies often occur together but are not known to be either
syndromes or sequences

Assortative mating Selecting a mate based on whether you have characteristics that are similar to or
dissimilar from him or her

Asthma A chronic disease of the airways mat is characterized by intermittent reversible

airflow obstruction

Atrial fibrillation An irregular heartbeat associated with quivering and resulting in diminished
pumping of blood to other tissues in the body. This results in a variety of
symptoms, depending on the tissue affected, such as dizziness, fainting, weakness,
fatigue, and shortness of bream

Autism A behavioral pattern in which a person has difficulty with social interactions and
the developmenr of language, often accompanied by a narrow range of repetitive
behaviors and interests

Autism spectrum Developmental problems that seem Likeautism but do not meet the threshold for
disorders ~ASDs) diagnosis as a pervasive developmental disorder

Autoimmune disease A condit jon of immune excess in which components of a person's immune
system no longer recognize the person's own cells, tissues, and organs as "self"
and attack them as if they were invading organisms

Autonomy The ethical principle of respecting a person's right to make his or her own
choices

Autosomes The 22 pairs of human chromosomes that do not code for the sexual
differentiation of the individual

Balanced A chromosomal translocation in which the right amount of DNA is presenr

translocation (no more and no less), but it is not located in its customary place

Base pairs Nucleorides (one purine and one pyrimidine) mat pair up loosely together when
DNA is double-stranded

ERRNVPHGLFRVRUJ
404 Glossary

Bases The four nucleoproteins that form the essential nitrogen-containing components
of DNA (adenine, cytosine, guanine, thymine)

Behavioral genetics The study of the way our genomes inAuence our behaviors

Behavioral phenotype Demonstrating the behaviors commonly associated with a particular disorder
Beneficence The ethical principle of making decisions based on what is considered "good" or
of the most benefit to others
Benign tumor A type of neoplastic cell growth that grows by expansion and does not invade
Bioavailability The amount of an administered drug dose that actually reaches the bloodstream,
regardless of the method of administration
Biologically plausible A situation in which it seems likely that a gene that has been associated with a
disorder could be involved, given the function of the protein the gene encodes
Bipotential gonad The early embryonic tissue that has the potential to develop into a testis or an
ovary, depending on which hormones and other factors inAuence it

Brachydactyly Fingers or toes that are unusually short compared to the palm of the hand or the
foot

Cancer Unregulated cell growth that has no useful purpose, is invasive, and that would
lead to death without intervention. Also known as malignancy

Canthus The angle that is formed by the meeting of the upper and lower eyelids. The
inner canthus is closest to the nose and the outer canthus is closest to the ears

Carcinogen Any substance or event that can damage a normal cell's DNA and lead ro cancer
development

Cardiomyopathy A primary disease of the heart muscle

Carrier A person who is heterozygous for an autosomal recessive gene allele and does not
fully express the trait or disorder but can transmit the allele to his or her children

Carrier testing Genetic testing done in persons who are nor affected by but suspect they have
genetic risk for a condition they could pass on to their children
Cell adhesion mol- A family of cell surface proreins that allow normal cells to adhere tighrly together
ecules (CAMs) and not migrate out of a specific tissue or organ. Also known as CAMs
Cell-free DNA (etONA) DNA that freely circulates briefly in the bloodstream. When derived from the
placenta it can be used for prenatal testing.

Centromere The pinched area of a chromosome where the two chromatids are connected

Certified genetic A genetics professional who has a master's degree in genetic counseling from
counselor (CGC) a graduate program accredited by the American Board of Genetic Counselors
(ABGC)

Channelopathy A disorder caused by a variation in a gene coding for an ion channel

ERRNVPHGLFRVRUJ
 Glossary 405

Chromatid The longitudinal half of a metaphase chromosome (split through the

centromere), including its p arm and q arm
Chromosome A temporary but consistent state of condensed DNA structure formed for the
purpose of cell division
Classic hemophilia A monogenic disorder in which the production of blood-clotting factor VIII is
either absent or greatly below normal

Cleft lip/palate A malformation caused by the failure of the lip and/or palate tissues to fuse
during development

Clinical geneticist A physician who first completes residency training in pediatrics, obstetrics,
internal medicine, or another related medical specialty and then is board certified
by the American Board of Medical Genetics and Genomics (ABMGG) after
completing a 3-year residency in an ABMGG-approved clinical genetics program
Clinical laboratory A docrorally prepared individual who has completed a 24-month specialty
geneticist fellowship in cytogenetics, molecular genetics, or biochemical genetics and
is certified in one of these subspecialries by the American Board of Medical
Genetics and Genomics (ABMGG)

Clinical utility The extent to which a genetic test is medically meaningful

Clinical validity The extent to which a genetic (est will improve healrhcare

Clinodactyly A laterally curved digit

Codominant A single gene trait in which TWO different dominant gene alleles are both
expression expressed equally

Codominant trait A single gene rrair in which TWO different dominant gene alleles are both
expressed equally

Codon A specific RNA base sequence conraining the complemen cary code to each amino
acid's DNA triplet

Collagen A group of glycoprotein fibers that forms the major component of the connective
tissue found in nearly all body tissues

Complementary pairs Nitrogenous bases that normally pair using hydrogen bonds. Adenine and
thymine are a complemenrary pair, and cytosine and guanine are the other
complementary pair

Complex disorders Multifactorial disorders that do not follow a predictive pattern of inheritance or
have a single generic cause

Complex traits Traits that are caused by several genes working together (polygenic) and/or a
combination of genes and environment. (Also known as multifactorial traits and
diseases)

Compound Presence of a different recessive mutation on each allele of one gene

hete rozygous

ERRNVPHGLFRVRUJ
406 Glossary

Congenital anomalies Defects that are present at birth

Contact inhibition of The inhibition of normal cells to undergo mitosis when membranes are
mitosis completely contacred with the membranes of other cells

Copy-number variants Variations in stretches of DNA found throughout the genome. These are often
(CNVs) either deletions or duplications

Coronary artery A disease caused by a waxy build up of cholesterol-containing plaque in the

disease (CAD) also major vessels. Because these coronary arteries supply the heart with oxygen and
known as Coronary nutrients, there is diminished blood Row causing angina, shortness of breath, and
heart disease (CHD) potentially a heart attack
Craniofa cial Variations from the usual formation of the skull and face
anomalies
Craniosynostosis A distortion in the shape of the skull that occurs when more than one of the
cranial sutures fuses together earlier than it should

Cyclins A family of proteins that, when active, stimulate the cell to move through the cell
cycle and complete cell division
Cystic fibrosis (CF) A monogenic disorder with autosomal recessive expression in which the CTFR
gene has one or more mutations that result in problems with the transmembrane
transport of chloride

Cytogenetic testing A "chromosome study" that looks for variations in the number and structure of
chromosomes from a cell's nucleus

Cytokinesis The separating of a cell at the M phase of the cell cycle into two new cells such
that each have a complete set of chromosomes

De novo mutation A new mutation that has not previously been found in the family members of
the proband

Deformation A defect in the shape or form of a body part that is due to compression from
mechanical forces

Deoxyribonucleic acid The basic genetic chemical structure, containing gene coding regions and
(DNA) noncoding regions, that can be compacted into a chromosome form

Developmental The ability of the environment to cause different phenotypes from the same
plasticity genotype
Developmental Period of time during which having toO little or toO much food could result
window in epigenetic changes that cause disease, both in the person affected and their
offspring

Diabetes mellitus A type of diabetes mellitus where the pancreas produces little or no insulin,
type 1 which is needed to assist glucose (sugar) to enter into cells for energy production.
The disorder is sometimes called juvenile diabetes or insulin-dependent diabetes.
It is a chronic illness with no cure but can be managed

Diagnostic testing Testing done to confirm or refute a particular diagnosis in a symptomatic person

ERRNVPHGLFRVRUJ
 Glossary 407

Differentiation The process by which a cell leaves me pluripotent stage and acquires the
maturational features and functions of a specific cell type
Diploid chromosome The complete set of chromosome pairs found in all of an individual's somatic
number cells (23 pairs (2Nj of human chromosomes, 46 chromosomes alcogether)
Direct-to-consumer Genetic testing that is offered directly to individuals. There is typically no input,
(DIG) genetic testing recommendation, or follow-up by a genetics professional

Disruption A defect in the shape or form of a body part that is due to a disturbance in the
normal developmental process

DNA antisense strand The single Strand of DNA exactly opposite me sense strand mat contains me
complementary base sequence to the gene, not me actual gene itself. It is used as
a template for RNA transcription. Same as antisense DNA

DNA coding region An area of DNA mat contains many genes that generally have the same base
sequences from one person to anomer

DNA noncoding A section of DNA containing multiple repeat sequences that is not composed of
region genes and does nor code for specific proteins
DNA replication A duplication or reproduction of one cell's DNA during cell division resulting in
two identical sets of DNA

DNA sense strand One strand of double-stranded DNA that contains me actual gene coding
sequence for me protein to be synthesized. Same as sense DNA

DNA sequencing Testing that consists of analyzing and reporting the order of bases in a stretch of
DNA. It is me most specific and accurate test for base sequence variation

DNA synthesis Formation of molecules of natural or artificial deoxyribonucleic acid (DNA)

DNA triplet The exact three-nucleotide base sequences mat code for a specific amino acid

Dominant trait A single gene trait mat is expressed regardless of whether the two gene alleles are
identical (homozygous) or difFerenr (heterozygous)

Driver mutation A mutation wi min a gene mat provides selective growth advantage resulting in a
cancer

Duchenne muscular A monogenic disorder of progressive muscle weakness caused by anyone of a

dystrophy (DMD) variety of mutations in an allele of me DMD gene, which codes for the protein
dystro ph in

Dutch hunger winter Period of time from 1944 to 1945 when food was extremely scarce in the
Netherlands
Duty to warn The ethical obligation of a health-care professional to inform a patient or his or
her family members they are at risk for a disease

Dysmorphology The study of congenital anomalies in the anatomical form or body parts of a
person or abnormal patterns of development

Dysplasia An alteration in me size, shape, and organization of ceLIs

ERRNVPHGLFRVRUJ
408 Glossary

Dystrophin A structural protein that functions co maintain the integrity of skeletal, cardiac,
and smooth muscles
Ehlers-Danlos A group of differem inherited disorders that occur as a result of mutations in
syndrome collagen formation or modification
Elimination The inactivation and final removal of drugs from the body

Enterohepatic A circulatory detour in which venous blood drained from the entire
circulation gastroimestinal tract enters liver circulation before emering the systemic
circulation

Enzyme A biological catalyst that causes a biochemical reaction to occur or increases the
rate of a biochemical reaction within a cell, body tissue, or organ

Enzyme-replacement The actual replacement of a missing or malfunctioning enzyme with one that has
therapy (ERT) been generated artificially
Epicanthic folds A fold of skin that partially or completely covers the inner canthus of the eye

Epigenetics The study of specific alterations of gene expression, which can be inherited but
are not changes in DNA sequence

Epigenomics A broader term than epigenetics; refers to the study of heritable changes in the
ways that genes are expressed, without changes in DNA sequence

Epistasis The process of gene-to-gene interaction

Ethical, legal, and The portion of the Human Genome Project that focuses on the ethical, legal,
social issues (ELSI) and social issues that come with advances in genetics

Ethnicity Quality claimed by a group of people who identify with each other and believe
that they share a common cultural heritage

Eugenics A program to "improve" the human race by the selective breeding of people
considered to have "good genes"

Euploid A cell nucleus containing the normal diploid number of chromosomes for the
species

Evolution Changes in allele frequency in a population over rime

Founder effect The reduction in genetic variability that comes from the separation of a
population subgroup and the reproduction of that less diverse subgroup

Executive fun ctions Those behavioral functions associated with prefrontal lobe brain activity,
including problem solving, impulse conrrol, planning, and goal-directed actions
Exome-wide sequenc- A laboratory technique used to sequence all of the exons (coding sequences)
ing (whole-exome within a genome
sequencing, WES or
WXS)

ERRNVPHGLFRVRUJ
 Glossary 409

Exons The sectional parts of DNA within a gene-coding region that actually belong in
the gene-coding sequence for a specific protein
Expansion disorder Group of disorders caused by unstable trinucleotide repeats (rnicrosarellite
repeats) that exceed the normal, stable threshold that differs with each gene
Expressivity The degree of trait expression a person has when a dominant gene is present

Externalizing The idea that conduct disorders, such as antisocial personality disorder and
psychopathology addictive behaviors, share both common and unique causes

F generations The succeeding generations of offspring or progeny produced from the parental
generation. Each succeeding generation is designated by a numeric subscript
(FI> F2, F3, etc.)

Fabry disease An X-linked recessive generic lysosomal storage disease in which there is
a deficiency of the enzyme alpha-galactosidase A (also known as ceramide
trihexosidase), which results in the accumulation of globorriaosylcerarnide
(GL-3) within the Iysosomes of many tissues and organs

Factor V Leiden A genetic disorder that results in increased risk for blood clots
Familial cancer Cancer that occurs at a higher-than-expected frequency within a kindred but
does not demonstrate any observable pattern of inheritance

Familial dilated car- A genetic disease that results in weakening and distending of the heart muscle,
diomyopathy (OCM) leading to ineffective pumping

Familial hypercholes- A single-gene disorder that follows an autosomal-dominant transmission pattern

terolemia (FH) and causes very high blood cholesterol levels, which greatly increases a person's
risk of myocardial infarction

Familial hypertro- A genetic disease that results in a thickening of the heart muscle wall and
phic cardiomyopathy possible obstruction to outflow of blood from the ventricle
(HCM)
Fertilization The union of one mature haploid sperm with one marure haploid ovwn to form
a diploid zygote

Fibrillin A glycoprotein that assembles into long strands of microfibrils and is an essential
component of specific connective tissues, especially those that respond by
stretching when a force is applied

Financial, ethical, The portion of the Human Genome Project that focuses on the financial
lega I, and soc ial implications of the ethical, legal, and social issues that come with advances in
issues (FELSI) genetics

First-pass loss The rapid liver metabolism and elimination of enteral drugs that are absorbed
inro the enreroheparic circulation before entering the systemic circulation

Fluorescence in situ A test that creates a fluorescencly dyed segment of nucleic acids that bind to
hybridization (FISH) complementary regions on DNA or mRNA

ERRNVPHGLFRVRUJ
410 Glossary

Fragile X syndrome A condition with varying degrees of physical and behavioral problems with reduced
(FXS) intellectual ability resulting from large numbers of trinucleotide repeat sequences
silencing the expression of the FMRJ (fragile X mental retardation J) gene

Frameshift mutations Disruptions of the DNA reading frame as a result of having a whole base or
group of bases added or deleted
Frontal bossing An unusual forehead with bilateral bulging of the frontal bone prominences

Gametes Mature, haploid, specialized germ cells (ova and sperm) capable of fertilization
into a zygote

Gametogenesis The conversion of diploid germ cells into haploid gametes that are capable of
unIting at conceptIon to start a new person

Gaucher disease An autosomal-recessive genetic lysosomal storage disease in which there is a

deficiency of the enzyme beta-glucosidase, which results in the accumulation of
glucosylceramide (also called gLucocerebroside) in macrophages and some other
mononuclear white blood cells

Gene A specific set of instructions cells use to produce a specific protein

Gene expression The activation of a gene leading to the transcription, translation, and synthesis of
a specific protein

Gene locus Specific chromosome location of an individual gene

Gene pool The combination of all the alleles in all the genes in all the people in a given
population

Gene therapy The process of inserting a gene or a modified gene into a patient's cell(s) to treat
or prevent a disease

Genetic anthropology The study of human ancestry and migration patterns using a combination of
DNA and physical evidence

Genetic counseling The process of helping people understand and adapt to the medical,
psychological, and familial implications of the genetic contribution to disease
occurrence or recurrence

Genetic drift Changes in allele frequency in a population that are due to chance

Genetic heterogeneity The situation in which several different genes can independently cause disease

Genetic information The information protected under GINA. This includes a person's genetic test
results and the genetic test results of his or her family members

Genetic Information The Genetic Information and Nondiscrimination Act, signed into U.S. law on
Nondiscrimination Act May 21, 2008. Protects personal genetic information and prevents discrimination
(GINA) related to health care and employment

Genetic resistance Having one or more gene variations that are protective and decrease the risk for
disease development or expression

ERRNVPHGLFRVRUJ
 Glossary 411

Genetic susceptibility Having one or more gene variations that increase the risk for disease expression

Genetic testing The analysis of DNA, RNA, chromosomes, proteins, and protein metabolites to
identify heritable genotypes, mutations, phenotypes, or karyorypes

Genetics The study of the general mechanisms of heredity and the variation of inherited
traits

Genetics clinical A genetics nurse with an AD or BSN level of education. The nurses perform
nurse (GCN) risk assessments, analyze the contribution of genetics to the possibility of disease
development, and educate patients and family about management of the disorder

Genome The complete set of genes for the species

Genome-wide asso- A test that looks for areas of the genome associated with a certain disease by
ciation study (GWAS) comparing the genomes of affected and unaffected populations

Genomic care Ensuring that the inAuence of a person's genetic history on health and disease is
considered as pan of general assessment information for all patients and families

Genomic imprinting An epigenetic event in which a gene (or gene allele) is inactivated by means other
than mutation so that the DNA sequence of the gene remains normal, but its
expression is inhibited

Genomics The study of the function of all the nucleotide sequences present within the
entire genome of a species, including genes and nongene areas of the DNA

Genotype The exact allele pair composition present for any given single-gene trait

Germline mutation A mutation that occurs in germ ceLis(sperm or ova) and can be passed on ro
one's children at conception

Gestalt The overall impression of a person's appearance

Gestational diabetes A disorder involving elevated blood sugar levels that is diagnosed as diabetes
mellitus (GDM) mellitus during pregnancy

Haploid chromosome A set of chromosomes in a germ cell's nucleus that consist of only half of each
number chromosome pair, 23 chromosomes (lN)

Haplotypes Groups of genes that tend to be inherited together

Hardy-Weinberg The idea that the frequency of alleles (and genotypes) in a population will remain
equilibrium the same as long as certain population criteria are met. It is demonstrated by the
equation: l r/
+ 2pq + = 1
Hemizygosity The expression in males of recessive single alleles on the X chromosome as if they
were all dominant

Hereditary hemochro- An autosomal-recessive disease that results in excessive absorption of dietary iron
matosis (HFE-HHC) by the gastric mucosa

Heteroplasmy A condition in which a newly produced daughter cell inherits mitochondria with
a mixture of normal mtONA and mutated mtDNA

ERRNVPHGLFRVRUJ
412 Glossary

Heterozygosity The proportion of a population who are heterozygous at a particular locus. If

98% of all alleles in a population are A, then heterozygosity will be low
Heterozygous Having rwo different gene alleles for a specific single-gene trait

Histones Globular protein balls that allow DNA to supercoil and compress tightly into
dense chromosome structures without damaging or disorganizing the order of
base pairs

Histone modification Changes to the proteins around which the DNA double helix winds
Homoplasmy A condition in which a newly produced daughter cell inherits mitochondria that
have either all normal mtDNA or all mutated mtDNA
Homozygous Having twO identical gene alleles for a specific single-gene trait

Human genetic The generic diversity within and between groups of people
variation
Human leukocyte Unique identifiers on the surface of most body cells
antigens (HLA)
Hunter syndrome An X-linked recessive genetic lysosomal stOrage disease in which there is a
deficiency of the enzyme iduronate sulfatase, which results in the accumulation
of mucopolysaccharides (MPSs) within the lysosomes of many tissues and organs.
Also known as mucopolysaccharidosis II

Hurler syndrome An autosomal-recessive genetic lysosomal storage disease in which there is a

deficiency of the enzyme alpha L-iduronidase, which results in the accumulation
of mucopolysaccharides (MPSs) in the lysosomes of most cells. Also known as
mucopolysacchnridosis I
Hyperaminoacidemia Anyone of several metabolic disorders in which one particular amino acid
accumulates in the blood to toxic levels

Hyperglycemia An elevated blood glucose level

Hyperplasia Mitotic cell growth in which the tissue/organ increases in size by increasing the
number of cells within it

Hypertelorism Eyes that are spaced widely apart

Hypertro phy The increase in tissue size from the expansion of the size of each individual cell
rather than by the generation of new cells that increase the number of cells in the
tissue

Hypotelorism Eyes that are spaced closely rogerher

Inherited cancer Cancer that occurs with an observable autosomal-dominant pattern of

inheritance among much-younger-than-expected individuals in a kindred

Initiation The first and irreversible step in malignant transformation that involves damage
to a cell's DNA, especially in suppressor genes, which leads to the reduced
expression of suppressor genes and the enhanced expression of oncogenes

ERRNVPHGLFRVRUJ
 Glossary 413

Insulitis An infiltration of the islet cells by white blood cells following a viral infection,
resulting in inAammation and destruction of these cells
Intellectual property Creative innovations and inventions that belong to the creator or inventor

Intended action The desired and expected change in the function of one or more tissues or organs
as a result of drug therapy. Same as therapeutic effect

Introns The sectional parts of DNA within a gene-coding region that do not belong to
the gene-coding sequence of the protein being synthesized
Jervell and Lange- A phenotype of LQTS that is transmitted as an autosomal recessive trait and
Nielsen syndrome includes sensorineural deafness
Karyotype An organized arrangement of all the chromosomes within one cell during the
metaphase section of mitosis
Kindred Extended family relationships over several generations. Same as kinship

Klinefelter syndrome A boy that is born with at least one extra X chromosome causing unusual
physical characteristics in males

Knockout mice Mice that are bred, using genetic engineering. with one or several genes "turned
off" (knocked out)

Laboratory-developed The design, manufacture. and use of an in vitro diagnostic test by only one
test (LOT) laboratory

Latency period The time between the initiation of a cell and the development of an identifiable
tumor

Liability model An estimate of the risk of experiencing a complex disease based on the number
of risk alleles in a kindred

Lip pits A depression in the lower lip that is usually lateral to the midline

Long fingers/toes Fingers or toes that are unusually long compared to the size of the palm or the
foot

Long OT syndrome A congenital or acquired disorder in which the phenotype shows lengthening of
(LOTS) the refractory period of the cardiac cycle and vulnerability to a potentially lethal
ventricular arrhythmia

Low-set ears The upper ears insert into the scalp below an imaginary horizontal line drawn
through the inner canthi of the eyes and going back to the ears

Lysosomal storage A disorder in which the enzyme within Iysosomes is defective or deficient,
disease causing the buildup of a precursor substance that becomes toxic to the cell

Lysosomes Intracellular vesicles that contain many enzymes whose function is to degrade the
protein and lipid by-products of metabolism

Macrocephaly An unusually large head in proportion to the body

ERRNVPHGLFRVRUJ
414 Glossary

Major anomaly A significant abnormality for which surgery would often be recommended to
treat a significant impairment of physical function or appearance
Malformation A defect in the shape or form of a body pan that is caused by an abnormal
developmental process
Malignant The many-stepped process by which a normal cell changes into a cancer cell.
transformation Also known as carcinogenesis and oncogenesis

Marfan syndrome An inherited genetic connective-tissue disorder in which the gene for the
(MFS) glycoprotein fibrillin is mutated

Maturity-onset dia- A single-gene disorder that causes hyperglycemia, usually before the age of 25
betes of the young
(MODY)
Medical geneticist A genetic professional with a doctorate (PhD), most commonly in population
genetics or epidemiology

Meiosis The process of chromosomal reduction cell divisions required during

gametogenesis to ensure that gametes are haploid
Meiotic cell division A special type of cell division in which the chromosome number per cell is
reduced to half .

Mendelian inheritance The patterns of inheritance for monogenic traits as first recognized by Gregor
Mendel in the 19th century

Metabolism Chemical reactions in the body that change the chemical shape, size, content,
and activity of the drug

Metastasis The spread of cancer cells to other body areas, via blood, lymphatics or across a
body cavity (rranscoelornic) where they may grow and damage additional tissues
and organs, often leading to death

Methylation The addition of a chemical tag called a methyl group to the cytosine base in the
DNA sequence itself

Microbiome All the microorganisms and their genomes Livingin and on a person

Microcephaly An unusually small head in proportion to the body

Micrognathia A smaller-than-normallength and width of the lower jaw

MicroRNA (miRNA) Elements that bind to messenger RNA, making it double-stranded; this binding
prevents the process of translation

Midface hypoplasia A disproportionately small central face, including the upper jaw, cheeks, and eye
region as compared with the rest of the face

Minimum effective The lowest blood or tissue drug level required to cause the intended action
concentration (MEC)

ERRNVPHGLFRVRUJ
 Glossary 415

Minor anomaly A variation in a body part that may be helpful with diagnosis but is not a threat
to the person's well-being (e.g., low-set ears)

Mitochondria Organelles within a cell's cytoplasm that are responsible for most of the
generation of the high-energy chemical adenosine triphosphate (ATP)
Mitochondrial DNA DNA located in the mitochondria, structures within the cell that convert energy
~mtDNA) from food into adenorriphosphace (ATP)

Mitosis A duplication cell division that results in twO new cells that are identical both to
each other and ro the original cell (parent cell) that began the mitosis

Modifier genes Genes that are nor the primary cause of the disorder, but their variants alter the
phenotype

Monogenic trait A trait whose expression is determined by the input of the twO alleles of a single
gene. Same as single-gene trait
Monosomy Inheritance of only one chromosome of a pair instead of two

Mosaicism The condition in which rwo (or more) different karyorypes are consistently
present in one individual

Multiple sclerosis A progressive autoimmune disorder that results in damage to the myelin sheath
~MS) of the neurons in the central nervous system

Mutagen Any substance or event that can inAict temporary or permanen t changes in the
normal DNA sequence

Mutation An alteration in the base sequence of DNA or RNA

Natural selection The process by which genetic traits become more or less common based on the
survival advantage they provide

Neoplasia New cell growth not needed for normal development or the replacement of dead
and damaged tissues. It can be benign or malignant

Newborn screening A test done shortly after birth to identify those infants at high risk of diseases for
which immediate treatment or intervention is available

Next-generation A complex, fast-moving new technology that enables an entire genome to be

sequencing sequenced in one day
~high-throughput
sequencing)
Nondirective Providing genetic information and counseling and presenting all facts and
available options in a way that neither promotes nor excludes any decision or
action (within legal boundaries)

Nondisjunction Failure of a chromosome pair to separate during meiosis so that one of the
two new cells is missing a chromosome, and the other new cell has both
chromosomes of the pair from the same parent

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416 Glossary

Nucleokinesis The process occurring in the M phase of cell division in which each chromosome
is pulled apart so that the two sets of chromosomes are separated within the
single large cell

Nucleoside A nitrogenous base of adenine, guanine, cytosine, or thymine attached to a five-

sided sugar (ribose sugar)

Nucleotide A nitrogenous base attached to a five-sided sugar and connected to a phosphate

group
Nutrigenomics The study of the interaction of nutrition and the genome

Oligohydramnios Not having enough amniotic Auid

Oncogenes A former prOtO-oncogene with mutations or increased expression causing it to be
permanently turned on or activated allowing it to grow out of control and lead
to a cancer
Oogenesis The process of forming oocyres from precursor germ cells

Osteogenesis imper- A group of genetic disorders in which collagen formation is impaired, resulting in
fecta (01) bones that fracture easily

Oxidative The metabolic pathway in mitochondria responsible for the efficient generation
phosphorylation of ATP under conditions in which oxygen and hydrogen ions are plentiful

p arm The segment of a chromosome above the centromere, The short arm originally
identified as the petite firm

PI generation The parental generation of a family or group being observed for a specific trait or
trai tS

Palpebral fissure The outlined space between the eyelids of each eye

Passenger mutation A change in a gene that is nonessential to the development and growth of a
cancer

Patents Government protection that gives the owner exdusive rights to keep others from
making or using whatever is patented

Pedigree A pictorial or graphic illustration of family members' places within a kindred and
their history for a specific trait or health problem over several generations

Penetrance How often, within a population, a gene is expressed when it is presem

Personalized medicine Tailoring the therapy to an individual patient's physical and genetic differences

Pharmacodynamics Body responses induced by a drug, induding mechanism of action, desired

effects, and side effects

Pharmacogenetics The use of single-gene information in the study of drug development and drug
therapy

Pharmacogenomics The use of genome-wide information in drug development and drug therapy

ERRNVPHGLFRVRUJ
 Glossary 417

Pharmacokinetics The actions of the body that change the physical and chemical properties of a
drug
Phenotype The observed expression of any given single-gene trait

Phenylketonuria (PKU) An autosomal-recessive genetic disorder in which rhe enzyme phenylalanine

hydroxylase (PAH) is deficient and rhe amino acid phenylalanine cannot be
enzymatically converted to tyrosine, resulting in an excess of phenylalanine and a
deficiency of tyrosine
Philtrum The groove or depression that lies in the midline between the upper lip and rhe
nose
Phosphorylation A chemical reaction in which a phosphate group is added to another chemical
through the action of a tyrosine kinase enzyme. The result of phosphorylation is
activation of rhe chemical
Plagiocephaly Asymmetrical distortion of rhe cranium

Pleiotropy An effect in which a single-gene disorder resulrs in problems expressed in many

tissues and functions

Ploidy The actual number of chromosomes present in a single cell's nucleus at mitosis

Pluripotent cell An undifferentiated early embryonic cell that, under the right conditions, can
become any human body cell

Point mutations Substitutions of one base for another and can occur in DNA or RNA

Po Iydactyly Having an extra finger or toe

Polygenic Inheritance controlled by a group of nonaLieic genes that together control a

quantitative characteristic of an organism. This can include traits, characteristics,
or structures

Polymerase chain A process used [Q amplify (gready increase the quantity of) tiny amounts of
reaction (peR) DNA for examination

Polyploidy Cells and organisms containing more than two paired sets of chromosomes

Population bottleneck The situation rhat occurs when some event severely reduces the number of
individuals in a population. Only rhe traits of those individuals who survive will
be passed on to future generations

Population genetics The study of the changes in the frequency of alleles, and the mechanisms for
those changes, based on alterations in populations

Posttranscri ptiona I A process mat eliminates rhe introns before the mRNA can be translated and
modifi cation used to direct rhe precise synthesis of rhe protein coded for by rhe gene

Posttranslational Further processing of a newly translated primary protein structure into its
modification secondary and tertiary structures (and sometimes even a quaternary structure)
needed to make it fully functional

ERRNVPHGLFRVRUJ
418 Glossary

Precision medicine Treatment of people with similar subgroups of diseases such that tailored therapy
is individualized based on predicted response or risk of disease determined by
genomlCs

Predictive testing Genetic testing designed for asymptomatic persons wanting to know about their
risk of getting a genetic disease in the future
Predispositional Predictive testing that, when positive, means the person being tested has a higher
testing likelihood of getting the disease in the future than the general population
Preimplantation A procedure done in conjunction with in vitro fertilization (IVF), in which six
genetic diagnosis to eight cell embryos are tested for specific genetic variants. Embryos that test
(PGD) negative can be used for IVF
Premutation A gene mutation in a male or female with fewer repeats than the number found
in persons with a [ull-rnurarion disorder. One example is a fragile X carrier with
55 to 200 CGG repeats in the FMRJ gene as opposed to a full mutation with
>200 CGG repeats

Prenatal testing Testing done during pregnancy to determine if the fetus carries a gene variant
Presbycusis Age-related hearing loss

Presymptomatic test A predictive test that, when positive, means that the individual will get the
disease at some point in his or her life as long as he or she does not die earlier
from some other means

Primary tumor The original tissue location in which normal cells develop into cancer

Private mutations Mutations that are very uncommon; frequently, they are found in only one
family

Proband The person within a family who brought the potential genetic issue to the
attention of a health-care professional

Prodrug A drug that is ingested as an inactive parenr compound and must undergo
first-stage metabolism to become active

Progression The continuing generic changes that occur in cancer cells that alter their physical,
biochemical. and metabolic processes and confer survival advantages [0 these cells

Promotion A step in cancer development that enhances the growth potential of a cell that
has been initiated

Protein A rnacronurrienr composed of amino acids, which builds and maintains body
tissues. One component of the Central Dogma of Biology

Protein synthesis The selective activation of a gene, resulting in its transcription and translation
into the production of the appropriate protein

Proteome The DNA that codes for the complete set of all proteins that a person can make

Proteomics The study of how protein genes are selectively expressed, how they are modified
after expression, and how they interact with each other

ERRNVPHGLFRVRUJ
 Glossary 419

Proto-oncogene A large group of genes that produce proteins that promote entering and
completing the cell cycle to regulate cell growth and differentiation. Also known
as promnotlc genes

Ptosis Drooping eyelids

Punnett squares Diagrams that are used to determine the risk of offspring being affected when the
mode of transmission and the parents' carrier status are known

q arm The long segment of a chromosome below the centromere. Originally labeled as
"q" because it follows "p" in the alphabet

Race A controversial term that denotes a group of people classified as sharing a

common geographical background, ancestry, and physical features

Receptors Sites on a cell surface or within a cell where naturally occurring substances can
bind and control cell function
Recessive trait A single gene trait that is expressed only when both gene alleles for the trait are
identical (homozygous)

Reciprocal A specific type of balanced translocation in which segments of two

translocation nonhomologous chromosomes break and are equally exchanged

Recurrence risk The risk of another child in a family being affected when one child is already
affected

Regression to the Extremes of a condition or trait tend to become more average over time in
mean successive generations

Replication The random sorting of newly synthesized mirochondria to new daughter cells
segregation
Research geneticist A docrorally prepared (PhD) individual with postdoctoral training in laboratory
genetics whose role is the performance of laboratory or "bench" research to
identify exact pathologic mechanisms that result from various genetic disorders
and to develop possible therapeutic approaches to reduce the effects of the
pathologic mechanisms

Restrictive A rare form of heart disease with stiff and poorly compliant heart muscle causing
cardiomyopathy restrictive filling of the ventricles. The contraction function of the heart is normal
but the relaxation or filling phase is abnormal. This causes back up of the blood
into the atria and symptoms of heart failure

Retrognathia A backward positioning of the lower jaw

Rheumatoid arthritis An autoimmune disorder that results in inRammation of the joints and the
tissues surrounding them

Ribonucleic acid A single strand of nitrogenous bases (adenine, guanine, cytosine, and uracil)
(RNA) constructed during transcription from a segment of DNA containing the gene for
a specific protein

ERRNVPHGLFRVRUJ
420 Glossary

Ribosome A cytoplasmic adapter molecule containing a complex of proteins and RNA that
essentially decodes the mRNA to place the proper individual amino acid into the
peptide chain during protein synthesis
Right to privacy The ethical obligation of health-care professionals to not disclose a patient's
private health-care information

Risk alleles Gene variants that confer increased risk for a particular trait or disorder

Risk stratification The process of identifying whether a person is at a high, moderate, or low risk of
developing a genetic disorder

Robertsonian A specific type of balanced translocation created by the fusion of the entire long
translocation arms of rwo acrocentric chromosomes (which include chromosome numbers 13,
14,15,21,and22)

Romano-Ward A phenotype of LQTS that is transmitted as an autosomal dominant trait and is

syndrome not accompanied by deafness

Segregate During meiosis of an organism, the separation (segregation) of paired alleles so

that a gamete has only one allele
Self-tolerance The ability of the immune system to recognize and not attack the body's own
cells and tissues

Sequence A group of anomalies that are thought to follow in a chain, from a single cause

Sex chromosome Any increases or decreases in the normal number of sex chromosomes
abnormality ~SCA)
Sex chromosomes The pair of chromosomes (XX or XY) that code for the sexual differentiation of
the individual

Sex reversal A condition in which sex genotype and phenotype are mismatched, with
phenotypic women having a 46,XY karyotype and phenotypic men having a
46,XX karyotype

Sickle cell crisis An acute period of low-oxygen tension in which extensive tissue hypoxia/anoxia,
cell sickling, and blood flow obstruction occur, leading to severe pain

Sickle cell disease A monogenetic disorder caused by a single nucleotide polymorphism in both
~SCD) alleles of the HBB gene that results in the abnormal formation of the beta chain
of hemoglobin (beta globin)

Sickle cell trait A monogenic disorder caused by a single nucleotide polymorphism in only one
allele of the HBB gene that results in red blood cells having only 50% or less of
abnormal hemoglobin molecules

Side effects Drug effects that are not the main purpose of the intended action

Signal transduction A set of communication system chains that allows information about events,
conditions, and substances external to the cell to reach the nucleus and influence
whether the cell then divides, undergoes apoprosis, or performs its differenriated
functions

ERRNVPHGLFRVRUJ
 Glossary 421

Single-gene trait A trait whose expression is determined by the input of the two alleles of a single
gene. Same as a monogenic trait
Single-nucleotide A type of point mutation commonly inherited in a gene that alters gene activity
polymorphism (SNP) in a certain percentage of the general population
Somatic mutation A mutation that occurs after conception in general body cells (somatic cells) and
cannot be passed on to one's children

Spermatogenesis The process of converting diploid spermatogonia into mature haploid sperm
Sporadic cancer A cancer that occurs usually as a resulr of environmental exposure and does not
have any observable pattern of inheritance within a kindred
Suppressor genes A set of master control genes that produce proteins that restrict a cell from
entering the cell cycle and that inhibit movement of a cell from one phase to the
next within the cell cycle. Some products of these genes also trigger apoptosis
Syndactyly A condition in which twO or more of the fingers or toes are joined together at
either the soft [issue or bone level

Syndrome A collection of anomalies that are related, most often with a known cause

Systemic lupus ery- An autoimmune disorder that affects multiple systems, including the skin, joints,
thematosus (SLE) and kidneys

Targets Cells with receptor sites that can bind with specific drugs and have a change in
their functional activity as a result of drug binding

Tay-Sachs disease An autosomal-recessive genetic lysosomal storage disorder in which there

is a deficiency of the enzyme beta-hexosaminidase A, which results in the
accumulation of GM2-ganglioside in brain cells

Teratogen A drug, chemical, or condition that can alter the development of an embryo or
fetus, resulting in a birth defect

Therapeutic effect The desired and expected change in the function of one or more tissues or organs
as a result of drug therapy. Same as intended action

Threshold The theoretical point at which genetic liability (number of risk alleles) is great
enough that the disorder is likely to be expressed

Thrombophilia A disorder that increases the risk of blood clots

Transcription The process of making a strand of RNA that is complementary to the DNA
sequence that contains the gene for the protein needed

Transcription factors A variety of prorniroric substances that enter a cell nucleus and signal to the cell
that specific gene transcription or mitosis is needed

Transfer RNA (tRNA) Specialized carrier and transfer molecules that can move an amino acid into
position to be incorporated into a growing peptide chain during protein synthesis

Translation The process of using a mature mRNA molecule as the directions for proper
placement of amino acids in the correct sequence to synthesize a protein

ERRNVPHGLFRVRUJ
422 Glossary

Translocation A chromosomal abnormaliry in which all or pan of a chromosome is transferred

to another nonhomologous chromosome

Transmission The term used to describe how a trait is inherited (passed) from one human
generation to the next
Triploidy The inheritance of an extra copy of each chromosome, resulting in an individual
who has 69 chromosomes per cell instead of 46

Trisomy The inheritance of an extra copy of one chromosome from one parent so that the
cells contain three copies of that chromosome instead of JUSttwO

Tumor of unknown Unusual type of cancer where the cells within the tumor do not resemble the
origin (carcinoma tissue site of the biopsy or have "lost" any markers that resemble other types of
of unknown primary normal tissue
[CUP))
Turner syndrome A disorder of the chromosomes with the lack of some or all of the second sex
chromosome in some or all of the cells. It affects only females

Twin concordance The percentage of time a person is likely to be affected if his or her twin is
affected. Concordance can be reponed for monozygotic or dizygotic twins

Type 1 diabetes An autoimmune metabolic endocrine disorder in which insulin-producing cells

mellitus in the pancreas have been destroyed and the person no longer synthesizes insulin

Tyrosine kinase (TK) A family of enzymes that function to activate other substances through the
process of phosphorylation

Unbalanced The inheritance from one parent of more or less than one copy of a chromosome
translocation or part of a chromosome

Uniparental disomy A condition in which both chromosomes of a pair in a child came from JUStone
(UPD) parent
Uracil A pyrimidine base nearly identical to thymine that is used in place of thymine in
RNA synthesis

von Wille brand A monogenic disorder in which the affected person produces less-than-normal
disease (VWD) amounts of von Wille brand factor (vWf)

Whole-exome See Exome-ioide sequencing

sequencing (WES)
Zygote The single diploid cell formed from fertilization that is capable of developing
into a multi celled embryo

ERRNVPHGLFRVRUJ
INDEX

Page nwnbers followed by f indicate figures; t indicate tables.

Aarskog syndrome, 181 Age-Related Eye Disease Studies (AREDS), 256

Abnormal nasal bridge, 180 Age-related hearing loss (ARHL), 256-257, 257t
ABO blood groups, 18-19, 19r, 158 Agc-relared macular degeneration (AM D), 255-256,
Absorption, in drug response, 348 333
N-Acetylrransferase (NAT), 356 Agonist, 344, 345f
Achondroplasia, 19t, 170, 178, 224-226, 225f-226f Agouti (Ary) gene, 103, 104f
Acquired disease, 272-273 Alburerol (Provenril), 346
Acquired immune deficiency syndrome (AIDS), 35, 295 Alcohol dehydrogenase (ADH), 313
Acute neuronoparhic-infanrile disease, 195 Alcohol dependence, 313-314
Adenine, 6-8, 6f-8f Aldurazyme. Sec Laronidase
Adenosine triphosphate (ATP), 141-142, 144 Allele, 18-20,71-72, 72r
in gametogenesis, 64 frequencies of, 389-390, 392r
in translation, 31 risk alleles in, 86-88, 87f
S-Adenosylmethionine (SAM-e), 104-105, 105r Alzheimer disease (AD), 253-255
Adrenergic ~3 receptor gene (ADRB3) gene, 249 American Academy of Pediatrics (AAP), 240
~-Adrenergic antagonist drug, 344-345 American Board of Generic Counselors (ABGC),
Adult-onset disorders 361-362
age-related hearing loss (ARHL) in, 256-257, 257t American Board of Genetics and Genomics (ABMGG),
age-related macular degeneration (AMD), 255-256 362-363
Alzheimer disease (AD) in, 253-255 American College of Cardiology (ACC), 276-277
a-I antitrypsin deficiency (AATD), 240-241, 242t American Diabetes Association, 245t, 246
autoimmune disorder and, 249-253, 251 f American Heart Association (AHA), 271, 276-277, 395
case study on, 259 Amino acid
chronic obstructive pulmonary disease (COPD) in, in translation, 30-34, 31 f-32f
240-241, 242t triplet code for, 24-26, 25t
complex disorders in, 245-253, 245t-246t, 251 f y-Aminoburyric acid (GABA), 313
diabetes mellitus (DM) in, 245-248, 245t-246t Analytical validity, 331
gestational diabetes mellitus (GDM) in, 248 Anaphase, 15f, 50, 59[.60, 63f, 64
hereditary hemochromatosis (HFE-HHC) in, Anaplastic morphology, 53
242-243 Androgen insensitivity syndrome (AIS), 137
introduction to, 239-240 Androgen receptor (AR) gene, 137
maturity-onset diabetes of young (MODy) in, Aneuploidy, 16
243-245,244t Angelman syndrome, 121-122, 122f, 177t
monogenic. 240-245, 242t, 244t Angiotensinogen converting enzyme inhibitor (ACEl),
multiple sclerosis (MS) in, 252 220
obesity and, 248-249 Angiotensin-receptor blocker (ARB), 207
of older adults, 253-257, 257t Amagonist, 344
rheumatoid arthritis (RA) in, 252-253 Anticipation, in FXS, 138
self-assessment questions on, 258-259 Anri-cirrullinared protein antibody (ACPA), 253
summary on, 257-258 Anti-Mullerian factor (AM F) , 136
systemic lupus erythematosus (SLE) in, 250-251, Antisense strand, of DNA, 27-29, 28f
251f An tisocial personal iry disorder, 3 16
Advanced Genetics Nursing (AGN), 364 n-t Antitrypsin deficiency (AATD), 240-241, 242t
Advanced-practice nurse in generics (APNG), 364 Aplasia cutis congenira (ACC), 179
Adverse reaction (ADR), 342[. 343 Apolipoprorein B-100 (ApoB), 268
Affective disorder, 311-312 Apolipoprorein E (ApoE), 254-255, 266, 271

423

ERRNVPHGLFRVRUJ
424 Index

Apoprosis, 50-52, 51f-52f, 55 environmental contriburions £0, 306-308, 310-313,

Apoproric prorease acrivation facror (Apaf-1), 51 316
Arachnodactyly, 175, 184 generic applications for, 304-306
Arocenrric chromosome, 17-18, 17f-18f genome-wide association srudy (GWAS) in, 303-304,
Arrhythmia, 272-274, 273f 308-312,314,316
Arrhythmogenic righr venrricular dysplasial inrroduccion ro, 303
cardiomyopathy (ARVD/C), 278 personality disorder in, 314-316, 315r
Ashkenazi Jewish generics, 195, 199,299,328, 328r, schizophrenia in, 303-306, 309-31 I, 31 Ot
389,394 self-assessment questions on, 318-319
Association, in congeniral anomalies, 173 substance use disorder in, 312-314
Assorrative mating, 391 summary of. 316
Asthma, 231-234 Behavioral generics, 305-306
Atherosclerosis, 265-268 Behavioral phenotype, 306
Arorvastatin (Lipiror), 349 Beneficence, 378
Aerial fibrillation (AF), 272-273 Benign mutation, 35-36
Arrcnrion-dcficir hyperacriviry disorder (ADH D), 132, Benign rumor, 284-285
308-309 Bcra blocker. See ~-adrenergic anragonisr drug
Auricular pits, 183 Beta globin. See Hemoglobin
Autism spectrum disorder (ASD), 132,306-308, 307r Bioavailabiliry, 348
Autoimmune disease, 227 Biologically plausible, 309
adulr-onser disorder and, 249-253, 251 f Bipolar disorder (BPO), 311
Autonomy, 375 Birth defects, 54-55, 55f
Aurosomal-dominanr (AD) transmission, 74-77, 74f. Blood rype
75r-76r genes of, 18-19, 19r, 158
Autosomal inheritance. See also Gamerogenesis transmission of, 77, 77f
case study on, 128 Borderline personality disorder, 316
genomic imprinting in, 123-124 Brachydacryly, 184
introduction to, 109-110 Brain-derived neurotrophic facror (BONF), 248
monosomy in, I 19 BRCA gene, 38, 52, 90, 381, 394
mosaicism in, 124-126, 126f in cancer development, 297r, 298, 298f
partial chromosomes and, 120-123, 122f-123f in generic resting, 326-327, 334
self-assessment questions on, 127-128 Breast cancer, 292r, 295
swnmary on, 127
rranslocations in, 110-115, 112f-114f Calcium channel
rriploidy in, 119-120 blockers of. 352r, 356
trisomic disorders of. 115-119, 117r-118r, in cardiovascular disease, 273, 278
118f-119f in psychiatric disorders, 308, 312
Autosomal-recessive (AR) transmission, 77-78, 77f-78f Calico car, 81-82, 83f
Cancer
Balanced trasnslocarion, 111-115, 112f-114f benign rumors in, 284-285
Base pairs, 6-8, 6f-8f case study on, 301, 302f
Becker muscular dystrophy (BMD), 218-220 causes and risk in, 291-293, 293f
Bcckwith-Wiedemann syndrome, 124, 175, ceUs of, 286-287
183 epigenerics and, 101-103, 294
Behavioral disorders external factors in, 293-294
affective disorders in, 311-312 familial cancer in, 295, 296f
acrenrion-deficir hyperactivity disorder (ADHD) in, inherited cancer in, 298-299, 298f
308-309 inrroducrion ro, 283-284
aurism in, 306-308, 307r malignant transformation in, 287-291, 288f, 289r
bipolar disorder (BPD) in, 311 merastasis in, 291, 292r

ERRNVPHGLFRVRUJ
 Index 425

personal facrors in, 294-295 Cell adhesion molecule (CAM), 45, 48-53, 48f,
promotion in, 288[, 290 51f-52[, 286, 291
self-assessment questions on, 300-301 Cell cycle
sporadic cancer in, 295, 295f, 296t metaphase (M phase) in, 9-11,9[, I Or, 13-14, 15f,
summary on, 299 47f,50
suppressor gene in, 284-288, 292-295, 293[, 297t, normal progression of, 46-52, 47f-48[, 51f-52f
298 synthesis phase (S phase) 0[, 9-10, 9f, lOt
Canthus, 176, 182 Cell division
Carcinogen, 286 adhesion molecule (CAM) in, 45, 48-53, 48[,
Cardiomyopathy, 274-278, 275[, 275t 51f-52f
Cardiovascular disorders apoprosis and, 50-52, 51f-52f
arrhythmia in, 272-274, 273f commitment in, 54-56, 55f
arrhythmogenic right ventricular dysplasial cyclins in, 47f-48f, 48-51, 51f-52f
cardiomyopathy (ARVD/C) in, 278 deoxyribonucleic acid (DNA) in
atherosclerosis in, 265-268 replication of, 8
atrial fibrillation (AF) in, 272-273 synthesis of, 9-11, 9[, io., II f
cardiomyopathy in, 274-278, 275f, 275t differentiation in, 53-56, 55f
case study 0 n, 280 embryonic cell biology and, 52-56, 53[, 55f
coronary artery disease (CAD) in, 265-268 gametogenesis and, 56-65, 57t, 58f-63f
Factor V Leiden in, 270-271 growth factors in, 48-52, 48f, 51 f-52f
familial dilated cardiomyopathy (DCM) in, 277 introduction to, 44
familial hypercholesterolemia (FH) in, 267-268 in normal cell biology, 44-50, 44[, 47f-48f
familial hypertrophic cardiomyopathy (HCM) in, oncogene in, 46-51, 54-55
274-277,275[' 275t oogenesis and, 57t, 62-65, 62f-63f
hypertension (HTN) in, 271-272 self-assessment questions on, 66-67
introduction to, 265 signal transduction in, 47-52, 48f, 51f-52f
long QT syndrome (LQTS) in, 273-274, 273f spermatogenesis and, 56-62, 57t, 58f-61 f
mitochondrial encephalomyopathy, lactic acidosis, summary on, 65
and srrokelike episodes (MELAS) in, 270 suppressor gene in, 46-52, 48f, 51 f-52f,
self-assessment questions on, 279-280 54-55
Stroke and, 268-271 transcription factors in, 47-52, 48f, 51f-52f
summary on, 278 Cell-free deoxyribonucleic acid (cf DNA), 323
Career, in human genetics, 366, 367t-370t Cell-free fetal deoxyribonucleic acid (cff DNA), 329
Carrier status, 78, 78f Centromere, 15f, 16
Carrier testing, 327-328, 327t-328t Cerebral autosomal-dominant arrerioparhy with
Case study subcortical infarcts and leukoencephalopathy
on adult-onset disorders, 259 (CADASIL), 269
on aurosomal inheritance, 128 Cerezyme. See Imiglucerase
on cancer, 301, 302f Certified genetic counselor (CGC), 361-362
on cardiovascular disorders, 280 Channelopathy, 272
on childhood-onset disorders, 237 Charcor-Marie-Tooth disease, 176
on congenital anomalies, 187 Chest deformity, 206f
on enzyme disorder, 209 Chicago, University of, 245t
on epigenerics, 107 Childhood-onset disorders
on family hisrory, 163-166, 164f-l66f achondroplasia in, 224-226, 225f-22M
on genetic testing. 339 asthma in, 231-234
on psychiatric and behavioral disorders, 318-319 case study on, 237
on sex chromosome inheritance, 149 classic hemophilia in, 220-223, 221f-222f
on social considerations, 385 complex disorders, 226-234, 227t, 230t-23lr
on variation, 397 cystic fibrosis (CF) in, 216-218

ERRNVPHGLFRVRUJ
426 Index

diabetes mellitus rype I in, 226-231, 227t, Cognitive impairment (CI), 17S-176
230t-231 r in adult-onset diseases,253-255
Duchenne musculardystrophy (DMD) in, 218-220, Collagen disorder, 200-207, 20 Ir. 202f, 20M, 20M
219f Collins, Francis, 395
environmental conrriburions ro, 228-229, 233 Colorecral cancer, 292t
introduction ro, 212 Commitment, of embryonic cells, 54-56, 55f
self-assessmentquestions on, 235-237 Complementary base pair, 6-8, M-8f
sickle cell disease (SCD) in, 212-216, 213f-214f, Complex traits, 8S-89, 87f, 88t
215t adult-onset disorders in, 245-2S3, 245t-246t, 2S1f
summary on, 234 childhood-onset disorders in, 226-234, 227t,
von Willebrand disease (VWD) in, 221f, 223-224 230t-231 t
Cholesterol, 266-269 Compound heterozygous,243, 24S
Christmas disease,220-221 Confidentiality, 366
Chromatin, 98f, 99, 240, 294 Congenital anomalies
Chromosomal analysis, 16-18, 17f-18f assessmentof, 173-185, 174f, 177t, 178f, 180f-183f
Chromosomal inheritance. Sec Autosomal inheritance case study on, 187
Chromosome classificationof, 170-172, 171f
crossing over of, 58, 59f-61 f, 63f, 64 clinodacrylyin, 169, 169f, 184
formation of, 13-14, 14f-15f cognitive impairment (CI) in, 175-176
in gametogenesis,56 deformation in, 170-172
Giemsa-banding of, 17-18, 17f disruption in, 171-172, 171f
histone in, 13-14, 14f dysplasiain, 170, 172
introduction to, 4-5, 4f-Sf fetal alcohol spectrum disorder (FASD) in, 173-175,
p arm of, Sf, 16-17, 18f 174f
q arm of, Sf, 16-17, 18f introduction to, 168
sex chromosome of, 17-18, 17f major and minor anomalies of, 169-170, 169f
structure of, 4-S, 4f-5f, 16 malformation in, 170-173
Chronic neuronopathic disease, 195 Pierre-Robinsequence in, 173, 173f, 180-181
Chronic obstructive pulmonary disease(COPD), self-assessmentquestions on, 186
240-241,242t sequence in, 172-173, 172f-173f
Chronic progressiveexternal ophthalmoplegia (CPEO), summary of, 185
145t syndrome in, 172-173, 172f-173f
Cleft lip CCL),168-170, 183-184 Congenital syphilis infection, 180
Cleft palate, 168-173, 173f, l77t, 183-184 Consanguinity, 179-180
Clinical applications, of epigenetics, 10S-106 Copy-number variant (CNV), 303-304, 306, 310,
Clinical geneticist, 362-363 312
Clinicallaborarory geneticist, 363 Corona radiara, 65
Clinical Laboratory Improvement Act (CLIA), Coronary arrety disease (CAD), 265-268
331 Coumadin. SeeWarfarin
Clinical utility, 331 Courr cases,379-380
Clinical validity,331 CoxsackieB4 virus, 228-229
Clinodacryly,169, 169f, 184 Craniofacialanomaly, 179
ClinVar database, 327 Craniosynostosis, 179
Clostridium difficile, 100-10 I Creatine kinase (CK), 219
Codeine, 350, 350f Cri du chat, 121, 176, l77t
Coding region, 26-29, 27f, 30f, 35-39 Crossing over, 58, 59f-61 f, 63f, 64
Codominant expression,73, 73t Cross-pollination, 71-72, 72r-73t
Codominant trait, 19 Cryptorchidism, 137
Codon, 28-33, 29f, 36, 36f Cydin, 47f-48f, 48-51, 51f-52f
Coffin-Lowrydisease, 177t Cydin-dependenr kinase (CDK), 47f, 49-SI

ERRNVPHGLFRVRUJ
 Index 427

Cysric fibrosis (CF), 19r, 73, 75r, 86, 90, 124, 157, rnaruriry-onser diabetes of young (MODY) in,
216-218,327r 243-245, 244t
drug response and, 355 viral infecrion and, 228-229
in generic resting. 328 Diabetes mellitus eype I (DMT I), 226-231, 227t,
Cysric fibrosis rransmembrane conducrance regularor 230t-23It
(eFT!?) gene, 73,216-218,355 Diabetes mellitus eype 2 (DMT2), 90-92, 91 f. 100
Cytochrome P450 (CYP), 37, 305, 348-349, 351-354, Diagnostic and Statistical Manual of Mental Disorders,
352r-354t fifth edition (DSM-SJ, 314
Cyrogeneric testing, 332 Diakinesis, 59f, 60, 64
Cytokinesis, lOr, 14, I sf. 50. See also Cell division Differentiation, 53-56, 55f
Cytoplasm, 3f. lOr Digoxin (Lanoxin), 356
in cell division, 56,60-61, 63f. 64 Dilated cardiomyopathy, 274, 275f, 275r
nuclear-to-cytoplasmic ratio and, 45, 53, 285-286 Dilaudid. See Hydromorphone
prenaral origins of. 142, 143f. 146-147 Diplotene stage, 59f. 60, 63f, 64
and pro rein synthesis, 24f. 30--31, 33 Direct-to-consumer (DTC) diagnostic test, 304, 322,
Cytosine, 6-8, 6f-8f 334
Discrimination, 377-378
Deformation, 170--172 Disease inheritance. See also Aurosomal inheritance
Deletions, of partial chromosomes, 120-123, 122f-123f carrier status in, 78, 78f
De novo mutation, 276 of cystic fibrosis (CF), 73, 75t, 86, 90
Deoxyribonucleic acid (DNA). See also Epigenetics of diabetes mellitus type 2 (DMT2), 90--92,
antisense strand of, 27-29, 28f 91f
base pairs in, 6-8, 6f-8f Mendelian patterns of. 74-76. 75t-76r
chromatin in, 98f. 99, 240, 294 multifactorial traits in, 85-89. 87f, 88t
coding regions of. 26-29, 27f. 30f, 35-39 of neurofibromatosis (NF I). 77
gene in, 3-5, 4f-5f susceptibility and resistance in. 89-92. 91 f-92f
introduction to, 3 Disorders
mutation and, 35-40, 36f adulr-onser
noncoding region of, 26, 29, 33,36, 39 complex disorders of. 245-253. 245t-246t.
replication of, 8-11, 9f, ro., II f, 13t 251f
self-assessment questions on, 21-22 monogenic disorders of. 240-245. 242t. 244t
sense strand of. 27-29, 28f of older adults, 253-257, 257t
sequencing of. 332 arrenrion-deficir hyperactivity disorder (ADHD) in,
supercoiling of, 13, 14f 132,308-309
synrhesis of, 9-11, 9f. lOt, II f autism spectrum disorder (ASD) in, 132, 306-308,
ropoisomcrase and, 13t 307t
triplets of. 25-26, 25 r with autoimmune basis, 227-229, 230t
Deoxyribose sugar, 6, 6f of behavior, 303-316, 307t, 310t, 31St
Department of Energy (DOE), U.S., 375-376 cardiovascular, 265-278, 273f. 275f. 275t
Depression, 305, 311 carrier status in, 78, 78f
Developmental plasticity, 100 childhood-onset
Developmental window, 104 achondroplasia in. 224-226, 225f-226f
Diabetes classic hemophilia in, 220-223, 221 f-222f
adult-onset and, 245-248, 245t-246t complex disorders in, 226-234, 227t, 230t-23I r
clinical manifestations of, 245-246 cystic fibrosis (CF) in, 216-218
clinical resources for, 245, 245t Duchenne muscular dystrophy COMO) in,
diagnosis of, 245, 246t 218-220,219f
genetic contributions of, 246-248 sickle cell disease (SCD) in, 212-216, 213f-214f,
gestational diabetes mellitus (GDM) in, 248 21St
long-term consequences of. 230-231, 231 r von Willebrand disease (VWD) in, 221 f, 223-224

ERRNVPHGLFRVRUJ
428 Index

of collagen,200-207, 201r, 202f, 204f, 20M ELELYSO.SeeTaliglucerase

of enzymes, 191-200, 191f, 192t-193t Elimination, in drug response, 350
of mitochondrial inheritance, 144-146, 14St Ellis-vanCreveld syndrome, 184
psychiatric,303-316, 307t, 310t, 31Sr Embryonic cell biology,52-56, 53f, SSf
Disruption, 171-172, 171f lethality in, 115
Disulfide bridge, 34 X-chromosome inactivation in, 81, 82f
Dizygotic twins, 160, 160f Endari. See Glutamine
Dominanr nair, 19,71-72, 72r Enrerohepatic circulation, 348
Donohue syndrome, 248 Environmental contributions
Double-srranded deoxyribonucleicacid (dsDNA), 6-8, to adult-onset disorders, 241, 242t, 250-253,
6f-8f 255-256
Down syndrome. SeeTrisomy 21 to atherosclerosis,268
Driver mutation, 284 to childhood-onset disorders, 228-229, 233
Drug response nature and nurture in, 103-105, 104f, 105r
generic testing in, 356-357 ro psychiarricdisorders, 306-308, 310-313, 316
genetic variations in, 350-354, 352r-354r Enzyme disorders
introduction to, 341-344, 342f, 343t case srudy on, 209
pharmacodynamics in, 344-346, 345f collagen disorder and, 200-207, 20 Ir, 202f, 204f,
pharmacogenomics (PGx) in, 354-356 20M
pharmacokinetics in, 346-350, 347f, 350f enzyme-replacementtherapy (ERT) in, 196, 200
self-assessmentquestions on, 358-359 Fabry diseasein, 193t, 198-199
summary on, 357 Gaucher diseasein, 193t, 195-196
Duchenne muscular dystrophy (DMD), 218-220, 219f Hunter syndrome in, 193c. 197-198
Duplication, of partial chromosomes, 120-123, Hurler syndrome in, 193t, 196-197
122f-123f hyperaminoacidemiain, 192, 192t
Dutch hunger winter, 96-97, 104 introduction to, 191-192, 191f
Duty to warn, 378-380, 379f lysosomalstorage diseasesin, 192, 193t, 195-199
Dysmorphology phenylketonuria (PKU) in, 192-195, 192t-193t
assessmentof, 173-175, 174f self-assessment questions on, 208-209
cognitive impairment (Cl) and, 175-176, 177( Tay-Sachs diseasein, 193t, 199-200
ear featuresof, 182-183, 183f Enzyme-replacementtherapy (ERT), 196, 200
eye featuresof, 181-182, 182f Epicanthic fold, 168, 177t, 181-182, 183f
facial featuresand, 174f, 180-181, 181f Epicardium, 97
fetal alcohol spectrum disorder (FASD) in, 173-175, Epidermal growth factor (EGF), 48
174f Epigenerics
introduction to, 168 cancer and, 101-103
of joints, 184-185 case study on, 107
major and minor anomalies in, 169-170, 169f future of, 105-106
mouth featuresof, 183-184 histone modification in, 99, 99f
skull featuresand, 179-180 introduction to, 96-97
swnmary on, 185 methylation in, 27f, 98-99, 98f, 102-103,
Dysplasia, 170, 172 104f
Dysrrophin, 218-220, 219f microbiome in, 100-101
micro-ribonucleicacid (miRNA) in, 100
Early-onsetAlzheimerdisease,254 nature and nurture in, 103-105, 104f, 105t
Ears, dysmorphic fearuresof, 182-183, 183f overviewon, 97-98, 98f
Edward syndrome. SeeTrisomy 18 in schizophrenia, 309
Ehlers-Danlossyndrome, 182-184,20 It, 202f, self-assessmentquestions on, 106-107
203-204,270 Epigenome-wideassociationstudy (EWAS),105-106
Elaprase.See Idursulfase Epitherapeuricdrug, 105

ERRNVPHGLFRVRUJ
 Index 429

Erlorinib (Tarceva), 354 First-pass loss, 350

Ethical. legal and social issues (ELSn. 375-376. See Fluorescence in situ hybridization (FISH), 332-333
also Social considerations Fluvastatin (Lescol), 349
Erhniciry; 394-395 Follicle-stimulating hormone (FSH). 132
Eugenics. 376 Food. See Nutrition
Euploidy. 16 Food and Drug Administration (FDA), 331, 336t, 355,
Evolution. 389-390 367t.382
Executive function. 194 Founder effect, 390-391. 393f, 394
Exeter/Peninsula Medical Center. 245t Fragile X mental retardation I (FMRJ) gene. 138
Exon, 29-30. 30f Fragile X syndrome (FXS). 138-140. 139t. 140f, l77t.
whole-exorne sequencing (WES) and. 333--334 380
Expansion, of genes. 138 Frameshifr mutation. 38-39
Expressiviry, 77 Frarernal twins. 160. 160f
Exrernalizing psychopathology. 314 Fronral bossing. 178
Extra X chromosome. 131-132
Eye n-Galacrosidase A (GLA) gene. 198
age-related macular degeneration (AMO) in. Gametogenesis. 56-65. 57r. 58f-63f
255-256 Ganglioside. 199
dysmorphic features of, 181-182. 182f Gaucher disease. 157. 168. 193r. 195-196.394
xanrhelasmas and. 267 Gene. 3--5. 4f-5f
allele and. 18-20
Fabry disease. 193t. 198-199.270 codorninanr trait and. 19
Factor V Leiden, 270-271 dominant trait and. 19
Familial cancer, 295. 296f expression of. 24. 24f
Familial dilated cardiomyopathy (OCM). 277 recessive trait and. 19
Familial hypercholesterolemia (FH). 267-268 single-gene traits and. 18-19. 19t
Familial hypertrophic cardiomyopathy (HCM). Gene expression .• 4. 7. 24. 387. See also Autosomal
274-277, 275f. 275t inheritance; Congenital anomalies; Epigenetics; Sex
Family Heald, History Initiative. 153 chromosome
Family history in cell division. 49-50. 54-56
case study on. 163-166. l64f-166f drug response and. 342
generic referral and, 153-154, 154t epigenetic elfecrs on. 97-100. 250
introduction to. 152-153 in inheritance. 77. 86
pedigree analysis and. 159-161, 160f micro-ribonucleic acid (miRNA) and. 33-34
pedigree construction in. 155-157. 155f-157f of oncogenes. 47. 49.55.287.291-294.309
Punnerr square and. 158. 158f toxins and. 103
self-assessment questions on. 162-163. 162f-163f Gene pool. 390
summary on. 161 General nurse. 364-366
Fat mass and obesiry-associared (FTO) gene. 249 Gene therapy 381-383. 382f
Feet, dysmorphic features of, 184 Genetic anthropology. 388
Fertilization, 61-62, 65 Genetic counseling. 361. See also Health professionals
Fetal alcohol spectrum disorder (FASO). 173-175. 174f Genetic discrimination. 375-378
Fetal development. 54-56, 55f Genetic drift. 391-394. 392f-393f
Fetal hemoglobin (HbF), 215 Genetic heterogeneity. 272
F generation, 71-72. 72f Genetic information. 378. See also Social
F-genes mnemonic, 153, 154t considerations
Fibrillin. 200, 204-205 Genetic Information and Nondiscrimination Act
Fidelity. 38-39 (GINA). 377-378
Financial, ethical, legal, and social issues (FELSn. 376. Genetic referral. 153-154. 154t
See also Social considerations Genetics clinical nurse (GCN). 364

ERRNVPHGLFRVRUJ
430 Index

Genetic testing Glycosaminoglycan (GAG), 197-198

carrier testing in, 327-328, 327t-328t Golgi apparatus, 34-35
case study on, 339 Gonadotrophin hormone. 132
cytogenetic testing and, 332 Grainyhend-lilu 2 gene, 256
diagnostic testing in, 326 Growth factor, 48-52, 48f, 51 f-52f
direct-to-consumer (OTC) testing in, 334 Guanine, 6-8, 6f-8f
DNA sequencing in, 332 Gynecomastia. 132
in drug responses, 356-357
fluorescence in situ hybridization (FISH) in, Hands. dysmorphic features of, 184
332-333 Haplorypes, 388
genome-wide association study (GWAS) in, 333 Hardy-Weinberg equilibrium. 390-391. 390t, 392t
for hemophilia, 324t-325t Health Insurance Portability and Accountability Act
inconclusive resulrs in, 327 (HIPAA), 378
introduction to, 322-323, 324t-325t Health professionals
newborn screening in, 329 advanced-practice nurse in genetics (APNG) in,
oversight of, 331 364
predictive testing in, 326-327 certified generic counselor (CG C) in. 361-362
prcimplanrarion genetic diagnosis (PGO) in, 329 clinical geneticist in, 362-363
prenatal testing in, 328-329 clinical laboratory geneticist in, 363
risks and benefits of, 334-336, 335-336t general nurses in. 364-366
sample and, 323-326 generics clinical nurse (GCN) in, 364
self-assessment questions on, 338 interdisciplinary careers in, 366, 367t-370t
summary on, 337 introduction to. 360-361
rypes of, 330, 330t-33I r research geneticist in, 363
whole-exome sequencing (WES) in, 333-334 self-assessment questions on. 371-372
Generic Testing Registry, 336 summary on. 370
Genome-wide association study (GWAS), 228, 333 HeLa cell line. 102-103
in adulr-onser diseases, 245, 247, 249, 257 Helicase, 13t
cancer and, 295 Helicobncter pylori, 101
in psychiatric disorder. 303-304. 308-312. 314. 316 Helper/inducer T lymphocytes. 35
Genomic imprinting. 123-124 Hematopoietic stem cell transplantation (HSCf).
Genomics, 3. See also Generic resting 196
nurrigcnomics in, 105 Hemisygosiry, 80
pharmacogenomics (PGx) in, 354-356 Hemoglobin
variation in health problems and. 89-92, 91 f-92f beta globin (HBB) gene. 27. 29, 37, 78, 124.
Genotype. 20, 71-73. 72t-73t 212-213
Genotype-phenotype mismatch, 135-138 beta globin protein, 24,26-29, 27f, 34.37
Germline cells, 16, 289, 383 fetal (HbF), 215
Germline mutation. 35 Hemoglobin C disease, 37
Gestalt, 173. 180 Hemophilia, 19t. 220-223, 221 f-222f
Gestational diabetes mellitus (GOM), 248 genetic testing on, 324t-325t
Giemsa-banded (G-banded) chromosome. 17-18. 17f Hepatocyte nuclear factor l-u (HNF-l d) gene, 244,
Gleevec. See Irnarinib mesylare 244t
Clossoptosis, 172 Herceptin. See Trastuzumab
Glucocorticoid remedial aldosteronism (GRA). 272 Hereditary hemochromatosis (HFE-HHC), 19t,
Glucokinase (GCK) gene, 244. 244t 242-243
Glucose, in diabetes, 245-246, 246t Hereditary nonpolyposis colon cancer (HNPCC).
Glucose-6-phosphate dehydrogenase (G6PO), 346, 356 378
Glutamate receptot gene. 256 Hereroplasmy, 146
Glutamine (Endari), 215 Heterozygosity, 390

ERRNVPHGLFRVRUJ
 Index 431

Heterozygous, 20, 124, 158f. See also Mendelian lnderal. See Propranolol
inheritance Inheritance
allele frequency and, 389-390, 392t of aurosomes
in childhood-onset disease, 214f. 216-218, 219f genomic imprinting in, 123-124
compound, 243, 245 inrroducrion to, 109-110
in dysrrophin, 219f monosomy in, 119
in pedigree analysis, 158f mosaicism in, 124-126, 126f
I3-Hcxosaminidase A, 199 partial duplications or deletions, 120-123,
High-density lipoprotein (HDL), 267-268 122-123f
Histone, 13-14, 14f translocation in, 110-115, 112f-114f
modification of. 99, 99f, 294 criploidy in, 119-120
Homoplasmy, 146 trisomy in, 115-119, 116t-117t, 118f-119f
Hornozygous, 20, 124, 158f. See also Monogenic of cancer, 298-299, 298f
inheritance case study on, 128
allele frequency and, 389-390, 392t complex disease and, 85-89, 87f, 88t
in childhood-onset disease, 214f. 216-218, 219f expressiviry in, 77
Human epithelial growth receptor (HER2), 299 genomic variation in health problems, 89-92,
Human generic variation, 388 9If-92f
Human Genome Epidemiology (HuGE), 249 Mendelian
Human Genome Project, 395 autosomal-dominant transmission in, 74-77, 74f,
Human immunodeficiency virus (HlV), 35,295 75t-76t
Human leukocyte antigen (HLA), 227, 250-251, autosomal-recessive (AR) transmission in, 77-78,
251 f 77f-78f
Hunrer syndrome, 193t, 197-198 codominanr expression in, 73, 73{
Huntington disease (HD), 19t, 75(, 76, 90, 304, 326, dominant and recessive expression in, 71-72,
375,391 72t
Hurler syndrome, 19r, 193t, 196-197 introduction to, 70-71
Hydrogen bond, 6-8, 6f-8f overview of, 71
Hydromorphone (Dilaudid), 345 pleiotropy in, 73
Hypcrarninoacidernia, In, Int sex-linkage in, 79-84, 79f, 81 f-83f
Hyperglycemia, 227, 227f, 229-231 penetrance in, 76-77
Hyperrnobiliry Ehlers-Danlos, 203 probability in, 84-85, 84f
Hyperphagia, 178 Punnetr square analysis in, 84-85, 84f
Hyperplasia, 44, 44f recurrence risk in, 88-89
Hypcrrelorisrn, 121, 168, 176, l77t, 181-182, self-assessment questions on, 94-95, 127-128
182f summary of. 92
Hypertension (HTN), 271-272 twin concordance in, 88, 88t
Hypertrophic cardiomyopathy, 274, 275f. 275t Initiation, of cancer, 288-290, 288(, 289t
Hypertrophy, 44, 44f Insulin,S, Sf. 27f. 227-230, 227c
Hypospadias, 137 Insuliris, 229
Hyporelorism, 181-182, 182f Inrellecrual property, 381
Intended action, 344
Idiosyncratic response, 346 Inrernarional Society of Psychiatric Generics (ISPG),
Iduronare sulfatase (IDS) gene, 197 304
n-l-Iduronidase gene (IDUA), 196 Interphase, 15f
Idursulfase (Elaprase), 198 Intracerebral hemorrhage (ICH), 269
Irnatinib mesylare (Gleevec), 287, 354 Intracyroplasmic sperm injection (rCSI),
Imiglucerase (Cerezyme), 196 132
Immortality, 287 Inrron, 29-30, 30f
Immunoglobulin E (IgE), 232-234 In vitro fertilization (NF), 132, 329, 376

ERRNVPHGLFRVRUJ
432 Index

Jervell and Lange-Nielsen syndrome, 274 Male-specific region (MSy), 267

Jewish population, 195, 199,299, 328, 328t, 389, Malformation, 170-173
394 Malignant transformation, of cancer, 287-291, 288f.
Joinrs, dysmorphology of. 184-185 289t
Malnutrition, 96-97
Kallmann syndrome, 182 Marfan syndrome (MFS), 19t, 175, 178-179,184,
Karyotype, 16-18, 17f 204-207, 206f, 270,326
of balanced translocation, 111-115, 112f-114f Maternal-spindle transfer (MST), 146-147
of reciprocal rranslocarion, I II, 113f Maruriry-onser diabetes of yOW1g(M ODy), 243-245,
of Roberrsonian translocation, II I, I 12f 244t
Kearns-Sayre syndrome (KSS), 145t Meiosis J, 56-61, 58f-61 f. 63f. G4
Kindred,74 Meiosis II, GI, G3f. G5
Klinefelter syndrome, 82, 132, 248 Melanocorrin 4 receptor (MC4R), 249
Knockout mice, 266 Melanoma, 292t
Krabbe disease, 193t Mendelian inheritance
Kuvan. See Saproprerin hydrochloride autosomal-dominant rransmission in, 74-77, 74f.
Kyphoscoliosis Ehlers-Danlos disease, 203-204 75t-7Gt
autosomal-recessive (AR) transmission in, 77-78,
Laboratory-developed test (LOT), 331 77f-78f
Laboratory generic report, 335, 335t-336t codominanr expression in, 73, 73r
Lacks, Henrietta, 101-102 dominanr and recessive expression in, 71-72, 72t
Lanoxin. See Digoxin overview of, 71
Laro nidase (Aldurazyme), 197 pleiotropy in, 73
Larency period, 290 sex-linkage in, 79-84, 79f, 81 f-B3f
Lare-onset Alzheimer disease, 254 Messenger ribonucleic acid (mRNA), 28-33, 28f. 30f,
Leber hereditary optic neuropathy (LHON), 144, 32f
145t in genetic resting, 332
Left ventricular hypertrophy (LVH), 276 Metabolism, in drug response, 348-350, 350f
Legal issues. See Social considerations Meracemric chromosome, 16-18, 17f-18f
Leptotene srage, 58, 59f. 63f Metaphase(M phase),9-11,9f, l Or, 13-14
Lescol, See Fluvasratin in normal ceU division, 47f, 50
Leukopenia, 305 plate of. 15f
Liability model, 86-88, 87f Metastasis, 192t, 291
Ligase, 13t Methylation, 27f, 98-99, 98f, 102-103, 10M
Lines of descent, in pedigree, ISS, 155 f Microbiome, 100-10 1
Lipiror, See Arorvasrarin Microcephaly, 177t, 180-181
Locus,S, Sf. See also Allele Micrognathia, 172-173, 172f, 180-181
Long fingers and roes, 173, 175 Micro-ribonucleic acid (miRNA), 33-34, 100, 294
Long QT syndrome (LQTS) , 273-274, 273f Midfuce hypoplasia, 178
Low-density lipoprotein (LDL), 266-268 Minimum effective concenrrarion (MEC), 346,
Low-set ears, 168, 175, 177r, 182 347f
Lung cancer, 292t Missense poinr mutation, 3G-37, 36f
Luteinizing hormone (LH), 132 Mitochondria
Lysosomal storage disease, 192, 193t, 195-199 deoxyribonucleic acid (DNA) in, 5
disorders of. 144-146, 145t
Macrocephaly, 179 function of, 141-142
Macrophage, 195 overview of, 140-141, 14,If
Major depressive disorder (MOD), 311 parental origin of, 142, 143f
Major hisrocornparibiliry complex (MHC) gene, replication of, 142-144
250-251 self-assessment questions on, 148-149

ERRNVPHGLFRVRUJ
 Index 433

Mitochondrial deoxyribonucleic acid (mtDNA). 5. 141. Nature and nurture. 103-105. 104f. 105t. 313. See also
145-146.145t Environmental contributions
Mitochondrial encephalomyopathy. lactic acidosis. and Naxos disease. 278
srrokelike episodes (MELAS). 144. 145t. 270 Neoplasia. 284-285
Mitosis. 8 Nephroblasroma, 121
deoxyribonucleic acid (DNA) in Neumega. See Oprelvekin
synthesis of. 9-11. 9f. l Or, l l F Neurofibromarosis (NF 1). 77
in normal cell division. 46-50. 47f-48f Newborn screening. 329
Modifier genes. 86 Nexr-generarion sequencing. 326
Mongolian SpOts. 170 Nicorine dependence. 267
Monogenic inheritance Noncoding region. 26. 29. 33. 36. 39
achondroplasia in. 224-226. 225f-226f Nondirective. 361
adult-onset disorders in, 240-245. 242t. 244t Nondisjunction, 115. 119. 126f. 133
autosomal-dominant (AD) transmission in. 74-77. Noninvasive prenatal screening (NIPS). 329
74f. 75t-76t Nonneuronopathic Gaucher disease. 195
autosomal-recessive (AR) transmission. 77-78. Nonsense point mutation. 36f. 37
77f-78f Nonsyndromic. 176
Becker muscular dystrophy (BMD) in. 218-220 Noonan syndrome. 168. 182
carrier status in. 78. 78f NOTCH gene. 269. 310
classic hemophilia in. 220-223. 221 f-222f Nuchal hygroma. 133
cystic fibrosis (CF) in. 216-218 Nuclear deoxyribonucleic acid. See Deoxyribonucleic
Duchennc muscular dystrophy (DMD) in. 218-220. acid
219f Nucleokinesis, io, 14. 15f. 50
sickle cell disease (SCD) in. 212-216. 213f-214f. Nucleoside. 6. 6f
215r Nucleotide, 6-8. 6f-8f. 10. 13t
Stroke and. 269-271 Nucleus. in protein synthesis. 24. 24f. See also Cell
von Willebrand disease (VWD) in. 223-224 division
X-linked transmission in. 79-84. 79f. 81 f-83f Nurrigenomics, 105
Y-linked transmission in. 79-80, 79f Nutrition
Monogenic rrair, See Single-gene trair Durch hunger winter and. 96-97. 104
Monosomy. 119. 133-135. 134t. 135f in epigenetics, 104-105, 104f. 105r
Monozygotic [Wins. 125-126. 126f. 160f. 161
Morphine. 350. 350f Obesity, 248-249
Mosaicism. 124-126. 126f Occipitofrontal circumference. 179
Mucopolysaccharide (MPS) disorder. 180. 196 Oligohydramnios. 171-172
Mullerian-inhibiring substance, 136 Oncogene. 101.309
Mulrifacroral disease, 85-89. 87f. 88r cancer and. 287. 290-295. 297r. 298
Multiple sclerosis (MS). 252 genetic influences on. 46-51. 54-55
Muscular dystrophy. 19t Oogenesis. 57r. 62-65. 62f-63f
Mutagen. 38 Oprelvekin (Neumega). 195-196
Mutarion, 35-40. 36f Osteogenesis imperfecra (On. 201-203. 201t. 204f
Myoclonic epilepsy with ragged red fibers (MERRF). Oxidative phosphorylation. 141-142
144.145t
PI generarion, 71-72. 72t
Nager syndrome. 184 Pachytene stage. 58. 59f. 63f. 64
National Insriture for Occupational Safery and Health Pacliraxel (Taxol). 356
(NIOSH). 283 Paipebralfissure.l77r.182.183f
National Institutes of Health (NIH). 375-376 Pancreatic cancer. 292r
Natural killer (NK) cell. 228-229 p arm. 5f. 16-17. J8f
Natural selection. 389. 393-394 Parrial chromosome inheritance. 120-123. 122f-J23f

ERRNVPHGLFRVRUJ
434 Index

Partial thromboplastin rime (P'l"T), 223 Polyploidy, 16

Passenger mutation, 284 Polyuria, 230
Patau syndrome. See Trisomy 13 Pompe disease, 193r
Patent, 381 Population borclenecks, 391-394, 392f-393f
Parent and Trademark Office (PTO), U.S., 381 Population genetics, 388-390
Patient advocacy, 366 Posnranscriprional modification, 29-30, 30f
Pedigree, 74, 74f, 77-78, 77f-78f. 81 f Posrrranslational modification, 34-35
analysis of. 159-161, 160f Porter syndrome, 175
of cancer, 295, 29M Prader-Willi syndrome (PWS), 122-123, 123f, 178,
construction of. 155-157, I 55f-157f 248
Penerrancc, 76-77 Precision medicine, 342
Pcnrasomy X, 132 Predictive resting, 326-327
Peroxisome proliferaror-activated receptor-gamma Predisposirional resting, 326-327
(PPARy), 247-248 Preimplanrarion genetic diagnosis (PGD), 329,
Personal factors, in drug metabolism, 343t. See also 376
Environmental conrr iburions Prernurarion, in genes, 138
Personality disorder, 314-316, 31St Prenatal development, 54-56, 55f
Personalized medicine, 342 Prenatal resting, 328-329
Pharmacodynamics, 344-346, 345f Preprohormone, 34
Pharmacogenetics, 305 Presbycusis, 256-257, 257t
Pharrnacogenomics (PGx), 354-356 Presymprornaric test, 326
Pharmacokinetics, 346-350, 347f, 350f Primary protein structure, 34
Phenotype, 20, 71-73, 72t-73t Primary tumor, 291
Phenylalanine hydroxylase (PAH), 192-194, 192t Primase, 13t
Phenylketonuria (PKU) , 19t, 192-195, 192t-193t, Privacy, right to, 378-380, 379f
304,329 Private mutations, 273
Philtrum, 174f, 176, 178f. 180-181 Probability, 84-85, 84f
Phosphate linkage, 6-8, 6f-8f Proband, 156-157, 159
Phosphorylation, 49, 141-142 Prognathism, 140f
Pierre-Robin sequence, 173, I73f, 180-181 Programmed cell death. See Apoprosis
Plagiocephaly, 179 Progression, 290-291
Pleiotropy, 73, 191, 200 Prohorrnone converrase 1/3 (PCSKJ) gene, 249
Ploidy, 45-46 Prometaphase, 15f
aneuploidy in, 16 Promiroric signal transduction pathway, 46-52, 48f,
of benign rumors, 285 5If-52f. 287
in cell division, 58f. 62f Promoter region, 28
rerraploidy in, 16f. 57, 58f-59f, 63f Promotion, 288f, 290
rriploidy in, 16, 119-120 Pronuclear transfer (PNT), 147
Pluripotent cell, 53-54 Prophase, 15f. 57-60, 58f-60f. 62f-63f
Poinr mutation, 35-36 Propranolol (Inderal), 344-345
Polar body, 56, 57r, 62f-63f, 64-65 Prosrare cancer, 292r
Polyadenylarion, 28 Prorein, structure of. 25, 25f. 34
Polycystic kidney disease, 75r, 86 Protein synthesis
Polydactyly, 184 inrroduction to, 24-26, 24f-25f, 25t
Polydipsia, 230 rnuration in, 35-40, 36f
Polygenic trair, 71 posttranscriprional modification in, 29-30, 30f
Polymerase, 13r posrrranslarional modification in, 34-35
Polymerase chain reaction (peR), 332 self-assessment questions on, 41-42
Polymorphism, 342f. 343. See also Single-nucleotide summary of. 40
polymorphism (SNP) transcription in, 26-29, 27f-29f

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transfer ribonucleic acid (rRNA) in. 30-33. 31 f-32f Reproduction. See Cell division
translation in. 30-34. 31 f-32f Research geneticist. 363
Proreomics, 4 Resistance. to health problems. 89-92. 91 f-92f
Prothrombin activator. 221-222. 221 f Restrictive cardiomyopathy. 274-275t. 275f, 277
Proto-oncogene. 284 Retinoblastoma, 121
Provenril. See Alburerol Rerrognarhia, 172-173. l72f
Psychiatric disorders Rh blood group. 19t
affective disorders in. 31 1-312 Rheumaroid arthritis (RA). 252-253
attention-deficit hyperacriviry disorder (ADHD) in. Ribonudeases (RNases), 33
308-309 Ribonucleic acid (RNA)
autism in. 306--308. 307t codons of, 25t. 28-32, 29f. 32f, 36
bipolar disorder (BPD) in. 311 splicing of, 29-30, 30f
case study on. 318-319 transcription and. 26--29. 27f-29f
environmental contributions to. 306-308. 310-313. Ribosomal ribonucleic acid (rRNA), 30
316 Ribosome, 31-33. 32f
genetic applications for. 304-30G Right to privacy. 378-380, 379f
genome-wide association study (GWAS) in. 303-304. Risk alleles. 8G-88. 87f
308-312.314.3IG Risk stratification. 153
introduction to. 303 Robcrtsonian translocation, III, 112f
personaliry disorder in, 314-3IG, 315t Rocker-bottom feet. IIG, 116t-117t, 119f
schizophrenia in, 303-30G. 309-311. 310t Romano-Ward syndrome, 274
self-assessment questions on, 318 Rubinsrein-Taybi syndrome. 175. l77t
substance use disorder in, 312-314
summary of, 31G Sapropterin hydrochloride (Kuvan), 194
Ptosis. IG8 Schizophrenia. 88t. 97-98. 303-306. 309-311.
Punnetr square analysis, 84-85, 84f, 158, 158f 310t
Purine, 6--8, Gf-8f Secondary protein srrucrure, 34
Pyrimidine. 6--8. Gf-8f Secretin gene. 27f
Segregation. 70-71
q arm, 5f, 16--17. 18f Self-assessment questions
Quaternary protein structure, 34 on adult-onset disorders. 258-259
on autosomal inheritance. 127-128
Rabson-Mendenhall syndrome, 248 on cancer. 300-301
Race and erhniciry, 394-395 on cardiovascular disorders. 279-280
Recessive trait, 19.71-72. 72r on cell division. GG-67
Reciprocal translocation, III. 113f on childhood-onset disorders. 235-237
Recognizable Patterns of Human Malformations (Smith). on congenital anomalies. 186
168 on DNA structure and function. 21-22
Recurrence risk. 88-89 on drug response. 358-359
Red blood cell (RBC), 25-26 on enzyme disorders. 208-209
in sickle cell disease. 212-216. 213f-214 f on epigenerics, 106--107
Regression to the mean. 86 on family history. 162-163. 162f-163f
Regressive-onset autism. 307 on gametogenesis. 66--67
Renin-angiotensin-aldosterone system (RAAS). on generic testing. 338
271-272 on health professionals. 371-372
Replication on inheritance. 94-95
of deoxyribonucleic acid (DNA). 8-11, 9f, lOt. 11f, on mitochondria. 148-149
13r on protein synthesis. 41-42
of mitochondria, 142-144 on psychiatric and behavioral disorders. 318
segregation, 145-146 on sex chromosome inheritance. 148-149

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on social considerations, 384-385 Somatic mutation, 35

on variation, 396-397 Some Concern, Reproduction, Early,Echniciryand
Self-pollination,71-72, 72t Nongenetic (SCREEN) mnemonic, 153-154, 154t
Self-tolerance, 249-250. Seealso Auroimmune disease Spermatogenesis, 56-62, 57t, 58f-61 f, 80
Serniconscrvarive model, 10-11, II f Sporadic cancer, 295, 295f, 296t
Sensestrand, of DNA, 27-29, 28f SRY gene, 136
Sequence, in congenital anomaly, 172-173, l72f-273f Stickler syndrome, 173, 180-183
Sex chromosome, 17-18, 17f. See also Mirochondria Stroke, 268-271
case study on, 149 Submcracenrric chromosome, 16-18, 17f-18f
inherirance of Substance use disorder, 312-314
extra X in, 131-132 Substrate restrictivetherapy (SRT), 196
extra Yin, 132-133 Sudden infant death syndrome (sroS), 179, 225
fragileX syndrome (FXS)in, 138-140, 139t, Sugar.See Deoxyribosesugar
140f Sulfide molecule, 34
gcnorype-phcnorype mismarch in, 135-138 Supercoiling, 13, 14f
monosomy in, 133-135, 134t, 135f Suppressorgene, 46-52, 48f, 51f-52f, 54-55,101
introduction to, 131 in cancer, 284-288, 292-295, 293f, 297t, 298
sclf-assessrnenr questions on, 148-149 Susceptibility,to health problems, 89-92, 91f-92f
Turner syndrome and, 133-135, 134r, 135f Syndactyly, 19t, 56, 180, 180f, 184
Sex chromosome abnormality (SCA), 131 Syndrome, in congenital anomaly, 172-173, l72f-273f
Sex-linked inheritance, 76r, 79-84, 79f, 81f-83f Synthesisphase (S phase), 9-10, 9f, lOt
Sex reversal,135-138 Syphilis, 180
Sickle ccIIdisease (SCD), 19t, 212-216, 213f-214f, Systemiclupus erythematosus (SLE), 250-25 I, 25 If
215t, 327r, 389
Side effect, 345-346 Taliglucerase (ELELYSO),196
Signal rransducrion, 47-52, 48f, 51f-52f Tarceva.See Erlotinib
Silent point murarion, 36, 36f Tardive dyskinesia,305
Single-gene trait, 18-19, 19r, 70. Seealso Mendelian Taxol. See Padiraxel
inheritance; Monogenic inheritance Tay-Sachsdisease, 19t, 157, 193t, 199-200,327,394
Single-nucleotide polymorphism (SNP), 37, 266, 269, Telecan th us, I81
333,388-389 Telophase, 15f, 50, 59f, 61, 63f
in psychiatricdisorders, 304-305 Terarogen, 54-55, 55f, 173, 180
Singlestranded deoxyribonucleicacid (ssDNA), 10, Tertiary protein structure, 34
IIf Testicular feminization (TFM)' 137
binding proteins of, 13t Testing. SeeGenetic testing
Skin, xanthomas in, 267 'Iesris-derermining mcror (TDF), 136
Skull, dysmorphic featuresof, 179-180 Terraploidy, 16(, 57, 58f-59(, 63f
Smith, David, 168 TetrasomyX, 131-132
Smirh-Lemli-Opirzsyndrome, 175, 180, 180f ~ Thalassemia,327£
Social considerations Therapeutic effecr, 343
case study on, 385 Thiopurine methylrransferase(TPMT) , 356
duty to warn in, 378-380, 379f Threshold value, of liability model, 86-88, 87f
ethical goals in, 375 Thrombophilia, 270-271
gene therapy in, 381-383, 382f Thymine, 6-8, 6f-8f, 27-28, 27f
genetic discrimination in, 375-378 Tissue growth, 44, 44f. See also Cell division
intellectual property in, 381 Topoisomerase, 13r
introduction ro, 374-375 Tanade de pointes, 273, 273f
right ro privacy in, 378-380, 379f Toxin, in epigenerics, 103
self-assessmentquestions on, 384-385 Tp53 rumor suppressor,50-51
summary of, 383 Transcription, 26-29, 27f-29f

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Transcriprion factors, 47-52, 48f, 51 f-52f Velaglucerase, 196

Transfer ribonucleic acid (tRNA), 30-33, 31 f-32f Velo-cardio-facial syndrome, 173, 181
Transforming growth Facror 13-3(TGFB-3), 278 Very-low-densiry lipoprotein (VLDL), 266-267
Translarion, 30-35, 31 f-32f Virus
Translocation, 110-115, 112f-1 14f diaberes and, 228-229
Transmembrane proteins (TMEM43), 278 in gene therapy, 381-383, 382f
Transmission, 74-75. See also Inheritance Viramin K epoxide reductase complex I (VKORCl)
Trasruzumab (Herceprin), 354 gene, 355
Treacher Collins syndrome, 175, 183 Von Willebrand disease (VWD), 221 f. 223-224
Tripier code, 25-26, 25t Von Willebrand Faeror (vWf). 221 f, 223-224
Triploidy, 16,119-120
Trisomy 13, 115, 117t-118r, 118-119, 125 WAGR syndrome. 120-121
in congeniral anomalies, 175, 183 Warfarin (Cournadin), 355
Trisomy 14, 114, 114f White blood cell. 35. 228-229. 348
Trisomy 18, 115-116, 117r-118r, 119f Whole-exome sequencing (WES), 333-334
Trisomy 21,115-116, 117r-118r, 118f, 125 Whole-genome sequencing (WGS). 333-334
in congcniral anomaly, 169, 172, l77r, 182 Williams syndrome, 176. I77r. 180. 182
Trisomy, X 131 Wilms rumor. 121
Tumor necrosis facror (TNF), 232 Wolf-Hirschhorn syndrome. 180
Tumor of unknown origin, 286 Women
Turner syndrome, 133-135, 134[, 135f,248 gender mismarch of, 135-138
Twin concordance, 88, 88r hereditary hemochromatosis (HFE-HHC) in, 243
Twins. Sec Monozygotic rwins and Dizygotic rwins maternal-spindle transfer (MSn and. 146-147
Tyrosine kinase (TK), 49-51, 287 oogenesis in, 62-65, 62f-63f
Turner syndrome in, 135
Unbalanced rranslocarion, I 10, I 15, 120
Uniparental disomy (UPD), 124 Xanthelasmas, 267
Uracil, 27-29, 27f-29f Xanthomas, 267
X chromosome, 17. 17f
Van der Woude syndrome (VWS), 183 extra X, 131-132
Variation fragile X syndrome (FXS) in, 138-140, 139t, 140f
allele freq uencies in, 389 in pedigree analysis. 159
case srudy on, 397 X-linked transmission of. 79-84. 79f, 81f-83f
founder effect in, 390-391, 393f, 394 XX males. 137-138
generic drift in, 391-394, 392f-393f
haplorypes in, 388 Y chromosome. 17. 17f
Hardy-Weinberg equilibrium in, 390-391, 390t, extra Y and, 132-133
392r in pedigree analysis, 159
introduction on, 387-388 Y-linked transmission of, 79-80, 79f
population bottlenecks in, 391-394, 392f-393f
population generics in, 388-390 Zika virus. 54, 180
race and ethniciry in, 394-395 Zona pellucida, 65
self-assessment questions on, 396-397 Zygosity testing. 330
swnmary on, 395 Zygote. 65
Vascular Ehlers-Danlos disease, 203-204 pronuclear transfer (PNT) in. 147
Vascular endothelial growth faeror (VEGF), 48, 290 Zygorene srage. 58. 59f, 63f

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