Genetic Disorders

GENETICS LECTURE

5
Genetic Disorders

Polydactyly Progeria
Hypertrichosis

Hemophelia Down Syndrome Sickle Cell Anaemia

 Introductio
n:
Genetic disorder: an illness caused
by one or more abnormalities in the
genome, especially a condition that
is present from birth (congenital).
 Most genetic disorders are quite
rare and affect one person in every
several thousands or millions.
 Genetic disorders may or may
not be heritable, i.e., passed
down from the parents' genes.
 Contd
..

 In non-heritable genetic disorders,

defects may be caused by new
mutations or changes to the DNA.

 The defect will only be heritable if

genetic disorder occurs in the
germ line.
Classification of Genetic
disorders
Single Gene
Disorders(Mendelian
Disorders)

 Gregor Mendel (1822 –1884)

conducted research on heritable
traits in pea plants.
 Sir Mendel’s studies of inheritence pattern in pea
plant represent a
solid foundation for our current understanding of single gene disorders
in humans.
 When a certain gene can be pin pointed as a cause of disease we
Mendelian Disorders
Mendelian Disorders
Transmission Patterns of Single
Gene Disorders

 Mendelian  Non-Mendelian
• Autosomal Dominant • Genomic Imprinting
• Autosomal Recessive • Trinucleotide repeats
• X-linked Recessive • Mutations in
• X-linked Dominant Mitochondrial genes
• • Gonadal
Y-linked
mosaicism
Transmission Patterns of Single
Gene
Disorders(Mendelian inheritence)
Patterns of Single Gene Inheritance depend on 2 factors:

1. Whether the gene is on an Autosome or a Sex chromosome

2. Whether the phenotype is Dominant or Recessive

Thus, there are 4 basic patterns of single gene inheritance

1. Autosomal Recessive
2. Autosomal Dominant
3. X-linked Recessive
4. X-linked Dominant
Y-linked disorders are exceedingly rare but the most
well-known examples typically cause
infertility. Only men
have a Y chromosome and so the Y is only
passed from father to son.
 Inheritence
Pattern
 The four most common patterns of
inheritance of genetic conditions due to a
change in a single gene in families are
therefore described as:
 Autosomal recessive
 Autosomal dominant
 X-linked recessive
 X-linked dominant
Knowledge is important for the purpose of
‘Genetic Counselling’
 Autosomal Dominant Disorders
Genotype and phenotype correlation with gene locus for
an autosomal dominant trait

A a
Dominant allele Recessive allele

Genotype: Homozygous Heterozygous Homozygous

Phenotype: affected unaffected

Phenotype expressed in both homozygotes and heterozygotes for a mutant
Autosomal Dominant Disorders
Autosomal Dominant
Disorders

• Manifested in heterozygous
state
• One parent usually
affected
Males and females equal ratio and both can
• transmit the disease
Affected person marries unaffected one, every
child has 1 chance in 2 or 50% chance
• Variable Expressivity: Trait in all gene carriers but
different expression among individuals
Reduced Penetrance: Mutant gene but phenotype
normal, e.g., 50 % penetrance
 50% of gene carriers will express the trait
Autosomal Dominant Disorders
Variable Expressivity:If a trait is seen in all individuals
carrying the mutant gene but is expressed differently among
individuals e.g in
Neurofibr omatosis type 1 manifestations range from
a) B rownish spot on the skin.
b) Multiple skin tumors.
c) Skelital diformities.
Huntington’s
Disease Huntington's disease
(HD) is an inherited,
degenerative brain
disorder which results
in an eventual loss of
both mental and
physical control. The
disease is also known
as Huntington's
chorea.
Chorea means "dance-
like movements" and
refers to the
uncontrolled motions
often associated with
the disease.
Huntington’s
Looking back at the
pedigree chart is
Huntington’s dominant
or recessive?

Scientists have
discovered that the
abnormal protein
produced by the
Huntington's disease
gene, which contains an
elongated stretch of
amino acids called
glutamines, binds more
tightly to HAP-1 than the
normal protein does.
 Autosomal Recessive
Disorders
Genotype and phenotype correlation with gene locus
for an autosomal recessive trait

A a

Dominant allele Recessive allele

Genotype: Homozygous Heterozygous Homozygous

Phenotype: unaffected unaffected affected
Autosomal Recessive
Disorders
Autosomal Recessive Disorders

Typical pattern is two heterozygous unaffected(carrier) parent.

Autosomal Recessive Disorders
Single largest category of Mendelian Disorders.
They occur when both alleles are mutated--Homozygous

state.
Chance of having an affected offspring
 Autosomal Recessive
Disorders
• Single largest category of Mendelian
disorders
• Affected when homozygous i.e., both alleles
affected
. Parents not necessarily affected (carriers) but siblings
may be affected

Siblings 1 in 4 chance of being affected (25%)

If mutant gene low freq. in population  strong likelihood

that diseased offspring result of consanguineous
marriage
 Autosomal Recessive
Disorders
Complete penetrance
• common

• Onset frequently early in

life
• New mutations occur but rarely detected  asymptomatic
heterozygote  many generations pass to mate with other carrier
to produce homozygous offsprings

• Almost all inborn errors of metabolism

included
Autosomal Recessive disorders
Autosomal Recessive disorders
Autosomal recessive
 X-Linked Disorders
• All sex linked disorders are x-
linked
• Almost all X-linked are
recessive
• Several genes on “Y”  all related to
spermatogenesis
• Male mutations in “Y” are infertile, hence no
Y-linked inheritance

•
CONT..
X-Linked disorders
Xlinked
Xlinked
X-linked Inheritance pedigree
chart
Pedigrees
Below is a sample of a pedigree from a family which carries
hemophilia.
 2. Chromosomal Genetic Disorder

• disorders, entire chromosomes, or large segments of

• In these
them, are missing, duplicated, or otherwise altered.
• Can be organized into two basic groups:
1) • Abnormalities: When an individual is missing either a
Numerical
chromosome from a pair (monosomy) or has more than two
chromosomes of a pair (trisomy)
2) Structural Abnormalities: When the chromosome's
structure is altered.
 Contd
..

• Some Examples: Cri-Du-Chat

Syndrome, Down Syndrome, 47
XXY Klinefelter Syndrome, Turner
Syndrome (Monosomy), William
Syndrome
 Cri-du-cat Syndrome

• The name of this syndrome is

French for "cry of the cat," referring
to the distinctive cry of children
with this disorder.
• The cry is caused by abnormal
larynx development, one of the
many symptoms associated with
this disorder.
• Cri-du-chat is caused by a deletion
(the length of which may vary) on
the short arm of chromosome 5.
• Multiple genes are missing as a
result of this deletion, and each
may contribute to the symptoms
 Contd
..

• Babies with cri-

du- chat are
usually small at
birth, and may
have
respiratory
problems.
• Often, the larynx
doesn't develop
correctly, which
causes the
signature cat-like
Down Syndrome
is a form of mental retardation and physical abnormalities.
It is caused by a duplicate 21st chromosome. Instead of two, they
have three 21st chromosomes.

This occurs when the chromosomes fail to seperate during

meiosis.
Down Syndrome
Down Syndrome
 Down Syndrome

• Down syndrome is a
developmental disorder
caused by an extra copy of
chromosome 21 (which is why
the disorder is also called
"trisomy 21").
• Having an extra copy of this
chromosome means that
individuals have three copies of
each of its genes instead of two,
making it difficult for cells to
properly control how much protein
Down’s Syndrome or Trisomy 21
Symptoms of Down Syndrome
 Upward slant to eyes.
 Small ears that fold over at the top.
 Small, flattened nose.
 Small mouth, making tongue appear large.
 Short neck.
 Small hands with short fingers.
 Low muscle tone.
 Single deep crease across center
of palm.
 Looseness of joints.
 Contd
..

People with Down syndrome have an

increased risk of developing a
number of medical problems:
 respiratory infections,
 gastrointestinal tract obstruction,
leukemia,
 heart defects,
 hearing loss,
 hypothyroidism
 various eye abnormalities.
 Contd
..

• No cure exists
for Down
syndrome.
• But physical
therapy
and/or
speech
therapy can
help people
with the
disorder
 47, XXY
(Klinefelter syndrome)
• Males (46, XY) and females (46, XX).
• 47, XXY (or XXY) is a genetic
condition caused when someone
has two X chromosomes and one
Y chromosome.
• Because people with an XXY
chromosome arrangement have a Y
chromosome, they are considered
genetic males.
• Most XXY individuals develop as
males, often not knowing they
have an extra chromosome.
Kleinfelter’s syndrome
(or Klinefleter’s)

 Disorder occurring due to nondisjunction of the X

chromosome.

 The Sperm containing both X and Y combines

with an egg containing the X, results in a male
child.

 The egg may contribute the extra X

chromosome.
 XXY
 Males with some development of breast
tissue normally seen in females.

 Little body hair is present, and such person

are typically tall, have small testes.

 Infertility results from absent sperm.

 Evidence of mental retardation may or

may not be present.
 Contd
..

• XXY is usually caused by what is

called nondisjunction.
• Nondisjunction happens when a pair
of sex chromosomes fails to
separate during egg (or sperm)
formation.
• The XXY chromosome
arrangement affects primarily
sexual development.
• Typically, testes don't fully develop,
and the levels of the hormone
 Contd
..

• As adults, nearly all XXY males

are unable to make sperm and
so cannot have biological
children.
• Many men discover their condition
only after they seek medical help
for infertility.
• Changes that appear at puberty can
include low growth of facial and
body hair, development of breast
tissue, and small testes.
Klinefelter’s syndrome
Klenifelter’s
Klinefleter’s
 Turner Syndrome

• Turner syndrome is caused by a

missing or incomplete X
chromosome.
• People who have Turner
syndrome develop as
females.
• The genes affected are involved in
growth and sexual development,
which is why girls with the disorder
are shorter than normal and have
abnormal sexual characteristics.
Turner’s
 Turner syndrome is associated
with underdeveloped ovaries, short
stature, webbed, and is only in
women.

 Bull neck, and broad chest.

 Individuals are sterile, and lack

expected secondary sexual
characteristics.
 Mental retardation typically not
evident.
Turner’s
Turner’s
Turner’s Syndrome
 2-e. Williams Syndrome

• Williams syndrome
is a rare genetic
disorder that
affects a child's
growth, physical
appearance, and
cognitive
development.
• People who have
Williams syndrome
are missing genetic
material from
Multifactorial Inheritance:
Congenital malformations
•Cleft lip/palate
•Congenital dislocation of the hip
•Congenital heart defects
•Neural tube defects
•Pyloric stenosis
•Talipes