

Prepared by:
Phanindra Prasad Poudel
Assistant Professor
Department of Anatomy
 BOOKS

1. Medical genetics : Jorde, Carey, Bamshad ,
White

2. Emery’s elements of medical genetics:

Robert F. Muller, Ian D.Young

3. Essentials of medical genetics : A.K. Datta

 SEX CHROMATIN/ BARR BODIES

Highly coiled genetically

inactive X- chromosome
Heterochromatin plano
convex body
Seen in female somatic
cells during interphase
Numbers of barr bodies in a cell =
total nos of X chromosomes – 1

 Female with-
 Double X chromosomes (XX), barr body is
1
 Triple X chromosomes (XXX), barr bodies
are 2
 Turner’s syndrome (45, X), no barr body

 Male with-
 Klinefelter’s syndrome (47, XXY), one
barr body
TYPES OF CHROMOSOMES


A. ON THE BASIS OF COILED OR UNCOILED

 Euchromatin:
uncoiled, genetically
active chromosome

 Heterochromatin:
coiled, genetically
inert chromosomes
 B. ON THE BASIS OF POSITION OF CENTROMERES:

Classified into 4 types:

o central cetromere
o arms of approx. equal length
o chromosomes- 1,3,19,20

o an off center centromere

o arms of different length
o chromosomes- 2,4-12,16-18
 KARYOTYPING
Laboratory test used to study an
individual’s chromosomes make up
Chromosomes are-
 Separated from cells
 Stained
 Arranged in order from largest to
smallest and
 Numbers and structures are studied
 Most accessible cells are lymphocytes
 About 5 ml venous blood is obtained

 Mixed with heparin

to prevent clotting

 Centrifuged that allows

the WBC to sediment out
as a distinct layer, the
buffy coat
 WBC are collected,
placed in tissue
culture medium,
stimulated by adding
mitogenic agent ,
phytohemagglutinin
 Hypotonic saline (sodium
citrate) is added &
incubated for 20min to
cause swelling of the cells,
lysing them and releasing
the chromosomes

 Chromosomes are fixed

by fixatives (ethanol &
acetic acid), mounted on
slides and stained by
Giemsa

 Chromosomes are
ready for analysis

 Karyotype is taken
 CLASSIFICATION OF HUMAN CHROMOSOMES

 According to Denver London system (1960) human

chromosomes are arranged into 7 groups from A to G in
order of decreasing length
 Group A:
o Pairs of 1, 2, 3 chromosomes
o Long, metacentric
o Chromosome 2- submetacentric

 Group B:
o Pairs of 4, 5 chromosomes
o Fairly long, submetacentric
o Pairs of 6 - 12 and X chromosomes
o Medium size
o Submetacentric

o Pairs of 13 - 15 chromosomes
o Medium size
o Acrocentric
o Satellite body is attached to free end of the short arm
 Group E :
o Pairs of 16 - 18 chromosomes
o Fairly short
o Submetacentric
 Group F:
o Pairs of 19, 20 chromosomes
o Short & metacentric
 Group G:
o Pairs of 21, 22 and Y chromosomes
o Very short, acrocentric
o 21 & 22 contain satellite bodies
o Distal end of long arms of Y- fluorescent bodies
CHROMOSOMAL ABERRATIONS/ CHROMOSOME
ABNORMALITIES/ CHROMOSOMAL DISORDERS

Abnormal chromosome constitution

Extra or missing chromosome either a
whole or a segment
May be-
A. Numerical chromosomal aberrations &
B. Structural chromosomal aberrations
C. Chimaerism
 NONDISJUNCTION

Failure of chromosome pair to separate

during meiosis I or two chromatids of a
chromosome during meiosis II or mitosis
As a result both chromosomes or
chromatids pass to one daughter cell & the
other cell receives neither
 NUMERICAL ABERRATIONS
 Alteration in chromosome numbers
 May be 2 types :
 Aneuploidy &
 Polyploidy

I. ANEUPLOIDY:
 Involves loss or gain of one or more chromosomes
 Cause: Nondisjunction during anaphase of meiosis
 Two types- trisomy and monosomy
a. Trisomy:
 presence of an extra
 chromosome
 trisomy of autosomes-
 Down’s syndrome- trisomy 21
 Patau’s syndrome- trisomy 13
 Edward’s syndrome- trisomy 18
 Spontaneous miscarriages-
trisomy16
b. Monosomy:
chromosome
 Absence of single
 Monosomy for an autosome:
 Almost incompatible with survival to
term
 Monosomy of sex chromosome
 Lack of sex chromosome- Turner’s
syndrome (45,X)
II. POLYPLOIDY:
Chromosome number is increased by the multiple

of haploid (23) chromosomes, other than diploid
number
Triploidy (69), Tetraploidy (92)
Triploidy (23x3)
 failure of a maturation meiotic division, eg-
retention of a polar body or formation of a
diploid sperm (dispermy)
 due to fertilization of an ovum by more than
one sperm (polyspermy)- result hydatidiform
mole
 results in early spontaneous miscarriage
STRUCTURAL ABNORMALITIES:
Types:
A. TRANSLOCATIONS
B. DELETIONS
C. INSERTIONS
D. INVERSIONS
E. RING CHROMOSOMES
F. ISOCHROMOSOMES
TRANSLOCATIONS
 Transfer of genetic material between non-homologous
chromosomes
 2 types :
I. Reciprocal translocation
II. Robertsonian translocation

I. Reciprocal translocation:
 Involves breakage of at least 2 chromosomes with exchange of
the fragments
 Chromosome numbers remain 46
 Common between the long arms of chromosomes 11 & 22-
balanced type
 Problems arise at meiosis
 Chromosomes involve forms pachytene quadrivalent instead
of bivalents
II. Robertsonian translocations:
 Particular type of reciprocal translocation
 Results from breakage of 2 acrocentric
chromosomes (nos 13, 14, 15, 21, 22) at or
close to their centromeres, with
subsequent fusion of their long arms,
short arms lost
 Total chromosome number is reduced to
45
 Functionally balanced rearrangement
 Robertsonian translocation on chromosomes 14 and 21-
after segregation at meiosis, the following gametes may
result:
14/21,
21
14,21 14/21

Normal Translocation Down’s

Normal carrier syndrome

14,
14 21 14/21

Lethal
B. DELETIONS
 Loss of a segment of chromosomes which may

be terminal or interstitial
 Syndromes
 Wolf hirschhorn syndrome (4p-)
 Cri-du-chat syndrome (5p-)
 Prader- willi- syndrome- microdeletion on
15q- paternal chromosome
 Angelman syndrome- microdeletion on 15q-
maternal chromosome
C. INSERTIONS
 A segment of one chromosome inserts into another
 Carriers of a balanced deletion-insertion rearrangement

are at a 50% risk of producing unbalanced gametes

D. INVERSIONS
 A part of chromosome is detached by 2 breaks and later
reunites with the same chromosome in inverted position
 May be-
 Pericentric- inversion segment involves the centromere
 Paracentric – inversion segment involves only one arm
 Balanced rearrangement
D. RING CHROMOSOMES
 When a chromosome is deleted at both ends leaving
two sticky ends on the central portion, which reunite as
a ring 
 If the involved chromosome is autosome, it is serious
 Unstable in mitosis

E. ISOCHROMOSOMES
 Chromosomes derived form the transverse splitting of
the centromere
 Metacentric, with duplication of genes
 Encountered in case of Turner’s syndrome with two
long arms of X chromosome
 CHIMAERISM
 Unusual condition

 
Individual present two or more genetically distinct cell lines
Derive from more than one zygote
 Two types:
i. Di-spermic chimaeras:
 Result from double fertilization
 Two genetically different X-bearing & Y-bearing sperms
fertilize two ova
 Result two zygotes & fuse to form a single embryo
ii. Blood chimaeras:
 Appear when two non identical twins in utero exchange their
cells thru’ the placental barrier
 PEDIGREE CHART
It is a family tree, a shorthand system of
recording the pertinent information about
a family.
Proband in the family is indicated by an
arrow.
Symbols used in pedigree chart-
PEDIGREE CHART SYMBOLS


 MENDELIAN INHERITANCE
Many disorders exhibit single gene or
unifactorial or mendelian inheritance
A trait or disorder, determined by a gene
on an autososme, is autosomal inheritance
A trait or disoder, determined by a gene on
one sex chromosomes is sex linked
inheritance

1. Autosomal dominant inheritance

2. Autosomal recessive inheritance
3. Sex linked inheritance
 AUTOSOMAL DOMINANT INHERITANCE
 Manifests in the heterozygous state
 Rare in population so mattings between two affected
individuals are uncommon 
 Punnett square for mating between normal parent with
an affected heterozygote:
Unaffected parent-aa (normal allele-’a’)

Affected parent -Aa a(normal) a(normal)

(mutant allele – ‘A’, normal
allele-’a’) A(mutant) Aa(affected) Aa(affected)
a(normal) aa(normal) aa(normal)
Features:
1. Males and females exhibit the disorder in
approximately equal proportions

2. Males & females are equally likely to transmit
the disorder to their offsprings
3. Transmitted from one generation to the next,
lack of skipped generations, k/a vertical
transmission pattern
4. All forms of transmission between the sexes are
occurred, i.e. male to male, female to female,
male to female and the converse
5. Recurrence risk for an autosomal dominant


disorder is 50% 
If one parent is affected by an autosomal dominant
disease (heterozygote) & other is normal, the
recurrence risk for each child is ½
 Because of each birth is independent event, this risk
remains constant no matter how many affected or
unaffected children are born
Eg. Postaxial polydactyly – presence of an extra
digit next to fifth digit
AUTOSOMAL DOMINANT INHERITANCE- PEDIGREE CHART:
Aa = affected individual (M)

aa = normal individual (F)

Aa
 aa

aa Aa aa aa

aa aa aa aa
Aa Aa
 AUTOSOMAL RECESSIVE INHERITANCE
 Recessive disorders are only manifest when the mutant allele is present
in homozygosity

 Individuals heterozygous for a recessive mutant allele show no features
of disorder and are healthy – carriers
 Carriers are more common than the affected
 Punnett square for mating between carrier parents :

Carrier parent- Aa (normal allele – a, mutant allele-A)

Carrier parent - Aa a(normal) A(mutant)

(normal allele – a,
a(normal) aa(normal) Aa(unaffected
mutant allele-A)
heterozygote)
A(mutant) AA(affected)
Aa(unaffected
heterozygote)
Features:


1. Affects males & females in equal proportions
2. Seen in multiple siblings, but usually not in earlier
generations k/a horizontal transmission pattern
3. Consanguinity supports the disease
4. Recurrence risks 25%
Eg: Cystic fibrosis, Alkaptonuria (inborn errors of
metabolism)
 AUTOSOMAL RECESSIVE INHERITANCE-
PEDIGREE CHART

Aa aa

aa Aa aa Aa aa

Aa aa Aa Aa aa

AA AA Aa aa
Aa aa
 X LINKED RECESSIVE INHERITANCE
 Disorders are carried on X chromosome, usually manifest in male
 Mutant allele on single X chromosome
Features:
 Males usually only affected 
 Transmitted through unaffected female- carrier to their sons
 Affected males, if they survive to reproduce, can have affected
grandsons through their daughters who are obligate carriers
 No male to male transmission, i.e. affected males cannot transmit the
disorder to their sons
 Eg.:
 Haemophilia
 Duchenne muscular dystrophy
 Red green color blindness
 Lesch-Nyhan Syndrome
 Affected male

Normal
female

Xh(mutant) Y(normal)
X(normal) XhX(carrier) XY(normal)
X(normal) XhX(carrier) XY(normal)

Carrier female

Affected Xh(mutant) X(normal)

male Xh(mutant) Xh Xh(affected) XhX
(carrier)
Y(normal) XhY(affected) XY(normal)
 X LINKED DOMINANT INHERITANCE
 Uncommon
 Superficially resembles to autosomal dominant trait

 Manifest in heterozygous female as well as in male who
has the mutant allele on single X chromosome
 Punett square:
a. Affected female (XhX) with normal male (XY)

Affected female(XhX)

Normal Xh(mutant) X(normal)

male(XY) X(normal) XhX(affected) XX(normal)
Y(normal) XhY(affected) XY(normal)
Features:


1. Both males & females are affected, but affected females
are more frequent than affected males-twice
2. Affected females can transmit disorders to both male
and female offspring, affected males can only transmit
to daughters (100%)
Eg: Vitamin D resistant rickets
CHROMOSOMAL
ABNORMALITIES
 DOWN’S SYNDROME
Karyotype:
In 95%- Trisomy 21
(47,XY,+21)- cause-
due to meiotic
nondisjunction
In 4% - robertsonian
translocation
In 1% - mosaicism
 Clinical features:

 Newborn period -
hypotonia, sleepy,
excess nuchal skin

 Craniofacial -
brachycephaly,
epicanthic folds,
protruding tongue,
small ears, upward
sloping palpebral
fissures
Limbs - single palmar crease
(simian crease), small middle
phalanx of fifth finger, wide
gap between 1st and 2nd toes

Cardiac - atrial & ventricular

septal defects, common
atrioventricular canal, PDA

Other - anal atresia,

duodenal atresia,
hirschsprung’s disease, short
stature, strabismus
 KLINEFELTER’S SYNDROME
Karyotype:
47, XXY, in most of
the cases

Barr body: present in

phenotypic male

Cause:
nondisjunction in
gametogenesis
Clinical features:
found only in males, these
are-
Taller than normal
males
Testicular atrophy
Dysgenesis of
seminiferous tubules
with azoospermia/
sterlity
Occasionally-
gynaecomastia &
mental retardation
 TURNER’S SYNDROME

 Karyotype:
 Monosomy X - 45,X- in most of the
cases (50%)

 Barr body: absent in phenotypic

female

 Cause: nondisjunction in
gametogeness
Clinical features:
found only in females, these
are-
Absence of ovaries
(gonadal dysgenesis)
Short stature
Webbed neck
Lymphedema of the
extremities
Skeletal deformities
Broad chest with widely
spaced nipples
 EDWARD’S SYNDROME
Karyotype:
 Trisomy 18 - 47XX, +18

Clinical features:
 Prominent occiput
 Mental retardation
 Low set ears
 Overlapping of fingers
 Micrognathia
 Congenital heart
defects
 Renal malformations
 Limited hip abduction
 Rocker bottom feet
 PATAU’S SYNDROME
Karyotype:
 Trisomy 13- 47XX,+13
Clinical features:
 Micropthalmia
 Microcephaly
 Mental retardation
 Polydactyly
 Cleft lip
 Cleft palate
 Cardiac defects
 Renal defects
 Umbilical hernia
 Rocker bottom feet
 FRAGILE X SYNDROME
Cause :
 fragile site for
mutation close to
telomere at end of
long arm of X
chromosome
 mutation in the
FMR1 gene, which
maps to Xq
Clinical features:
 Mental retardation
 Recognizable facial
appearance:
 High forehead
 Large everted ears
 Long face
 Prominent jaw-large
mandible
 After puberty most
affected males have
large testes (macro-
orchidism)
 Autistic features
 Hyperactive behavior
 Speech tends to be
halting & repetitive
 CYSTIC FIBROSIS
Type: autosomal recessive inheritance
Cause :
 mutation in CF associated gene
Clinical features:
 principal defect-chloride ion transport
 resulting in high salt concentrations in sweat &
viscous luminal secretions in respiratory and GI
tracts
 Meconium ileum
 Infertility by formation of plug in vas deferens
 Cardiorespiratory complications: chronic cough,
pulmonary infections
 Pancreas insufficiency: malabsorption of protein
& fat and faecal loss
 Malabsorption: large foul stools, abdominal
distension, poor weight gain
THE END