Upendra Sharma.U.

S
PIMS

introduction
Normal human cells contain 23 pairs of

chromosomes
This includes one pair of sex chromosome
XX or XY
During cell division we can identify
chromosomes
Lymphocytes incubated for 2-3 days or
uncultured bone marrow in 4-24 hours

continue
Haploid: set of 23 chromosomes
Diploid: normal number of 46

chromosomes
Aneuploidy: less than an even multiple of
23 usually is 45 or 47 and rarely 48,49
Triploidy: 69 chromosomes
Mosaicism
Abnormal in deletion and
translocation(balanced and
unbalanced)Balanced

Incidence
The earlier the abortion the more likely to be

chromosomal
50% of spontanous abortion are chromosomal
abnormal
Mostly triploidy. 45 XO, trisomy 16
98% of fetus with turner abort
Generally 6/1000 the incidence of
chromosomal abnormalities

When to suspect it
Unexplained infertility/ balanced

translocation
Multiple abortion >2
Prior case of defective baby

When to suspect it
continue
Presence of congenital anomalies
45% have minor single anomalies
9% 3 minor anomalies
1.5% HAVE major anomaly

2 or more major anomalies may represent

genetic syndrome or chromosomal

abnormalities(10%).

Down Syndrome
Incidence 1/700
2/3 of down fetus spontaneously abort
Clinical diagnosis depend on gestalt
Trisomy 21 in 94% of cases with extra

chromosome from mother mostly(95%)

Risk correlate with maternal age
<25 y/o 1/1600
>40 y/0 1/80

2% are mosaic

Other Clinical features

Hypotonia without weakness
Clinodactaly protruded tongue,small

ears,brachycephaly,small up turned nose,

depressed nasal bridge.
Mental retardation, socially do better with
good environment (Happy children)

Clinical issues
Cardiac and GI
Hypothyriodism
Transient leukemoid reaction
Alzheimers disease up to 25% over 40 y/o
Early death relate to cardiac dysfunction

Trisomy 18
Incidence 1/8000
Overlaps with trisomy 13
Sever Mental retardation
>90% dead in 1st year

Trisomy 18
Small face with prominant occiput
Small sternum and pelvis
Flexion deformity of the finger
VSD and horseshoe kidney

triploidy
Complete extra set of chromosomes
Mostly miscarriages
Fetal wastage skeleton more than cephalic,

2% survive to be recognized
Large hydatidiform placenta
VSD, ASD, Syndactaly
Genital and CNS abnormalities

Trisomy 13
Sever developmetal retardation
Incidence 1/20000
90% dead in the 1st year

Trisomy 13
Midline brain defect
Malformed ear
Microophalmos and coloboma
Scalp defect

Turner syndrome
Most common abnormality in early abortion
Female, short stature, primary amenorrhea,

sterility, spares hair and underdeveloped

breast
Neonatal: wide spaced nipple, lymphedema ,
shield chest,
Coarctation of the aorta

Continue turner
syndrome
Normal IQ scale with difficulty in spatial
orientation such as map
Present with short stature or delay sex
maturation
Hormonal therapy

continue
Mosaisim (15%), remove gonads
Recurrent risk is 1-2%
Noonan syndrom AD, fresh mutation
Pulmonary stenosis, nl stature, microceph,

mental retardation

Klinefelter syndrome
20% of aspermic adult male (blocked

spermatogenesis
47 XXY in 80% and mosaic in 20%
IQ is 98 (normal) with mild decrease in verbal
IQ
Scoliosis, decrease libido may improve with
testesterone, gynecomastia

Fragile X Syndrome
Moderate to sever mental retardation
Speech delay, short attention, hyperactivity
Poor motor coordination and mouthing objects
Poor socialization, temper tantrum
Mood disorder (bipolar), schizophrenia

Fragile X syndrome
Long protruding ears
Long face and prominent jaw
Flattened nasal bridge
High arch palate
Macroorchidism
Genetic is complex, 80% penetration in male

and 30% penetration in female

Genetic imprinting
Means: as genomes pass through miosis it is

normal for part of it to change.

During miosis inactive X chromosome become
active and changes on fragiloe X gene
(imprinting) make it malignant

Angelman syndrome
Sever mental retardation
Inappropriate laughter
Decrease pigmentation of choroid or iris

(pale blue eyes)

Ataxia and jerky eye movement
Sever speech proplem
Deletion of b15q11q13, maternal in origin
Paternal uniparental disomy

Prader-willi syndrome
(A fat red faced boy in state of

somnolency) Charles Diickens

Early hypotonia
Obesity
Short stature as adult
Almond shaped blue eyes
Mental retardation (mild to moderate)
Narrow hands

Variation In Chromosome
Structure
Amount of genetic information in the chromosome

can change

Deficiencies/Deletions
Duplications

The genetic material remains the same, but is

rearranged

Inversions
Translocations

Deficiencies (Deletions)

A chromosomal deficiency occurs when a

chromosome breaks and a fragment is lost

Figure 8.3

Deficiencies

Phenotypic consequences of deficiency depends on

Size of the deletion

Functions of the genes deleted

Phenotypic effect of deletions usually detrimental

Duplications

A chromosomal duplication is usually caused by

abnormal events during recombination

Figure 8.5

Duplications

Phenotypic consequences of duplications

correlated to size & genes involved

Duplications tend to be less detrimental

Bar-Eye Phenotype in Drosophila

Phenotype: reduced number of ommatidia
Ultra-bar (or double-bar) is a trait in which flies have even

fewer facets than the bar homozygote

Both traits are X-linked and show intermediate dominance

Duplications and Gene

Families
Majority of small duplications have no phenotypic

effect

However, they provide raw material for evolutionary

change

Lead to the formation of gene families

A gene family consists of two or more genes that are

similar to each other
derived from a common gene ancestor

Genes derived
from a single
ancestral gene

Figure 8.9

Gene Families
Well-studied example is the globin gene family
Genes encode proteins that bind oxygen

Globin gene family

14 homologous genes derived from a single ancestral gene
Accumulation of mutations in the members of generated
Globin genes expressed during different stages of development
Globin proteins specialized in their function

Expressed very
early in embryonic
life

Expressed maximally during the Expressed after

second and third trimesters
birth

Better at binding
and storing
oxygen in muscle
cells

Figure 8.10

Duplication

Better at binding
and transporting
oxygen via red
blood cells

Inversions

A segment of chromosome that is flipped relative to

that in the homologue

Centromere lies
within inverted
region

Figure 8.11

Centromere lies
outside inverted
region

Inversions

No loss of genetic information

Many inversions have no phenotypic consequences

Break point effect

Inversion break point is within regulatory or structural portion of a

gene

Position effect
Gene is repositioned in a way that alters its gene expression
separated from regulatory sequences, placed next to constitutive

heterochromatin

~ 2% of the human population carries karyotypically

detectable inversions

Inversion Heterozygotes

Individuals with one copy of a normal chromosome and one

copy of an inverted chromosome
Usually phenotypically normal

Have a high probability of producing gametes that are abnormal in

genetic content
Abnormality due to crossing-over within the inversion interval

During meiosis I, homologous chromosomes synapse with

each other

For the normal and inversion chromosome to synapse properly, an

inversion loop must form
If a cross-over occurs within the inversion loop, highly abnormal
chromosomes are produced

Inversions Prevent Generation of

Recombinant Offspring Genotypes
Only parental chromosomes (non-

recombinants) will produce normal progeny

after fertilization

Translocations

When a segment of one chromosome becomes

attached to another

In reciprocal translocations two non-homologous

chromosomes exchange genetic material

Usually generate so-called balanced translocations

Usually without phenotypic consequences

Although can result in position effect

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Nonhomologous chromosomes

Fig. 8.13b(TE Art)

1 1

7 7

Crossover between
nonhomologous
chromosomes

Reciprocal
translocation
Nonhomologous crossover

Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

Fig. 8.13a(TE
Art)
22
22

Environmental agent
2
causes 2 chromosomes
to break.

DNA repair enzymes

recognize broken ends
and connect them.

Reactive ends

Chromosomal breakage and DNA repair

In simple translocations the transfer of genetic

material occurs in only one direction

These are also called unbalanced translocations

Unbalanced translocations are associated with

phenotypic abnormalities or even lethality
Example: Familial Down Syndrome

In this condition, the majority of chromosome 21 is

attached to chromosome 14 (Figure 8.14a)

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8-38

Familial Down Syndrome is an example of

Robertsonian translocation

This translocation occurs as such

Breaks occur at the extreme ends of the short arms of

two non-homologous acrocentric chromosomes
The small acentric fragments are lost
The larger fragments fuse at their centromeic regions to
form a single chromosome

This type of translocation is the most common type

of chromosomal rearrangement in humans
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8-39

Balanced Translocations and Gamete

Production

Individuals carrying balanced translocations have a

greater risk of producing gametes with unbalanced
combinations of chromosomes

This depends on the segregation pattern during meiosis I

During meiosis I, homologous chromosomes

synapse with each other

For the translocated chromosome to synapse properly, a

translocation cross must form

Refer to Figure 8.15

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8-40

Figure 8.15

8-42

Meiotic segregation can occur in one of three ways

1. Alternate segregation

Chromosomes on opposite sides of the translocation cross

segregate into the same cell
Leads to balanced gametes

Both contain a complete set of genes and are thus

viable
2. Adjacent-1 segregation

Adjacent non-homologous chromosomes segregate into the

same cell
Leads to unbalanced gametes

Both have duplications and deletions and are thus

inviable
3. Adjacent-2 segregation

Adjacent homologous chromosomes segregate into the same

cell
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8-41

Consider a fertilized Drosophila egg that is XX

One of the Xs is lost during the first mitotic division

This produces an XX cell and an X0 cell

The XX cell is the

precursor for this side of
the fly, which developed
as a female

The X0 cell is the

precursor for this side of
the fly, which developed
as a male

Figure 8.26

This peculiar and rare individual is termed a bilateral

gynandromorph
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8-71