Chromosomal Abnormalities I

SDK
October 21, 2013

Chromosomes

Chromosomes are tiny string-like structures in cells of

the body that contain the genes
Each person normally has 23 pairs of chromosomes, or
46 in all.
We inherit one chromosome per pair from our mother
and one from our father.

Chromosomal Abnormalities

However, When a baby is born with too many

or too few chromosomes, or with one or more
chromosomes that are missing a piece or are
rearranged, is suffering from chromosomal
abnormalities.

Chromosomal Abnormalities

About 1 in 150 babies is born with a chromosomal

abnormality.
A change in the number or structure of chromosomes can
cause problems with growth, development, and function
of the bodys systems.
Children with a chromosomal abnormality have mental
and/or physical birth defects.
95% of chromosomally abnormal conceptus are aborted
spontaneously
Abortion mostly occurs in 1st trimester

Chromosomal Abnormalities
The majority of human chromosomal abnormalities occur in
the Autosomes.
Most of these abnormalities are monosomies or trisomies.

In the case of a monosomy, there is only one copy of each kind of

chromosome instead of the usual pair of homologous chromosomes.
With trisomy, there are three of each type of chromosome.

All fetuses with autosomal monosomies spontaneously abort

early in pregnancy.
Likewise, almost all fetuses with trisomies die before birth.
Those that survive usually have multiple physical
malformations, mental retardation, and relatively short lives.

Chromosomal Disorders
50% of 1st trimester miscarriages(Before 24
week)
5% of stillbirths(from 24 week to)
0.5% of live borns
Down syndrometrisomy 21
Fragile X syndrome

Somatic cell abnormalities in cancers

Chromosomal
Abnormalities
What are chromosome abnormalities?

A chromosome abnormality reflects an

abnormality of chromosome number or
structure. We can classify them into:
I- NUMERICAL ABNORMALITIES
II- STRUCTURAL ABNORMALITIES

I. NUMERICAL ABNORMALITIES

NUMERICAL ABNORMALITIES
HOW DOES IT HAPPEN
Chromosomal abnormalities in the number of
chormosomes.

1. Euploidy
2. Aneuploidy

NUMERICAL ABNORMALITIES
HOW DOES IT HAPPEN
1.Euploidy: Cells has chromosomes multiple of
23 such as
23, 46. 69, and 92

These may be normal or Abnormal

Abnormal
Normal
Tripoloidy 3 copies of each chromosome 23 x 3= 69

1cells
Haploid
egg fertilized
by 2 sperms
: Gametes
has 1 copy each 23 cells
Tetra ploidy.
4 copiescells
of each
23x2=
x 4=46
Diploid
cells: Somatic
has 2chromosome
copy each 23
69
1 egg fertilized by 3 sperms

2.Aneuploidy
Deviation from normal number of chromosomes due to
loss or gain of specific chromosomes.
Generally caused by non-disjunction of chromosome
during meiosis.
It is a major cause of human reproductive failure.
Most human miscarriages are aneuploids.
All autosomal monosomies are lethel
Most of all Trisomies are also lethel
But some Trisomies[ three copies of a particular chromosomes] are
compatible with survival to term with chromosomes 13, 18, and 21.

Types of Aneuploidy
The different conditions of aneuploidy are:

Nullisomy - the loss of both pairs of homologous chromosomes;

individuals are called nullisomics and their chromosomal
composition is 2N-2. Humans with this condition will not
survive.
Monosomy - the loss of a single chromosome; individuals are
called monosomics and their chromosomal composition is 2N-1
Trisomy - the gain of an extra copy of a chromosome; individuals
are called trisomics and their chromosomal composition is 2N+1
Tetrasomic - the gain of an extra pair of homologous
chromosomes; individuals are called tetrasomics and their
chromosomal composition is 2N+2

Cause of Aneuploidy
The development of aneuploids may have arisen by a
process called non-disjunction.
Non-disjunction occurs when paired chromosomes do
not separate either during meiosis I or meiosis II.
The direct result of this event is that gametes develop
that have too few or too many chromosomes.
If this occurs during meiosis I normal gametes are not
developed,
If it occurs during meiosis II half of the gametes will be
normal and the other half will be abnormal.

Meiosis(Normal)

Non Disjunction at Meiosis I

Non Disjunction at Meiosis II

Non Disjunction (Quick Review)

Autosomal Chromosome Problems

Down Syndrome (Trisomy 21)

First identified by Dr. John Langdon Down in
1866
Trisomy 21
Associated with increased maternal age
The result of an extra copy of chromosome 21.
People with Down syndrome are 47, 21+.

Down Syndrome (Trisomy 21)

Down syndrome affects 1:700 children and alters the child's
phenotype either moderately or severely:
Characteristic facial features, short stature; heart defects
Susceptibility to respiratory disease, shorter lifespan
Often sexually underdeveloped and sterile, usually some degree of
mental retardation.
Down Syndrome is correlated with age of mother but can also be the
result of nondisjunction of the father's chromosome 21 in 1%
cases.

Clinical findings
Newborn hypotonia , increased sleepiness , excess nuchal skin
Mental retardation
The average IQ of children with Down syndrome is around 50,
compared to normal children with an IQ of 100.
Small stature
Craniofacial findings brachycephaly ( flat occiput ) , epicanthic
folds , upward slanting eyes , protruding tongue, low set ears , flat
nose , low nasal bridge , high arched palate .
Short broad hands
Clinodactyly ( incurving ) little finger
ASD,VSD , PDA
Anal duodenal atresia
Happy & affectionate

Clinical Features

Patau syndrome (Trisomy 13)

Patau Sundrome, also known as Trisomy 13 and Trisomy D.
Is a chromosomal abnormality, a syndrome in which a patient
had an additional chromosome 13 due to non-disjunction of
chromosomes during meiosis.
Some are caused by Robertsonian Translocations.
The extra chromosome 13 disrupts the normal course of
development, causing serious eye, brain, circulatory defects as
well as cleft palate, heart and kidney defects.
. 1:5000 live births. Children rarely live more than a few
months.

Clinical Features
Polydactyl
Cleft Palate
Cutis Aplasia(Congenital absence of skin). is a
congenital focal absence of epidermis.
Kidney Failures

Patau syndrome (Trisomy 13)

Edwards Syndrome (Trisomy 18)

Edwards Syndrome also kwnon as Trisomy 18 (T18) or Trisome
E.
It is a genetic disorder caused by the presence of all of an extra
18th chromosome (Trisomy 18).
It is named after John H. Edwards, who first described the
syndrome in 1960.
It is the second most common autosomal trisomy, after Down
Syndrome, that carries to term.
Edwards Syndrome occurs in around one in 6,000 live births and
around 80 % of those affected are female.
Children with full Trisomy 18 generally do not live more than a
few months

Edwards Syndrome (Trisomy 18)

Clinical Features

Almost every organ system affected

Upturned Nose
Kidney Malformations
Omphalocele.
An omphalocele is a type of abdominal wall defect in which the
intestines, liver, and occasionally other organs remain outside of
the abdomen in a sac because of a defect in the development of the
muscles of the abdominal wall.
Arthrogryposis
Arthrogryposis, is characterized by multiple joint contractures
and can include muscle weakness and fibrosis.
Microcephaly
Underdeveloped Phalanges

DiGeorge syndrome(Monosomy 22)

22q11.2 deletion syndrome
Congenital thymic aplasia, and thymic
hypoplasia
Is a syndrome caused by the deletion of a small
piece of chromosome 22.
The deletion occurs near the middle of the
chromosome at a location designated q11.2
Characteristic signs and symptoms may include birth defects
such as congenital heart disease, defects in the palate, most
commonly related to neuromuscular problems

DiGeorge syndrome

Precursor T cell differentiation defect

Lack of T helper (Th) cells , Cytotoxic T cells (CTL) and
T regulatory (Treg) cells
B cells are present but T-dependent B cell responses are
defective
Anti-viral and anti-fungal immunity impaired
Developmental defect in the 3rd and 4th pharyngeal pouch
Results in facial defect and congenital heart disease
Treated with thymic transplant
Autosomal dominant trait

Pallister-Killian Syndrome
Pallister-Killian Syndrome also known as Tetrasomy 12p
Mosaicism or Pallister Mosaic Aneuplody Syndrome.
Is a genetic disorder occurring in humans.
Pallister-Killian occurs due to the presence of the anomalous
extra isochromosome 12p, the short arm of the twelfth
chromosome.
An isochromosome is a chromosome that has lost one of its arms and replaced it with an
exact copy of the other arm

This leads to the development of Tetrasomy 12p. Because not all

cells have the extra isochromosome, Pallister-Killian is a mosaic
condition.
TETRASOMY in the smaller arm of chromosome 12.
2n+2 or 48 chromosomes

Clinical findings
Hypo/Hyper Pigmentation
Epilepsy
High Foreheads
Flat nose
Supernumerary Nipples
Psychomotor Retardation

IDIC 15
(Isodicentric 15)
Isodicentric 15, also called idic(15), partial tetrasomy 15q, or
inverted duplication 15 (inv dup 15).
Isodicentric chromosome 15 is the scientific name for a
specific type of chromosome abnormality.
Individuals with isodicentric chromosome 15, or "idic(15)",
have 47 chromosomes instead of the typical 46 chromosomes.
The extra chromosome is made up of a piece of chromosome 15
that has been duplicated end-to-end like a mirror image.
Individuals with idic(15) have a total of four copies of this
chromosome 15.
With extra genetic material in chromosome 15.

47 chromosomes

IDIC 15
(Isodicentric 15)

Clinical Features
Epicanthal Folds in the Eye
Short Stature
Delayed Language Development
Seizures
Some are Mentally Retarded

Which of the following is an example of

monosomy?
A. 46,XX
B. 47,XXX
C. 69,XYY
D. 45,X

Sex Chromosome(X Y) Abnormalities

Male Sex
Female Sex

X Chromosome

Y Chromosome

Sex Chromosome Abnormalities

The majority of known types of chromosomal

abnormalities involve Sex chromosomes.
In frequency of occurrence, they are only
slightly less common than
autosomal
abnormalities.
However, they are usually much less severe in
their effects.
Sex chromosome abnormalities are gender
specific.

Male Sex
1. Klinefelter Syndrome

Klinefelter syndrome: males inherit one or more extra X chromosomes--their

genotype is XXY.
1 in 660 live male births
They characteristically have relatively high-pitched voices, asexual to feminine body
contours as well as breast enlargement, and comparatively little facial and body hair.
They are sterile or nearly so, and their Testes and Prostat glands are small.
As a result, they produce relatively small amounts of testosterone.
Higher risk of breast cancer, extragonadal germ cell tumor and
autoimmune diseases
47,XXY-90% cases
15% cases are mosaics

Male Sex
1. Klinefelter Syndrome

Clinical features
Scarce beard
Pubic ,chin & axillary hair absent
Longer fingers and arms
Sterile
Delicate skin
Normal lifespan

2. XYY Syndrome

XYY syndrome males inherit an extra Y

chromosome, their genotype is XYY.
As adults, these "super-males" are usually tall (above
6 feet) and generally appear and act normal.
However, they produce high levels of testosterone.
During adolescence, they often are slender, have
severe facial acne, and are poorly coordinated.
They are usually fertile and lead ordinary lives as
adults.

2. XYY Syndrome

Female Sex
1. Turner syndrome

Female Sex
1. Turner syndrome
Turner syndrome occurs when females inherit only one X
chromosome--their genotype is X0.
If they survive to birth, these girls have abnormal growth
patterns.
They are short in stature, averaging 4 foot 7 inches as adults, and
often have distinctive webbed necks (i.e., extra folds of skin),
small jaws, and high arched palates.
They generally lack prominent female secondary sexual
characteristics. They have exceptionally small, widely spaced
breasts, broad shield-shaped chests, and turned-out elbows.
Their ovaries do not develop normally and they do not ovulate.

Female Sex
1. Turner syndrome

Genes associated with most of the features of

Turner(SHOX genes)
Researchers have not determined which genes on the X
chromosome are associated with most of the features of Turner
syndrome.
They have, however, identified one gene called SHOX(short
stature homeo box) that is important for bone development and
growth.
The loss of one copy of this gene likely causes short stature
and skeletal abnormalities in women with Turner syndrome.

Cytogenetic Location of Turner(SHOX )genes

Cytogenetic Location: The SHOX gene is
located on the short (p) arm of the X
chromosome at position 22.33 ; on the short
(p) arm of the Y chromosome at position 11.3.
Xp22.33;
Yp11.3

2. Triple-X females
Inherit three X chromosomes--their genotype is
XXX or more rarely XXXX or XXXXX. As
adults, these "super-females" are usually an
inch or so taller than average with unusually
long legs, but otherwise appear normal.
They have normal development of sexual
characteristics and are fertile. They may have
slight learning difficulties and are usually in the
low range of normal intelligence (especially the
XXXX and XXXXX individuals).

Sex Chromosome Abnormalities

Female
Genotype

Syndrome

Male
Genotype

Syndrome

XX

normal

XY

normal

XO

Turner

XXY

Klinefelter

XXX

Triple-X

XYY

XYY

Mosaicism and Chimerism

Mosaics and chimeras are persons that have more than one
genetically-distinct population of cells.
In mosaics, the genetically different cell types all arise from a
single zygote.
Mosaic: The post-fertilization occurrence of two or more
cell lines with different genetic or chromosomal
constitutions within a single individual or tissue.
an organism or one of its parts composed of cells of more
than one genotype.
In chimeras originate from more than one zygote.

Mosaicism
Chromosomal mosaicism: When an individual has two or
more cell populations with a different chromosomal makeup,
this situation is called chromosomal mosaicism.
Germline mosaicism: Two or more genetic or cytogenetic
cell lines confined to the precursor (germline) cells of the egg
or sperm; formerly called gonadal mosaicism

Chimerism(cellular mosaicism )
The occurrence in an individual of two or more cell
populations of different chromosomal constitutions, derived
from different zygotes.
This contrasts with mosaicism in which the different cell
populations are derived from a single zygote.
Chimeras are formed from at least four parent cells (two
fertilized eggs or early embryos fused together).
Each population of cells keeps its own character and the
resulting organism is a mixture of tissues. Chimeras are
typically seen in animals; there are some reports of human
chimerism

Chimerism(cellular mosaicism )
This condition is either inherited, or it is acquired
through the infusion of allogeneic hematopoietic cells
during transplantation or transfusion.
In nonidentical twins, chimerism occurs by means of
blood-vessel anastomoses.
The likelihood of offspring being a chimera is
increased if it is created via in vitro fertilization

Chromosome instability syndromes

They are a group of inherited conditions
associated with chromosomal instability and
breakage. They often lead to an increased
tendency to develop certain types of
malignancies.
The
following
chromosome
instability
syndromes are known:
-

Ataxia Telagiectasia
Bloom Syndrome
Fanconi Anaemia

Thank You