2. A chromosomal disorder is one in which there is visible
change in the number or structure of a chromosome
A gene disorder is one in which there is mutation in
one or both alleles of a gene on autosomes, sex
chromosomes or mitochondrial DNA.
3. Chromosomal aberrations are present in 1 out of every 160
newborn infants.
2% of all pregnancies in women over 35 years old carry
chromosomal aberrations.
50% spontaneous abortions during first trimester are due to
chromosomal aberrations.
20% of fetal deaths during second trimester and 10%
stillbirths are due to chromosomal disorders.
4. Causes of chromosomal aberrations
1. Radiation
2. Viruses
3. Heat
4. Chemicals
5. Errors in recombination
5. A karyotype is a standard arrangement of a
stained metaphase chromosome spread in
which chromosome pairs are arranged in
order of decreasing length.
7. The International System for Human
Cytogenetic Nomenclature (ISCN) is used
to describe any normal or abnormal
chromosome complement.
8. Karyotypes are usually described using a
shorthand system of notations.
Numerical aberrations:
Following order is used:
Total number of chromosomes is given first,
followed by the sex chromosome complement,
and finally the description of abnormalities in
ascending numerical order. For example, a male
with trisomy 21 is designated 47,XY,+21.
9. Structural chromosomal aberrations:
Short arm of a chromosome is designated p (for petit), and
the long arm is referred to as q (the next letter to p).
In a banded karyotype, each arm of the chromosome is
divided into two or more regions by prominent bands. The
regions are numbered (e.g., 1, 2, 3) from the centromere
outward.
Each region is further subdivided into bands and sub-bands,
and these are ordered numerically.
Thus, the notation Xp21.2 refers to a chromosomal
segment located on the short arm of the X chromosome, in
region 2, band 1, and sub-band 2.
12. In man
46 number of chromosomes is called diploid (2n) number
23 number is called haploid (n) number of chromosomes
Multiples of haploid number is called euploid , e.g. diploid
46 (2n), triploid 69 (3n), tetraploid (4n) etc.
If chromosome complement is not multiple of 23, it is
called aneuploidy.
13. Triploids (3n) probably results from an ovum or sperm
having 2n number of chromosomes. Triploids usually
give rise to hydatidiform mole or spontaneous
abortion.
Tetraploids are always 92,XXX or 92,XXYY and result
from failure of early cleavage division of the zygote.
Tetraploids are either early aborted of give rise to severly
malformed fetuses.
14. Aneuploidy (trisomies and monosomies) is
the most common chromosomal aberration
and occurs 3-4% of all pregnancies. Trisomy
21 is the most common aneuploidy found in
liveborn infants.
The most common features of aneuploidy are
mental retardation, growth retardation or
dysmorphic features.
15. The usual causes of aneuploidy are
1. Meiotic Non-disjunction
2. Meiotic Anaphase lag
16. Trisomies of some autosomes and sex chromosomes
are compatible with life
Monosomies of autosomes are usually lethal except
that of sex chromosomes which are compatible with
life.
Partial monosomies of autosomes do exist in clinical
practice
17. If in the same individual are present two or more cell
population, this condition is called mosaicism.
Mosaics affecting the sex chromosomes are common,
like 45,X/46XX.
Mosaics of autosomes are less common, like
46,XX/47,XX,+21
47. Structural anomalies of chromosomes
result from chromosome breakage followed
by abnormal reunion or non-union.
48. Clastogens are those agents which
induce chromosome breaks , like
radiation, viral infections, chemicals
etc.
49. The number of induced chromosomal
aberrations increase with increasing dose
of radiation. At least 10-20 rads cause
detectable abnormalities.
50. Rearrangements (aberrations) of chromosomes cause instability
of the genetic material leading to
1. Embryonic wastage or fetal death, abortions and stillbirths
2. Viable pregnancy with carriers of balanced rearrangements
or chromosomal diseases
3. Evolutionary process
51. 1. Deletions
Deletion is a loss of a chromosome segment, resulting
in chromosome imbalance. It is also called partial
monosomy. Sometimes only a few genes are missing
called microdeletion.
52. The clinical features depends
upon the size of the deleted
segment and number and
functions of genes involved.
69. A duplication is the opposite of a deletion.
Duplications arise from an event termed
unequal crossing-over that occurs during
meiosis between malaligned homologous
chromosomes.
71. Types of translocations
1. Reciprocal translocation : Exchange of segments
between two nonhomologous chromosomes.
2. Robertsonian translocation:
72. Translocations can also be classified as
1. Balanced (even exchange of material between
two chromosomes without extra or missing
information)
2. Unbalanced: Where the exchange of
chromosome material is unequal resulting in
extra or missing genes.
73. Reciprocal translocations are common and have no phenotypic
effect.
But they can be associated with increased risk of abnormalities
in the offspring giving rise to “Duplication-Deletion Syndromes”
due to the formation of imbalanced gametes.
74.
75. Reciprocal balanced translocations
1 in 500 normal people carry a balanced reciprocal
translocation.
This type of rearrangement results from reciprocal exchange
of broken-off segments between nonhomologous
chromosomes. Such translocations are usually harmless.
76. Balanced translocations can cause genetic disorder due to following reasons;
1. Carriers of balanced reciprocal translocations have increased risks of generating
gametes with unbalanced genetic material leading to spontaneous abortions,
perinatal deaths, or children with abnormalities.
2. At the site of the break the gene may be disrupted leading to mutation.
Balanced translocations are often a cause of mental retardation, spontaneous
abortions and infertility.
Genetic counseling and genetic testing are often offered to families that may carry
a translocation.
77. This type of rearrangement involves two acrocentric
chromosomes that fuse near the centromere region
with loss of the short arms. This leaves only 45
chromosomes since two chromosomes have fused
together to make one which may be monocentric or
dicentric. This has no direct effect on the phenotype
since the only genes on the short arms of
acrocentrics are common to all of them and are
present in variable copy number (nucleolar
organiser genes).
Robertsonian translocations
78.
79. The corresponding marker chromosome formed
by the fusion of the satellited short arms of
these chromosomes is usually lost or appear as
a marker chromosome.
The unbalanced gametes of Robertsonian
translocations produce trisomy or monosomy
for a complete chromosome.
82. Robertsonian translocations have been seen involving all
combinations of acrocentric chromosomes, 13,14,15,21,22.
The most common translocation in humans involves
chromosomes 13 and 14 and is seen in about 0.97 / 1000
newborns.
Carriers of Robertsonian translocations are not associated
with any phenotypic abnormalities, but there is a risk of
formation of unbalanced gametes which lead to
miscarriages or abnormal offspring.
For example, carriers of Robertsonian translocations
involving chromosome 21 have a higher chance of having a
child with Down syndrome.
83. Some human diseases caused by translocations are:
Cancer: leukemia (acute myelogenous leukemia and
chronic myelogenous leukemia), Ewing's sarcoma.
Infertility
Down syndrome is caused in a minority (5% or less)
of cases by a Robertsonian translocation of the
chromosome 21 long arm onto the long arm of
chromosome 14.
84. The International System for Human Cytogenetic
Nomenclature (ISCN) is used to denote a translocation
between chromosomes. The designation t(A;B)(p1;q2) is
used to denote a translocation between chromosome A
and chromosome B. The information in the second set of
parentheses, when given, gives the precise location
within the chromosome for chromosomes A and B
respectively—with p indicating the short arm of the
chromosome, q indicating the long arm, and the
numbers after p or q refers to regions, bands and
subbands seen when staining the chromosome with a
staining dye.
86. A female presented with amenorrhea and
chromosomal constitution 45,XY,t(13q:14q)
May be a case of Testicular Feminization
87.
88.
89.
90.
91. 4. Inversion
An inversion is a chromosomal aberration
in which a broken segment of the
chromosome is reversed end to end.
92. Two breaks occur in the same chromosome
followed by inversion of the intermediate
segment before joining of the loose ends.
93. Types of inversions
1. Paracentric: These inversions do not include
the centromere and both breaks occur in one arm
of the chromosome.
2. Pericentric: These inversions include the
centromere and there is a break point in each
arm.
94.
95.
96.
97. An inversion is a balanced
rearrangement does not cause abnormal
phenotype in the carrier. However,
carriers of inversions are at high of
producing unbalanced gametes that may
lead to unbalanced offspring.
98. The most common inversion
seen in human chromosomes
is a small pericentric inversion
of chromosome 9.
99. 5. Ring chromosome
Breakage at both ends of a chromosome and
subsequently joining of the two broken ends
forming a ring. Rings may also be formed by
telomere dysfunction triggering fusion of
reactive chromosome ends without major loss
of genetic material.
The distal segments are lost.
100.
101.
102.
103.
104.
105.
106. 5. Isochromosome
It is a chromosome in which one arm is
missing and the other is duplicated.
107. An isochromosome has lost one of its arms and
replaced it with an exact copy of the other arm.
The most common isochromosome is
isochromoomes of chromosomeX, i(Xq). An
isochromosome may have two centromeres
108. An isochromosome lacks one arm (e.g. the short arm)
and has an extra arm (e.g. the long arm) of the
affected chromatid (or vice versa).
It can also be formed by union of two short arms or
two long arms of two sister chromatids or
homologous chromosomes.
A person with 46 chromosomes and carrying an
isochromosome has single copy of genetic material of
one arm and three copies of the genetic material of the
other arm. So, he is partially monosomic and partially
trisomic.
117. Dicentric chromosome
Every normal chromosome has one centromere that pulls it to the
pole of the spindle and is essential to the chromosome at the time
of cell division.
However, a dicentric chromosome is pulled to the opposite poles
of the spindle when the cell divides, causing the chromosome to
break. The broken ends of the chromosome fuse with each other
in the daughter cell and form a new dicentric chromosome.
This remarkable sequence of events was discovered by Barbara
McClintock in 1941 who studied dicentric chromosomes in maize
(corn) and later won a Nobel Prize.
118.
119.
120. 2. Marker chromosomes
An additional small chromosome of unknown
origin is called a marker chromosome.
About 90% are derived from acrocentric
chromosomes mostly from chromosomes 15.
121. Marker chromosomes are also called
supernumerary chromosomes.
Nature of marker chromosomes is usually
identified by molecular cytogenetic
techniques involving FISH with specific
DNA probes.
122. Cat-eye syndrome is a dysmorphic syndrome
having a supernumerary chromosome formed by
the short arm (p) and a small section of the long
arm (q) of human Chromosome 22. So there
present three (trisomic) or four copies
(tetrasomic) of the genetic material instead of
the usual two copies.
Cat-eye syndrome has iris coloboma, anal atresia,
microcephaly, cardiac and renal anomalies.
123.
124. 3. Insertions
An insertion is a non-reciprocal type of
translocation. A segment removed from one
chromosome is inserted into a different
chromosome, either in its original orientation or
inverted.
Carriers of insertions can make unbalanced
gametes so abnormal offspring.
125. 3. Microdeletions
Microdeletions are extremely small and can occur
within a gene or extend over several adjacent
genes. These deletions can be detected by high
resolution techniques or by FISH.
Deletions smaller than 2000kb can not be
identified by ordinary banding technique.
127. 10 yrs old female had
generalized hypotonia,
clumsy gait and severe
mental retardation. At birth
she was hypotonic and had
feeding difficulties during
first year of life and
required NG feeding. She
had voracious appetite since
infancy. Her wt was 90 kg
and Ht 138 cm. Craniofacial
examination showed
almond-shaped eyes with
squit. Chromosomal
analysis showed 46,XX.
132. The most common cause of mental retardation in males.
1 in 1000 in male population
Coarse face, mental retardation, long ears, long face, and large
testes after puberty.
X-linked. Gene at Xq27.3
Folic acid deficient medium 199 is used to see expression of
fragile site.
Molecular diagnosis is also possible to identify tri-nucleotide
repeats (CGG).
133.
134.
135. 5’
“Upstream” “Downstream”
Start of
transcription
5’ untranslated
region
Termination codon
3’ untranslated region
Figure 4. Schematic view of the gene mutation in fragile X syndrome (FMR1)
showing trinucleotide repeats their expansion in relation with emergence of this
syndrome. Within the gene the exons (coding regions) are shown in red and
introns (intervening sequences) in black color.
(CGG) 15-50
Normal allele
(CGG) 50-200
(CGG) 200-1000
Premutation
Full mutation
136. A major limitation of karyotyping is that it
is applicable only to cells that are dividing
or can be induced to divide in vitro.
Karyotyping is slow and report may be
available after some days.
137. The above limitation of karyotyping can be
overcome by using following techniques
1. Fluorescence in situ hybridization (FISH)
2. Chromosome painting
3. Spectral karyotyping
139. It is used to detect and localize the presence or absence of
specific DNA sequences on chromosomes.
FISH uses fluorescent probes that bind to only those parts of
the chromosome with which they show a high degree of
sequence complementarity. Fluorescence microscopy can be
used to find out where the fluorescent probe bound to the
chromosomes.
FISH can also be used to detect and localize specific mRNAs
within tissue samples.
140. FISH is a cytogenetic technique developed by Christop
Lengauer.
In FISH technique first of all the DNA on slide is
denatured, then exposed to DNA probes that recognize
chromosome-specific sequences. Such probes are
labeled with fluorescent dyes and applied to interphase
nuclei. The probe binds to its complementary sequence
on the chromosome and thus labels the specific
chromosome, which can then be visualized under a
fluorescent microscope. Thus, FISH can be used to
enumerate chromosomes in interphase nuclei as well as
metaphase spread.
142. FISH at interphase nuclei can be used
for rapid diagnosis of
Trisomy 21
Trisomy 13
Trisomy 18
SRY gene, etc
143. FISH metaphase spread
FISH. A metaphase spread in which two
fluorescent probes, one for the terminal ends of
chromosome 22 and the other for the D22S75
locus, which maps to chromosome 22, have
been used. The terminal ends of the two
chromosomes 22 have been labeled. One of the
two chromosomes does not stain with the probe
for the D22S75 locus, indicating a
microdeletion in this region. This deletion gives
rise to the 22q11.2 deletion syndrome.
144. Spectral karyotyping: By using a combination of five
fluorochromes and appropriate computer-generated
signals, the entire human genome can be visualized
