Cytogenetic Disorders/CHROMOSOMAL

DISORDERS

ALTERATIONS IN CHROMOSOME NUMBER:

(GENOME MUTATION)
• Chromosome mutation –
• Genome mutation – loss or gain of whole chromosomes:
monosomy and trisomy
• sex chromosomes
• autosomes
• Structural changes within the chromosome
• Deletion
• Inversion
• Duplication
• Translocation
GENOME MUTATION
• EUPLOID (46XX or 46XY)- normal
➢ANEUPLOID –gain or loss of one
chromosome
• MONOSOMY- autosome or sex chromosome
• TRISOMY- autosome or sex chromosome
➢POLYPLOID
Polyploidy refers to gain of whole genome-
chromosome number will be 46+ 23, 46+23+23

Common cause of chromosomal numerical

disorder is - nondisjunction
MOSAICISM
• In genetics, a mosaic, or mosaicism, is the presence of two or more
populations of cells with different genotypes in one individual, who
has developed from a single fertilized egg.
• Causes-

mechanisms including chromosome non-

disjunction, anaphase lag and endoreplication
 Nondisjunction

Nondisjunction is the failure of homologous

chromosomes or sister chromatids to separate
properly during cell division.
• Non disjunction occurs when either homologues fail
to separate during anaphase I of meiosis, or sister
chromatids fail to separate during anaphase II.

• The result is that one gamete has 2 copies of one

chromosome and the other has no copy of that
chromosome. (The other chromosomes are
distributed normally.)

• If either of these gametes unites with another during

fertilization, the result is aneuploidy (abnormal
chromosome number)
• The frequency of nondisjunction is quite high in humans, but
the results are usually so devastating to the growing zygote
that miscarriage occurs very early in the pregnancy.

• If the individual survives, he or she usually has a set of

symptoms - a syndrome - caused by the abnormal dose of
each gene product from that chromosome.
Nondisjunction during early mitotic division in
developing zygote causes presence of two or
more cell line , a phenomenon known as
mosaicism

Causes of nondisjunction
1. Advanced maternal age
2. Radiation
3. Delayed fertilization after ovulation
 XX
Meiosis I

X X
Meiosis II

I I I I

Normal monosomic gamete

 XX
Meiosis I
Non disjunction

XX

Meiosis II

II II

Disomic gamete Nullisomic gamete

 XX
Meiosis I

X X
Meiosis II
Non disjunction

II I I

Disomic Nullisomic Normal monosomic

gamete gamete gametes
• Anaphase lag describes a delayed movement during anaphase,
where one homologous chromosome in meiosis or one chromatid
in mitosis fails to connect to the spindle apparatus, and fails to be
included in the reforming nucleus. Instead, the chromosome forms
a micronucleus in the cytoplasm and is lost from the cell.
• The lagging chromosome is not incorporated into the nucleus of
one of the daughter cells, resulting in one normal daughter cell and
one with monosomy.
• Endoreduplication (also referred to
as endoreplication or endocycling) is replication of the
nuclear genome in the absence of mitosis, which leads to elevated
nuclear gene content and polyploidy.
• Genetic mosaics may often be confused with chimerism, in which
two or more genotypes arise in one individual similar to
mosaicism. However, the two genotypes arise from the fusion of
more than one fertilized zygote in the early stages
of embryonic development, rather than from a mutation.
CHROMOSOME ABNORMALITIES
NUMERICAL
Autosomal Trisomies—

• Down syndrome (21) ·

• Edwards syndrome (18) ·
• Patau syndrome (13)
Trisomy 9 · Warkany syndrome 2 (8) ·
• Trisomy 22/Cat eye syndrome (22) ·
• Trisomy 16
TRISOMY-21
Trisomy 21-Down Syndrome
• Most common chromosomal disorder
• Affects 1 in 750 newborns overall, is related to
maternal age
• 1 in 1550 live births of mothers > 20 years
• 1 in 25 live births of mothers > 45 years
• Usually results from meiotic nondisjunciton of
chromosome 21
• 4% result from Robertsonian translocation of
chromosome 21 to another chromosome
• 1% result from mitotic nondisjunction of
chromosome 21 during early embryogenesis:
mosaics
TRISOMY-21
• Most trisomies (monosomies, aneuploidy) are from
maternal non-disjunction
• (non-disjunction or anaphase lag BOTH are possible)
•#1 cause of mental retardation
• Maternal age related
• Congenital Heart Defects, risk for acute leukemias, GI
atresia
Clinical Features of Down Syndrome

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© 2005 Elsevier
Symptoms of Trisomy 21

• Mental retardation
• Epicanthic fold
• Abundant neck skin
• Single palmar crease ( simian crease)
• Congenital heart disease
• Umbilical hernia
• Intestinal stenosis
• Hypotonia
SEX CHROMOSOME DISORDERS

• Problems related to sexual development and fertility

• Discovered at time of puberty
• Mental Retardation related to the number of X chromosomes
• If person has at least ONE “Y” chromosome, it is male
X-Chromosomal Disorders

• Imbalances of X-chromosomes are better tolerated than those

of autosomes
• Lyonization – Mary Lyon
• during 16th day of embryonic life one X-chromosome in
females is randomly inactivated
• inactivation persists in all subsequent cells
• X/Y linked
• Monosomy——-
• Turner syndrome (XO)

• Trisomy/tetrasomy,
other karyotypes/mosaics————
• Klinefelter's syndrome (47,XXY)
• · 48,XXYY
• · 49,XXXXY
• Triple X syndrome (47,XXX)
• · 48,XXXX ·
Klinefelter Syndrome

• A male hypogonadism that occurs when there are two or more X-

chromosomes and one or more Y-chromosomes
• Incidence is 1 in 500 male births
• Usually (82% of cases) 47,XXY
• maternal (60%) or paternal (40%) nondisjunction during meiotic
divisions
• 15% are mosaics, usually 46,XY/47,XXY
 Clinical Features

• No frontal baldness
• Poor growth of beard
• Narrow shoulder
• Breast development
• Long limbs
• Wide hip
• Female type distribution of pubic hair
• Small testicles
• Testicular abnormality does not develop before
puberty
• seminiferous tubules are atrophic resulting in
reduced spermatogenesis, infertility, small firm
testes, and increased FSH
• testosterone levels are reduced
• impotence and increased LH
• lack of secondary male sexual
characteristics
• Mental retardation is unusual but IQ may be below
normal
• Mosaics are less severely affected
Turner Syndrome

• Results from complete or partial monosomy of the X-chromosome

in females
• Most common sex chromosome abnormality in females, incidence
1 in 1000 live births
• Classical cytogenetics
• 45,X (57%)
• structural abnormalities of X-chromosomes (14%)
• mosaics (29%)
Clinical Features And Karyotypes Of Turner
Syndrome

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© 2005 Elsevier
 Changes in Chromosome Structure -Can
Affect Gene Expression

◼ A chromosomal rearrangement may affect a gene because

the break occurred in the gene itself
◼ A gene may be left intact, but its expression may be
altered because of its new location
◼ This is termed a position effect
• Structural abnormalities

• When the chromosome's structure is altered. This can

take several forms:

• Deletions: A portion of the chromosome is missing or

deleted. Known disorders in humans include Wolf-
Hirschhorn syndrome, which is caused by partial
deletion of the short arm of chromosome 4; and Jacobsen
syndrome, also called the terminal 11q deletion disorder.
• Duplications: Due to unequal cross over a portion of
the chromosome is duplicated, resulting in extra
genetic material. Known human disorders include
Charcot-Marie-Tooth disease type 1A which may be
caused by duplication of the gene encoding peripheral
myelin protein 22 (PMP22) on chromosome 17.

• Translocations: When a portion of one chromosome is

transferred to another chromosome. There are two
main types of translocations. In a reciprocal
translocation, segments from two different
chromosomes have been exchanged.
• Eg. Philadelphia chromosome- exchange of genetic
material between chromosome 22 and 9.
• Found in 95% of cases of CML
• In a Robertsonian translocation, an entire chromosome has
attached to another at the Centromere - in humans these only
occur with chromosomes 13, 14, 15, 21 and 22.

• Inversions: A portion of the chromosome has broken off, turned

upside down and reattached, therefore the genetic material is
inverted. May occur in both arm ( pericentric) or in single arm (
paracentric)

• Rings: A portion of a chromosome has broken off at both end

and form a circle or ring. This can happen with or without loss
of genetic material.

• Isochromosome: there is loss of one arm followed by duplication of

another arm to form a new chromosome with both arm made of
either p or q .
• Deletion
• Inversion
• Translocation*
• Duplication