Structural & Numerical

Abnormalities of Cell
Division
By Dr. Tayyaba Qureshi
Learning Objectives
• Identify the appropriate stage of cell division in clinical scenarios provided
by facilitator
• Describe the structural abnormalities in chromosomes like
➢ Euploid
➢ Aneuploid
➢ Trisomy
➢ Nondisjunction
➢ Translocation
• Co-relate the structural abnormalities with clinical conditions like Downs
Syndrome, Klinefelters Syndrome, Turner syndrome
Case scenario
• A vitally stable newborn was
brought to a neonatologist right
after birth, for routine neonatal
examination. The doctor was
alarmed to see the dysmorphic
features.
• Karyotyping showed trisomy 21.
Syndrome

• A pattern of multiple defects thought to be pathogenetically related

and not known to represent a single sequence or defect
• Often implies a single cause
• The pattern of defects is known
Mitosis or meiosis may occasionally malfunction
• Many defective zygotes, blastocysts, embryos
abort spontaneously
• Frequency of chromosomal aberrations in
these embryos is 50%
• Chromosomal abnormalities account for 10%
of major birth defects
• Gene mutations account for an additional 8%
Changes in chromosome

Numeric Structural
Numeric Chromosomal Abnormalities

• In the United States, approximately

1 in 120 neonates
• Usually result from nondisjunction
Non disjunction ?
Nondisjunction

An error in cell division in which there is failure

of a chromosomal pair or two chromatids of a
chromosome to disjoin during mitosis or meiosis
 Chromosomal pair
or chromatids pass
to one daughter cell

Other daughter cell

receives neither
INACTIVATION OF GENES

During embryogenesis, one of the two X chromosomes

in female somatic cells is randomly inactivated

Appears as a mass of sex chromatin

Occurs during implantation

 Maternal X Paternal X

Mitosis

Inactivation
of X

Inactivation of Inactivation of Inactivation of Inactivation of

Paternal X Maternal X Paternal X Maternal X
EUPLOIDY

Exact multiple of n
Polyploid

• A person who has a

chromosome number that is
a multiple of the haploid
number of 23 other than the
diploid number (e.g., 69)
TRIPLOIDY
• Triploid fetuses have severe intrauterine
growth retardation with severe head-body
disproportion
• Results from fertilization of an oocyte by two
sperms (dispermy)
• Failure of one of the meiotic divisions
resulting in a diploid oocyte or sperm, may
account for some cases
TETRAPLOIDY
• Doubling of the diploid chromosome number from 46 to 92
• Occurs during the first cleavage division of the zygote
• Embryos abort very early
• An empty chorionic sac is recovered (blighted embryo).
Aneuploidy
• Any chromosome number that is not
euploid(multiple of n)
• 3% to 4%
• Missing chromosome: monosomy
• Extra chromosome present: trisomy
• Nondisjunction during cell division
Trisomy of Autosomes
• Most common abnormalities of chromosome number.
• The usual cause of this numeric error is meiotic nondisjunction of
chromosomes
• Occurs with increasing frequency as maternal age increases.
• Trisomy of autosomes is mainly associated with three syndromes

Trisomy 21 Trisomy 18 Trisomy 13

Down syndrome
• The most common
aneuploidy seen in older
mothers
• Errors in meiosis occur with
increasing maternal age
• 95% have trisomy 21
• 4% have an unbalanced
translocation
• 1% is caused by mosaicism
Trisomy 18
• Edward syndrome
Trisomy 13
• Patau syndrome
• The incidence is approximately 1
in 20,000 live births
• More than 90% of the infants die
in the first month after birth
• Approximately 5% live beyond 1
year.
CHROMOSOMAL SYNDROME INCIDENCE USUAL CLINICAL MANIFESTATIONS
ABERRATION
Trisomy 21 Down 1 in 800 Mental deficiency; brachycephaly, flat nasal
syndrome bridge; upward slant to palpebral fissures;
protruding tongue; transverse palmar flexion
crease; clinodactyly of the fifth digit; congenital
heart defects; gastrointestinal tract abnormalities

Trisomy 18 Edward 1 in 8000 Mental deficiency; growth retardation; prominent

syndrome occiput; short sternum; ventricular septal defect;
micrognathia; low-set, malformed ears, flexed
digits, hypoplastic nails; rocker-bottom feet

Trisomy 13 Patau 1 in 12000 Mental deficiency; severe central nervous system

syndrome malformations; sloping forehead; malformed
ears, scalp defects; microphthalmia; bilateral cleft
lip and/or palate; polydactyly; posterior
prominence of the heels
Trisomy of Sex Chromosomes
• No characteristic physical findings
in infants or children, the disorder
is not usually detected until
puberty
• Two masses of sex chromatin are
found in the nuclei of XXX females
(trisomy X)
• The nuclei of XXY males (Klinefelter
syndrome) contain a mass of sex
chromatin
Turner Syndrome
• Only monosomy compatible with
life
• Incidence is 1 in 8000 live births.
• One half of affected individuals
have 45,X
• Others have a variety of
abnormalities of a sex
chromosome
• The phenotype of Turner
syndrome is female
• 18% of all abortions caused by
chromosomal abnormalities.
• Nondisjunction is in the paternal
gamete
• In approximately 75% of cases; it is
the paternal X chromosome that is
usually missing.
KLINEFELTER SYNDROME
• Clinical features found only in males
• Sterility
• Testicular atrophy
• Hyalinization of the seminiferous tubules
• Gynecomastia
• 47 chromosomes
• XXY type
• Barr body is found in 80% of cases
TRIPLE X SYNDROME
• Girls frequently have problems
with speech and self-esteem.
• They have two sex chromatin
bodies in their cells.
 Trisomy of Sex Chromosomes
Chromosome Sex Incidence Usual characteristics
complement

47,XXX Female 1 in 1000 Normal in appearance; usually fertile; 15% to 25% are
mildly mentally deficient

47,XXY Male 1 in 1000 Klinefelter syndrome: small testes, hyalinization of

seminiferous tubules; aspermatogenesis; often tall
with disproportionately long lower limbs. Intelligence
of siblings is less than normal. Approximately 40% of
these males have gynecomastia

47,XYY Male 1 in 1000 Normal in appearance, usually tall, and often exhibit
aggressive behavior
MOSAICISM
• A person with at least two cell lines
with two or more genotypes is a
mosaic
• The autosomes or sex chromosomes
may be involved
• The defects usually are less serious
than in persons with monosomy or
trisomy
• Usually results from nondisjunction
during early cleavage of the zygote
Increased maternal age
• Current trend of increasing maternal age
• By the end of this decade, children born to
women older than 34 years will account for
39% of infants with trisomy 21.
• Translocation or mosaicism occurs in
approximately 5% of the affected children.
Structural Chromosomal Abnormalities
Chromosome
banding
Structural Chromosomal Abnormalities
• 1 in 375 neonates.
• Result from chromosome breakage
• Followed by reconstitution in an
abnormal combination
• May be induced by environmental
factors such as ionizing radiation,
viral infections, drugs, and
chemicals.
Translocation
• Transfer of a piece of one chromosome to a
nonhomologous chromosome
• If two nonhomologous chromosomes
exchange pieces, it is called a reciprocal
translocation
• Does not necessarily cause abnormal
development
• Between 3% and 4% of infants with Down
syndrome have translocation trisomies
Deletion
• When a chromosome breaks, part of it may be lost
Contiguous gene syndromes
• When the deletions & microduplications span several contiguous
genes
Cri Du Chat syndrome
• A partial terminal deletion
from the short arm of
chromosome 5
• Affected infants have a weak
cat-like cry, microcephaly,
severe mental deficiency, and
congenital heart disease
Prader-Willi syndrome (PWS)
• Associated with short
stature, mild mental
deficiency, obesity,
hyperphagia and
hypogonadism
• A visible deletion of band
q12 on paternal
chromosome 15
Angelman syndrome (AS)
• Characterized by severe mental
deficiency, poor motor
development ,prolonged periods
of laughter and ataxic movements
of the limbs and trunk.
• Maternal chromosome 15 is
involved
Genomic imprinting
• Differential expression of genetic material depends on the sex of the
transmitting parent.
• Loss of expression of the active allele leads to neurodevelopmental
disorders
Let’s create a story
Let’s create a story
Fragile X syndrome
• CGG repeats in the FMRI
gene on the long arm of
the X chromosome
Thankyou