Chromosomal abnormalities can cause genetic disorders by changing the number or structure of chromosomes. Some abnormalities are caused by changes in the number of sex chromosomes, such as Turner syndrome (XO) in females which causes short stature and infertility. Klinefelter syndrome (XXY) in males results in breast development and infertility. Fragile X syndrome, the most common inherited cause of intellectual disability, is caused by a trinucleotide repeat expansion in the FMR1 gene on the X chromosome.

1. PRESENTED BY,
GOPIKA BEENA CHANDRAN
RGITBT, PUNE

2. Chromosomal abnormalities
• Chromosomal mutations are abnormal
changes in the number and structure of
chromosomes.
• Numerical changes are known as ploidy
changes.
• Ploidy changes bring about abnormal
alterations in the karyotype which causes
serious genetic disorders.

4. • Some of the genetic disorders caused by
ploidy changes and abnormal karyotypes are:
a) Autosomal anomalies
b) Sex chromosomal anomalies

6. Sex Chromosome Aneuploids:Female

7. • First reported by Henry Turner & his team in 1938.
• Also called ovarian dysgenesis.
• Abnormal female(sterile) condition (44A + X0).
• Caused by sex chromosomal monosomy, absence
of an X chromosome(XO Syndrome)
• The syndrome affects 1 in 2,500 female births.

8. • Can be caused in two ways:
a) Lack of Barr body.
b) Missing only part of an X chromosome or are
mosaics, with only some cells missing an X.

9.  At birth (looks normal) :
• puffy hands
• impaired lymph flow in feet
 In childhood:
• wide set nipples
• soft nails that turn up at the ends
• slight webbing at the back of the neck
• short stature
• coarse facial features
• low hairline at the back of head
• impaired hearing with frequent ear infection due
to defect in shape of coiled part of inner ear.

10.  At sexual Maturity :
• sparse body hair develops
• rudimentary / immature ovaries
• very small uterus, normal cervix and vagina
• Intelligence is normal.
• “Turner neurocognitive phenotype” may impair
the ability to solve math problems that entail
envisioning objects in three-dimensional
space.
• may cause memory deficits

11. • Offsprings of mosaics are at high risk of having
abnormal numbers of chromosomes.
• XO syndrome is unrelated to the age of the mother.
• Life span is shortened slightly.
• Adults more likely to develop other disorders like
osteoporosis, types 1 and 2 diabetes, and colon
cancer.

12. • many signs and symptoms of XO syndrome result from
the loss of specific genes:
eg:-a) loss of a gonadal dysgenesis gene accounts for
the ovarian failure
b) absence of a transcription factor causes short
stature.
c) Deletion of another gene causes the hearing
defect.

13. What can be done?
• Hormones (estrogen and progesterone) can be
given to stimulate development of secondary
sexual structures for individuals diagnosed
before puberty, and prompt use of growth
hormone can maximize height.

14. • Presence of an extra X chromosome. (3X)
• Occurs in about one in 1000 females.

15. Symptoms
• Tall stature
• Menstrual irregularities
• Rarely mentally retarded
• Tend to be less intelligent than their siblings

16. Sex Chromosome Aneuploids: Male

17. • Due to an extra X chromosome (47, XXY) caused by
chromosomal trisomy.
• First reported by Klinefelter in 1942.
• Results from non disjunction of chromosomes
during gametogenesis.
• Observed in About 1 in 500 males.
• Appear normal in childhood.
• Abnormalities seen in adults.
• Conditions such as 44A + XXYY, 44A + XXXY, 44A +
XXXYY, 44A + XXXXY are also observed.

18. Symptoms
• rudimentary testes and prostate glands
• sparse pubic and facial hair
• They have very long arms and legs, large hands and
feet
• may develop breast tissue( gynaecomastia)
• genetic or chromosomal cause of male infertility.
• Mental retardation in cases of more than 2 X
chromosomes.
• may be slow to learn

19. XXYY
• more severe behavioral problems
• tend to develop foot and leg ulcers, resulting from
poor venous circulation.
• childhood and adolescence include:
 attention deficit disorder
 obsessive compulsive disorder
 learning disabilities
• In the teen years:
 testosterone level is low
 development of secondary sexual characteristics
is delayed, and the testes are undescended
• infertile

20. What can be done?
• Testosterone injections during adolescence can limit
limb lengthening and stimulate development of
secondary sexual characteristics.
• Men with XXY syndrome have fathered children,
with medical assistance.
• Doctors select sperm that contain only one sex
chromosome and use the sperm to fertilize oocytes.

21. XYY Syndrome
• One male in 1,000 has an extra Y chromosome.
• Found by Jacobs et al in 1965, hence called Jacob’s
Syndrome.
• can arise from nondisjunction in the male,
producing a sperm with two Y chromosomes that
fertilizes an X-bearing oocyte.

22. Symptoms
• great height
• acne
• speech and reading problems
• Sterile
• Hypergonadism
• More aggressive than normal people.

23. • Previously called ‘X linked mental retardation’.
• In 1969 , a clue emerged to the genetic basis of X-
linked mental retardation.

24. • The tips at one chromosome end dangled,
separated from the rest of each chromatid by a thin
thread.

25. • When grown under specific culture conditions
(lacking folic acid), this part of the X chromosome
was very prone to breaking—hence, the name
‘fragile X syndrome’.
• affects 1 in 2,000 males and 1 in 4000 females.

26. Symptoms
• Youngsters look normal
• By young adulthood,
 faces are very long and narrow
 a long jaw
 protruding ears.
• The testicles are very large
• Mental impairment
• behavioral problems include mental retardation, learning
disabilities,repetitive speech, hyperactivity, shyness, social anxiety,
a short attention span, language delays, and temper outbursts.

27. INHERITANCE OF FRAGILE X SYNDROME

28. • inherited in an unusual pattern
• transmitted as any X-linked trait is, from carrier mother
to affected son.
• However, penetrance is incomplete.
• One-fifth of males who inherit the chromosomal
abnormality have no symptoms.
• As they pass on the affected chromosome to all their
daughters, are called “transmitting males.”
• A transmitting male’s grandchildren may inherit fragile
X syndrome.

29. How is it caused?
• A triplet repeat mutation.
• Normally, the fragile X area contains about 30
repeats of the sequence CGG, in a gene called
the fragile X mental retardation gene (FMR1).
• In people who have the fragile chromosome
and show its effects, this region is expanded
to 200 to 2,000 CGG repeats.

30. Contd.
• The FMR1 gene encodes fragile X mental
retardation protein (FMRP).
• This protein, when abnormal, binds to and disables
several different mRNA molecules whose encoded
proteins are crucial for brain neuron function.

31. • A distinct type of disorder has been described in the
maternal grandfathers of boys who have fragile X
syndrome.
• mothers of boys with fragile X syndrome reported the
same symptoms in their fathers—
• tremors, balance problems, and then cognitive or
psychiatric difficulties (inability to plan or pay attention,
and inappropriate behaviors).
• The grandfathers’ symptoms worsen with time and can
lead to premature death.

32. FXTAS
• New condition, called fragile X-associated tremor/ataxia
syndrome (FXTAS) developed.
• Ataxia is poor balance and coordination.
• develop tremors
• balance problems
• nervousness
• memory impairment.
• the symptoms of FXTAS arise from excess FMR1 mRNA,
which attracts and disables other mRNAs.

35. • rare, being estimated to occur in about
1/30,000 live births.
• if the translocated chromosome is lyonised (X
inactivation) , the genes on the translocated
autosome also get inactivated.
• Mechanism of inactivation is not clear.
• Unbalanced X; autosome translocation can
result in multiple congenital
abnormalities/mental retardation syndrome
due to chromosomal imbalance.