Molecular Pathology

1
Medical Genetics

• LECTURE
• Klinefelter,Turner Down Syndrome
• Muhammad Faiyaz-Ul-Haque, PhD, FRCPath

2
Lecture Objectives

• By the end of this lecture, the students should
  be able to
• Define non-disjunction and describe its
  consequences for meiosis and mitosis.
• Classify chromosomal abnormalities
• Understand the common numerical chromosomal
  disorders mono and trisomy
• Understand the common numerical sex chromosome
  disorders Turners Klinefelters syndromes

3
Stages of Mitosis Meiosis
Mitosis
Meiosis
4
Non-disjunction in Meiosis

• Nondisjunction ("not coming apart") is the
  failure of chromosome pairs to separate properly
  during meiosis stage 1 or stage 2.
• As a result, one daughter cell has two
  chromosomes or two chromatids, and the other has
  none.
• The result of this error is a cell with an
  imbalance of chromosomes (Aneuploidy)

5
Meiotic non-disjunction

• can affect each pair of chromosomes
• is not a rare event
• non disjunction in first meiotic division
  produces 4 unbalanced gametes.
• non disjunction in second division produces 2
  normal gametes 2 unbalanced gametes

6
MEIOSIS
MITOSIS
7
(No Transcript)
8
Down Syndrome
9
Downs Syndrome

• Three copies of chromosome 21

10

• 3 copies trisomy

1 copy monosomy
11
Down syndrome, trisomy 21Karyotype 47, XY, 21

• The incidence of trisomy 21 rises sharply with
  increasing maternal age
• Most cases arise from non disjunction in the
  first meiotic division
• The father contributing the extra chromosome in
  15 of cases (i.e. Down syndrome can also be the
  result of nondisjunction of the father's
  chromosome 21)
• A small proportion of cases are mosaic and these
  probably arise from a non disjunction event in an
  early zygotic division

12
Down Syndrome

• Short, broad hands
• Stubby fingers
• Rough skin
• Impotency in males
• Mentally retarded
• Small round face
• Protruding tongue
• Short lifespan

13
Features of Down Syndrome

• Low muscle tone
• Head and facial malformations
• Abnormalities of the extremities
• Developmental delays
• Heart malformations
• Increased risk of infectious disease
• Early death

14
Down Syndrome
15
Turners Syndrome
16
Turner Syndrome

• Monosomy of sex chromosome
• (only one X chromosome present)
• Occurrence 1 in 2500 live female births

17
Turners syndrome (Monosomy X 45, XO)

• Monosomy of sex chromosome (only one X chromosome
  present)
• Occurring in 1 in 2500 phenotypic females
• The only viable monosomy in humans
• Characteristics Webbed neck, Individuals are
  genetically female, not mature sexually, Sterile,
  Short stature, Broad chest, Low hairline, Streak
  ovaries, Normal intelligence, Normal life span

18
Features of Turner Syndrome

• Short stature
• Lack of ovarian development
• Neck abnormalities
• Skeletal disorders
• Increased risk of osteoporosis, cardiovascular
  constriction, diabetes, and kidney and thyroid
  problems

19
XO Turner Syndrome
96-98 do not survive to birth
Turner Syndrome (XO), Incidence 1 in 2500 female
births
20
Turners Syndrome
Cardiovascular Bicuspid aortic valve
Coarctation of the aorta Thoracic aortic
aneurysm (aortic root dilatation) Skeletal
Short stature Short fourth metacarpal/matatarsal
bone may be unusually short (/- short 3rd and
5th). Osteoporosis (due to lack of estrogen)
Scoliosis Reproductive Women with Turner
syndrome are almost universally infertile.
21
Klinefelters Syndrome
22
Klinefelters Syndrome
1 in 1,100 births 47 chromosomesXXY only 47,
XXY 23 Trisomy Nondisjunction
23
Klinefelter Syndrome 47,XXY males

• Male sex organs unusually small testes which
  fail to produce normal levels of testosterone?
  breast enlargement (gynaecomastia) and other
  feminine body characteristic
• Patients are taller and thinner than average and
  may have a slight reduction in IQ but generally
  they have normal intelligence
• No spermatogenesis ? sterile
• Very rarely more extreme forms of Klinefelter
  syndrome occur where the patient has 48, XXXY or
  even 49, XXXXY karyotype. These individuals are
  generally severely retarded.
• Klinefelter Syndrome (XXY), Incidence 11000
  male births

24
Klinefelters Syndrome
Scarce beard Longer fingers and
arms Sterile Delicate skin Low mental
ability Normal lifespan
Brown spots (nevi)
25
Features of Klinefelter Syndrome

• Tall
• Sexually underdeveloped
• Infertility
• Sparse facial and body hair
• Developmental delays
• Increased risk of autoimmune disorders, breast
  cancer, osteoporosis, leg ulcers, depression, and
  dental problems

26
Sex chromosome unbalance is much less deleterious
47, XYY May be without any symptoms. Males are
tall but normally proportioned. 10 - 15 points
reduction in IQ compared to sibs. XXX females It
seems to do little harm, individuals are fertile
and do not transmit the extra chromosome. They do
have a reduction in IQ comparable to that of
Kleinfelter's males
27
When to do a chromosomal test

• Prenatal
• maternal agegt37yrs USS changes Family history
• Triple test increased risk
• Postnatal
• Learning developmental disability growth
  retardation
• Infertility
• Recurrent miscarriage, primary infertility

28
Aneuploidy

• Autosomal
• Trisomy 21 (Down syndrome)
• Sex chromosome
• 47XXY (Klinefelter syndrome)
• 45X (Turner syndrome)

29
Rapid Aneuploidy Screening by FISH

• Available on amniocentesis sample
• Uncultured amniocytes
• FISH probes for X,Y, 21
• Result in 24-48 hours
• Proceed onto full karyotype (11-14 days)

30
New techniques

• qf (quantitative) PCR able to measure number of
  copies of a chromosome used for trisomy
  screening
• Fetal DNA at 6-8 weeks to determine sex look
  for presence of Y chromosome material

31
Not all chromosomal mutations are harmful.

• Polyploidy (extra sets of chromosomes) can
  produce stronger and larger plants.
• Important crop plants are produced this way,
  including bananas!

32
Take home message

• Chromosome abnormalities can be numerical or
  structural.
• Numerical abnormalities include aneuploidy and
  polyploidy.
• In mono or trisomy, a single extra chromosome is
  absent or present, usually as a result of
  non-disjunction in the 1st or 2nd meiotic
  division.
• Structural abnormalities include translocations,
  inversions, deletions, isochromosome rings.