Medical Genetics

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: Turner`s & Klinefelter`s syndromes

3. Mitosis Meiosis Stages of 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

8. Down Syndrome

9. Down’s 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. Turner’s Syndrome

16. Turner Syndrome • Monosomy of sex chromosome (only one X chromosome present) • Occurrence – 1 in 2500 live female births

17. Turner’s 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. Turner’s 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. Klinefelter’s Syndrome

22. Klinefelter’s Syndrome 1 in 1,100 births 47 chromosomesXXY only 47, XXY #23 Trisomy Nondisjunction

23. 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: 1:1000 male births Klinefelter Syndrome: 47,XXY males

24. Klinefelter’s 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 age>37yrs; 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. 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. Take home message