1. Clinical Cytogenetics Mohamad Nusier M.D., Ph.D.

2. REVIEW OF MITOSIS AND MEIOSIS Clinical Cytogenetics

3. Rules about chromosomes  The nuclei of somatic cells contain a fixed number of chromosomes typical of that particular species  The chromosomes in the nuclei of somatic cells are present in pairs  Cells that contain two similar sets of chromosomes are called diploid  One chromosome of each pair is derived from the maternal parent and the other from the paternal parent

4.  Germ cells (gametes) contain only one set of chromosomes, consisting of one member of each of the pairs  The nuclei of gametes are haploid  The haploid gametes unite in fertilization to produce the diploid state of somatic cells  Mitosis maintains chromosome number while meiosis halves that number

6. Cell cycle

7. Mitosis  Definition: Nuclear division in which two daughter cells receive a diploid complement of chromosomes  Diploid complement of chromosomes in the daughter cells is identical to that of the parent cell  Mitosis is accompanied by cytokinesis  In cytokinesis, the cytoplasm of the cell is divided in half

8. Mitosis Overview

12. Meiosis  Daughter cells contain only one member of each pair of chromosomes  It results in four daughter cells, each genetically different and each containing one haploid set of chromosomes  Meiosis consists of two successive rounds of nuclear division  In animals, meiosis takes place in meiocytes (primary oocytes, and spermatocytes)

15. Crossing over  Takes place in prophase 1 of meiosis 1.  Homologous chromosomes find each other in the cell, interact and pair in a process called synapsis  During synapsis, chromosomes align themselves along their entire length (gene for gene)  Chromosomes exchange pieces of their DNA through a process called "crossing over"

16. Crossing over

17. CHROMOSOMAL ABNORMALITIES Clinical cytogenetics

18. Chromosomal Abnormalities

19. Abnormalities of Chromosome Number Euploid: cell that contains a multiple of 23 chromosomes in its nucleus, thus haploid gametes and diploid somatic cells are euploid Polyploidy: the presence of a complete set of extra chromosomes in a cell –Triploidy (69 chromosomes in the nucleus of each cell, karyotype 69,XXX), the most common cause is the fertilization of an egg by two sperm (dispermy), Meiotic failure –Tetraploidy (92 chromosomes in each cell nucleus, karyotype 92,XXXX) might be caused by mitotic failure and by the fusion of two diploid zygotes Autosomal Aneuploidy : cells contain missing or additional chromosomes mostly caused by nondisjunction –Monosomy: the presence of only one copy of a chromosome in an otherwise diploid cell –Trisomy: three copies of a chromosome Autosomal monosomies are almost always lethal, but some autosomal trisomies are compatible with survival

20. Origin of aneuploids by non-disjunction at Meiosis I or II

22. Mosaicism  Presence of two or more populations of cells with different genotypes in an individual who developed from a single zygote  May result from mitotic non disjunction  May also be the result of random X chromosome inactivation in females

24. Robertsonian translocation between chromosomes 14 and 21  Robertsonian translocations are limited to the acrocentric chromosomes  Involves chromosomes 13, 14, 15, 21, and 22  The long arm (q arm) of one chromosome will become attached to the q arm of another, with the loss of the two p arms  Loss of the p arms does not seem to affect viability

25. Abnormalities of Chromosome Number Trisomy 21: –Karyotype: 47,XY,+21 or 47,XX,+21 –Causes Down’s syndrome, is the most common autosomal aneuploidy seen among live births (1 of every 800 to 1000) –Approximately 95% of Down’s syndrome cases are caused by non-disjunction, with most of the remainder being caused by chromosome translocations –The extra 21 st chromosome is contributed by the mother in approximately 90% of cases –There is a strong correlation between maternal age and the risk of producing a child with Down’s syndrome

26. Down’s syndrome …cont –Mosaicism is seen in 2% to 4% of Down’s syndrome cases, and it often accompanies a milder phenotype, 47,XY,+21[10/46,XY[10] –Some individuals may have tissue specific mosaicism –Specific genes contributing to the Down’s syndrome phenotype, DYRK and APP The most significant clinical problems are: –Mental retardation –Gastrointestinal tract obstruction –Congenital heart defects –Respiratory infections –Leukemia

28. Down’s syndrome …cont

29. One of the 21st chromosomes completely reattaches to another chromosome Parents known as “carriers” - DS not expressed One of the 21st chromosomes completely reattaches to another chromosome Parents known as “carriers” - DS not expressed Balanced: One of the 21st chromosomes completely reattaches to another chromosome Parents known as “carriers” - DS not expressed

30. Gametes from a 14q, 21q translocation  Six gametes are possible: 1. translocated 14/21 and normal 14 2. normal 14 and normal 21 3. translocated 14/21 and normal 21 4. normal 21 only 5. normal 14 only 6. translocated 14/21 only

32. Down’s syndrome …cont Unbalanced: Part of 21st chromosome is reattached to another chromosome DS is expressed

33. Down’s syndrome

34. Abnormalities of Chromosome Number Trisomy 18: –Karyotype: 47,XY,+18 –Causes Edward’s syndrome –The second most common autosomal trisomy, 1 per 6000 live birth –Approximately 90% of trisomy 18 cases are the result of a maternal contribution –Most babies die in the first year and many within the first month.

35. Edward’s syndrome

36. Clenched fist

37. Rocker bottom feet

38. Edward’s syndrome

39. Abnormalities of Chromosome Number Trisomy 13: –Karyotype: 47,XY,+13 –Caused Patau’s syndrome –About 80% of patients with Patau’s syndrome have full trisomy 13, most of the remaining patients have trisomy of the long arm of chromosome 13 due to a translocation –50% of these babies die within the first month and very few survive beyond the first year. There are multiple dysmorphic features. –Most cases, as in Down's syndrome, involve maternal non- disjunction.

40. Patau’s Syndrome