染色体病

1. 染色体病 张咸宁 zhangxianning@zju.edu.cn Tel：13105819271; 88208367 Office: C303, Teaching Building 2014/09

2. Chromosome Disorders Are A Major Category of Genetic Disease Large proportion of: Reproductive wastage (miscarriages) Congenital malformations Mental retardation Significant role in pathogenesis of malignancy

3. Chromosome Disorders Are A Major Category of Genetic Disease Specific chromosomal abnormalities are: Responsible for >100 identifiable syndromes Collectively more common than all of the Mendelian single gene disorders together!

4. Chromosome Disorders Are A Major Category of Genetic Disease ~ 1% of live births ~ 2% of prenatal diagnoses in women >35 yrs old 50% of all first trimester spontaneous abortions（自发性流产）

5. What are the indications for ordering a chromosome analysis? Growth and developmental abnormalities Family history of chromosome abnormalities Infertility Pregnancy with “advanced maternal age” (AMA) Stillbirth/neonatal death Infertility/history of pregnancy loss Neoplasia

6. How is a karyotype（核型） prepared? Sample: blood, skin, amnio（羊水）, CVS（绒毛膜取样术） Cells grown in culture Blocked in metaphase using colchicine（秋水仙素） Spread on slide and stained Abnormalities detected by number, morphology and banding pattern

8. Chromosome Anatomy Centromere placement p (short arm) q (long arm) Size Banding pattern (Giemsa stain) Heterochromatin 异染色质(inactive, condensed) - dark Euchromatin 常染色质 (active, decondensed) - light

9. Interphase & Metaphase NucleiGiemsa Staining (G-banding)

10. Normal Human Male KaryotypeIndividual Chromosomes Cut from Metaphase Spread

11. Ideogram of Human Male G-banded Metaphase Chromosomes(400 bands per haploid karyotype)

13. Abnormalities of Chromosome Number Heteroploid（异倍体） Any chromosome number other than 46 (1) Euploid （整倍体） An exact multiple of the haploid chromosome number (n), where n = 23 (2) Aneuploid （非整倍体） Any chromosome number that is not an exact multiple of the haploid number (n)

14. Triploidy（三倍性） Most often due to fertilization by two sperm (dispermy) or occasionally a diploid sperm or egg Partial hydatidiform moles (葡萄胎。remnants ofplacenta ± small atrophic fetus): triploid with extra paternal set “Mole”: from the Latin mola,for false conception Extra maternal set: early spontaneous abortions

15. Aneuploidy（非整倍性） Trisomy（三体）: three copies 47,XY+21: Down syndrome Monosomy （单体） : one copy 45,X: Turner syndrome Nondisjunction（不分离）: failure of a pair of chromosomes to separate (to disjoin) normally in meiosis I or II

16. Different Consequences to the Gamete of Nondisjunction at Meiosis I or Meiosis II both parental 21s present 2 copies of one parental 21

17. Abnormal Male Karyotype:47,XY +21

18. Down syndrome • Most common trisomy 1:800 in new born • Most common sever mental retardation • Related with advanced maternal age

19. Down syndrome

20. Trisomy 18 （Edward syndrome） • 1:7500 in liveborn and more common in abortion and stillbirth • Severe mental retardation and multiple structural anomalies

21. Trisomy 18

22. Trisomy 13（Patau syndrome） • 1:20,000 in liveborn and more common in abortion and stillbirth • Severe structural anomalies lead to death in one month

23. Trisomy 13

24. Trisomy 13

25. Monosomy • Almost all monosomy for an entire chromosome is lethal • Turner syndrome: 45,X, the only monosomy can be born and survive

26. XXY, Klinefelter syndrome • 1:1,000 in male liveborn • Hypogonadism • Infertility

27. Abnormalities of Chromosome Structure Balanced: nothing gained or lost Unbalanced: material gained or lost

28. Balanced Rearrangements（平衡性重排） Individuals with balanced rearrangements appear normal Therefore, they may not be detected until: Birth of a child with an unbalanced rearrangement Infertility evaluation (recurrent pregnancy loss)

29. Balanced and Unbalanced Translocations（平衡易位、非平衡易位）

30. Translocation • Reciprocal ~ （相互易位） Resulted from breakage of nonhomologous chromosomes, with reciprocal exchange of the broke-off segments

31. Reciprocal Translocation (9;22)

32. Robertsonian Translocation（罗氏易位） • Two acrocentric chromosomes fuse near the centromere region with loss of the short arms, which carry multiple copies of genes for rRNA. • Only 45 chromosomes with balanced karyotype and phenotype

33. 45, XX, rob ( 13q14q)

34. Balanced translocation in meiosis High Risk to produce unbalanced offspring

35. Translocation Down Syndrome 4% of all Down cases One chromosome is a Robertsonian translocation 21q + q of another acrocentric chromosome, usually 14 or 22 46,XX,rob(14;21),+21 or 46,XY,rob(14;21),+21

37. Offsprings

38. The Tools:Cytogenetic Analysis Conventional Karyotyping SKY(spectral karyotyping)

39. What is FISH? Fluorescence in situ hybridization Detects a specific position or gene on an intact chromosome Can be used to detect numeric problems or rearrangements – Banding could not be detected < 4Mb

40. Fluorescence In Situ Hybridization（FISH） • Using DNA probe labeled with a certain marker • Hybridizing with DNA in chromosomes and nuclei on slides • Probes hybridized with the fragment in chromosome are detected by signals from the labeled markers Cs + Probe Co-denature Anneal,hybridize

41. Down syndrome----FISH

42. Chromosome Painting

43. Specific Cytogenetic Changes in Cancer Association of cytogenetic changes with specific forms of cancer Breakpoints may be associated with structural rearrangements of oncogenes Cytogenetic changes in cancer are numerous and diverse Many seen repeatedly in same type of tumor Evaluate by FISH and chromosomal painting

44. Philadelphia Chromosome in Chronic Myelogenous Leukemia

46. Ph Chromosome FISH

47. 嵌合体：Mosaic and chimera Aberration Mosaic Aberration Chimera

48. Submicroscopic polymorphic chromosome region copy number variants are increasingly being detected by high-resolution techniques such as aCGH.

49. Array Comparative Genomic Hybridization (aCGH)