1. Mendelian Disorders 张咸宁 zhangxianning@zju.edu.cn Tel ： 13105819271; 88208367 Office: A705, Research Building 2012/09

2. Genotype: The combination of alleles that an individual possesses. Phenotype: The physical characteristics of a cell or organism as defined by its genetic constitution.

3. Major Patterns of Monogenic Inheritance –Patterns of autosomal dominant inheritance (AD) 常染色体显性 –Patterns of autosomal recessive inheritance (AR) 常染色体隐性 –Patterns of X-linked recessive inheritance (XD) X- 连锁显性 –Patterns of X-linked dominant inheritance (XR) X- 连锁隐性 –Patterns of Y-linked inheritance Y- 连锁

4. Symbols Commonly Used in Pedigree Charts

7. Proband （先证者） : III-5 Pedigree drawing software ： Progeny, etc.

10. AD

14. AR

18. XR

22. XD

24. Y-linked

25. Special features of mitochondrial genetics mtDNA is maternally inherited. Paternal inheritance of mtDNA disease has been documented in only 1 instance. Schwartz M, Vissing J. NEJM, 2002;347:576–580

28. Unusual Features of AD 1.Reduced penetrance 2.Variable expressivity 3.High frequency of new mutations

29. CFTR Gene 1st gene identified by positional cloning Identified by the research group led by Dr. Lap-Chee Tsui ( 徐立之 ) at Toronto, Canada - (1989) Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245: 1059-1065. - (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245: 1066-1073. - (1989) Identification of the cystic fibrosis gene: genetic analysis. Science 245: 1073-1080.

30. DMD (OMIM 310200): Xp21.2, 79 Exons, 2.4 mb

31. DMD: Gower’s maneuver

34. Factors affecting pedigree patterns Onset age Pleiotropy: multiple effects of a single gene (one gene, more than one effect ) Genetic heterogeneity Expressivity and penetrance Coefficient of relationship and consanguineous marriage Sex-limited phenotypes and sex-influenced phenotypes genomic imprinting Anticipation X inactivation, …

35. Pleiotropy （ 多效性） multiple effects of a single gene (one gene, more than one effect ) Eg: Marfan syndrome (FBN1 gene)

36. Genetic Heterogeneity （遗传异质性） The phenomenon that a disorder can be caused by different allelic or non-allelic mutations. Locus heterogeneity Allelic heterogeneity Phenotypic (Clinical) heterogeneity

37. Genetic Heterogeneity Allelic heterogeneity: In a population, there may be a number of different mutant alleles at a single locus. In an individual, the same or similar phenotypes may be caused by different mutant alleles rather than by identical alleles at the locus. Eg: nearly 1400 different mutations have been found worldwide in the CFTR among patients with cystic fibrosis (CF).

38. Genetic Heterogeneity Locus heterogeneity: The production of identical phenotypes by mutations at two or more different loci. Eg: Osteogenesis Imperfecta (OI) or Brittle bone disease: Cs 7 & 17.

39. Genetic Heterogeneity Phenotypic (Clinical) heterogeneity: The term describing the occurrence of clinically different phenotypes from mutations in the same gene. Eg: RET gene mutation caused Hirschsprung disease or multiple endocrine neoplasia type 2A and 2B or both.

40. Genomic imprinting （基因组印迹） The phenomenon of a gene or region of a chromosome showing different expression depending on the parent of origin.

42. Anticipation （ 遗传早现 ） The tendency for some AD diseases to manifest at an earlier age and/or to increase in severity with each succeeding generation.

43. Trinucleotide CAG repeat sizes in Huntington disease Normal ≤26 Mutable 27-35 Reduced penetrance 36-39 Fully penetrance ≥40

45. 49,XXXXY

46. X inactivation ( X 染色体失活。 lyonization ) Inactivation of genes on one X chromosome in somatic cells of female mammals, occurring early in embryonic life, at about the time of implantation.

47. Mechanisms of Epigenetic Inheritance Epigenetic: The term that refers to any factor that can affect gene function without change in the genotype. DNA methylation Genomic imprinting (parent-of-origin silencing) Histone Modifications Regulatory non-coding RNAs

48. An adult organism has an estimated 10 14 cells. Cells =2 organisms:nucleus-cytosol + mt. Mitochondria are bacterial symbionts, ~ 2-3 X 10 9 YRA. Mitochondrial genome ~ 1500 genes (mtDNA + nDNA). Each cell has 100s of mitochondria and 1000s mtDNA. Mutations in mtDNA can be inherited maternally or acquired as somatic mutations.

49. Mitochondrial inheritance due to a mutant gene carried on the mitochondrial genome transmitted only through mothers because sperm contain very few mitochondria (maternal inheritance 母系遗传 ) inheritance and expression variable because of heteroplasmy (differing proportions of normal and mutant DNA in oocytes and tissues) Examples: Leber hereditary optic atrophy, several myopathies

50. Homoplasmy & Heteroplasmy Homoplasmy （纯质性） : The presence of only one type of mtDNA in the mitochondria of a single individual. Heteroplasmy （杂质性） : The presence of more than one type of mtDNA in the mitochondria of a single individual.

51. Many of the pathogenic mtDNA mutations are heteroplasmic. For expression of a disease it is required that a certain threshold （阈值） level of mutant mtDNA should be exceeded.

52. Mitochondrial diseases

53. Mode of inheritanceSome characteristic patterns in pedigree AR·Affected offspring usually born to unaffected parents · Chance of affected offspring is 25% for children of carriers · If both parents are affected, all children will exhibit trait · Affects either sex · Increased incidence with parental consanguinity ADAffected individual has at least one affected parent Children with one affected parent have 50% risk of being affected Affects either sex XR· Affects almost exclusively males · Not transmitted from father to son · If female inherits, father must have trait XDAll daughters of affected fathers exhibit the trait All sons of an unaffected mother will not have trait Y-linked· Females never exhibit trait · Son always has same phenotype as father Mt inheritanceAll children of an affected mother inherit the disorder None of the children of an affected father inherit the disorder

54. Acknowledge （ PPT 特别鸣谢！） UCLA David Geffen School of Medicine www.medsch.ucla.edu/ANGEL/ Prof. Grody WW (Divisions of Medical Genetics and Molecular Pathology), et al.Prof. Grody WW (Divisions of Medical Genetics and Molecular Pathology), et al.