Mendelian Disorders

张咸宁zhangxianning@zju.edu.cn

Tel ： 13105819271; 88208367 Office: A705, Research Building

2012/09

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

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

Symbols Commonly Used in Pedigree ChartsSymbols Commonly Used in Pedigree Charts

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

AD

AD

AD

AD

AR

AR

AR

AR

XR

XR

XR

XR

XD

XD

Y-linked

Special features of mitochondrial geneticsmtDNA is maternally inherited.

Paternal inheritance of mtDNA disease has been documented in only 1 instance. Schwartz M, Vissing J. NEJM, 2002;347:576–580

Unusual Features of AD

1. Reduced penetrance

2. Variable expressivity

3. High frequency of new mutations

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.

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

DMD: Gower’s maneuver

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, …

Pleiotropy （多效性）• multiple effects of a single gene (one gene,

more than one effect )• Eg: Marfan syndrome (FBN1 gene)

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

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).

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.

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.

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.

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.

Trinucleotide CAG repeat sizes in Huntington disease

• Normal ≤26

• Mutable 27-35

• Reduced penetrance 36-39

• Fully penetrance ≥40

49,XXXXY

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.

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

An adult organism has an estimated 1014 cells.

Cells =2 organisms:nucleus-cytosol + mt.

Mitochondria are bacterial symbionts, ~ 2-3 X 109 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.

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

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.

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.

Mitochondrial diseases

Mode of inheritance Some 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

AD Affected 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

XD All 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 inheritance All children of an affected mother inherit the disorder

None of the children of an affected father inherit the disorder

Acknowledge （ PPT 特别鸣谢！）

• UCLA David Geffen School of Medicine

• www.medsch.ucla.edu/ANGEL/

• Prof. Grody WW (Divisions of Medical Prof. Grody WW (Divisions of Medical Genetics and Molecular Pathology), et al.Genetics and Molecular Pathology), et al.