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Mendelian Disorders
张咸宁
[email protected]
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 Charts
Proband（先证者）: III-5
Pedigree drawing software：Progeny, etc.
AD
AD
AD
AD
AR
AR
AR
AR
XR
XR
XR
XR
XD
XD
Y-linked
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
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
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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
•
•
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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
AR
Some characteristic patterns in pedigree
·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
Genetics and Molecular Pathology), et al.