Download 医学神经科学与行为I模块2教学内容

Lecture Notes
孟德尔遗传方式疾病
张咸宁（细胞生物学与医学遗传学系）
2013/09
I.
Mendelian 疾病的分类和举例
A. Autosomal Dominant
 requires mutation in only one allele to produce disease
 males and females equally affected
 family history usually positive, with affected members in each generation
 may show apparent generation skipping due to variable penetrance, variable
expressivity, or appearance of a new mutation in the family
 Examples: Huntington disease, neurofibromatosis, familial breast/ovarian
cancer
B. Autosomal Recessive
 requires mutation of both alleles to produce disease
 males and females equally affected
 higher frequency in consanguineous matings
 higher frequency of mutation carriers in particular ethnic groups
 family history often negative
 often associated with enzymatic defects causing metabolic disorders
 Examples: sickle cell disease, phenylketonuria, cystic fibrosis
C. X-linked Dominant
 due to a dominant mutation located on the X-chromosome
 males and females usually equally affected
 no male-to-male transmission; all daughters of an affected father are affected
 Examples: hypophosphatemic rickets, incontinentia pigmenti
D. X-linked Recessive
 due to a recessive mutation located on the X-chromosome
 males predominantly or exclusively affected
 mothers are carriers
 no male-to-male transmission
 some cases due to appearance of a new mutation in the family
 Examples: Duchenne muscular dystrophy, color blindness, hemophilia A
E. Mitochondrial Inheritance
 due to a mutant gene carried on the mitochondrial genome
 transmitted only through mothers because sperm contain very few
mitochondria (maternal inheritance)
 inheritance and expression variable because of heteroplasmy (differing
1
proportions of normal and mutant DNA in oocytes and tissues)
 Examples: Leber hereditary optic atrophy, several myopathies
II.
影响家系分析的因素

New mutations（新突变）are a common cause of the appearance of a genetic
disease in a person with no previous family history of the disorder. The recurrence
risk for the person's siblings is very low, but the recurrence risk for the person's
offspring may be substantially increased.

Germline mosaicism（种系嵌合现象）occurs when all or part of a parent's
germline is affected by a disease mutation but the somatic cells are not. It elevates the
recurrence risk for offspring of the mosaic parent.

Reduced penetrance（降低的外显率）describes the situation in which persons
who have a disease-causing genotype do not develop the disease phenotype.
Age-dependent penetrance is observed in many genetic diseases. It complicates the
interpretation of inheritance patterns in families.

Variable expression（可变的表现度）of a genetic disease may be caused by
environmental effects, modifier loci, or allelic heterogeneity.
 A disease that can be caused by mutations at different loci in different
families is said to exhibit locus heterogeneity（基因座异质性）.

Genes that exert effects on multiple aspects of physiology or anatomy are
pleiotropic. Pleiotropy（多效性）is a common feature of human genes.

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.
A striking disease example of imprinting is provided by a deletion of about 4 Mb
of the long arm of chromosome 15. When this deletion is inherited from the father, the
child manifests a disease known as Prader-Willi syndrome. When the same deletion is
inherited from the mother, the child develops Angelman syndrome

Consanguinity（近亲婚配）increases the chance that a mating couple will
both carry the same disease-causing mutation. It is seen more often in pedigrees
involving rare recessive diseases than in those involving common recessive diseases.
 At the population level, consanguinity increases the frequency of genetic
disease and mortality. The closer the degree of consanguinity, the greater the increase.

III.
还有 X 染色体失活、遗传早现等等。
Summary (Table 1)
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
2
AD
XR
XD
Y-linked
Mt inheritance
· If both parents are affected, all children will exhibit trait
· Affects either sex
· Increased incidence with parental consanguinity
Affected individual has at least one affected parent
Children with one affected parent have 50% risk of being
affected
Affects either sex
· Affects almost exclusively males
· Not transmitted from father to son
· If female inherits, father must have trait
All daughters of affected fathers exhibit the trait
All sons of an unaffected mother will not have trait
· Females never exhibit trait
· Son always has same phenotype as father
All children of an affected mother inherit the disorder
None of the children of an affected father inherit the disorder
3