Chapter 062. Principles of Human Genetics (Part 20) docx

Segregation of genotypes in the offspring of parents with one dominant A and one recessive a allele.. Autosomal Dominant Disorders Autosomal dominant disorders assume particular relevan

Chapter 062 Principles of

Human Genetics

(Part 20) Figure 62-9

Figure 62-10

Segregation of alleles Segregation of genotypes in the offspring of parents

with one dominant (A) and one recessive (a) allele The distribution of the parental alleles to their offspring depends on the combination present in the parents Filled symbols = affected individuals

Autosomal Dominant Disorders

Autosomal dominant disorders assume particular relevance because mutations in a single allele are sufficient to cause the disease In contrast to recessive disorders, in which disease pathogenesis is relatively straightforward because there is loss of gene function, dominant disorders can be caused by various disease mechanisms, many of which are unique to the function of the genetic pathway involved

In autosomal dominant disorders, individuals are affected in successive generations; the disease does not occur in the offspring of unaffected individuals Males and females are affected with equal frequency because the defective gene resides on one of the 22 autosomes (Fig 62-11A ) Autosomal dominant mutations

alter one of the two alleles at a given locus Because the alleles segregate randomly at meiosis, the probability that an offspring will be affected is 50% Unless there is a new germline mutation, an affected individual has an affected parent Children with a normal genotype do not transmit the disorder Due to differences in penetrance or expressivity (see above), the clinical manifestations of autosomal dominant disorders may be variable Because of these variations, it is sometimes challenging to determine the pattern of inheritance

Figure 62-11

Dominant, recessive, X-linked, and mitochondrial (matrilinear) inheritance

It should be recognized, however, that some individuals acquire a mutated gene from an unaffected parent De novo germline mutations occur more frequently during later cell divisions in gametogenesis, which explains why

siblings are rarely affected As noted before, new germline mutations occur more frequently in fathers of advanced age For example, the average age of fathers with new germline mutations that cause Marfan's syndrome is ~37 years, whereas fathers who transmit the disease by inheritance have an average age of ~30 years