Population genetics of Alport's syndrome. Hypothesis of abnormal segregation and the necessary existence of mutation.

The diagnosis of Alport's syndrome is generally not considered in the absence of a positive family history. Family studies indicate that transmission occures by a rare autosomal dominant gene. The deviation of transmission ratios from the classical Mendelian pattern is best explained by abnormal segregation. Based on observed pedigree data, calculations were made of the expected equilibrium population frequency of Alport's syndrome assuming mutation rates of zero, 10, and 50 per million gametes. Zero mutation rate should result in disappearance of the Alport gene. An equilibrium frequency corresponding to that actually observed in Rhode Island implies a mutation rate of 10 per million gametes. Furthermore, up to 18% of all newborns with the Alport genotype may represent new mutants. Thus, isolated cases of Alport's syndrome may occur in the absence of other affected family members.