Genetics of hereditary nephropathy with deafness (Alport's disease)

The inheritance of Alport's disease, hereditary nephropathy with deafness, has been re–examined using data from a large French–Canadian kindred and reports from the literature. Sibships in wliich a parent and grandparent were known to carry the gene were used to test for partial sex–linkage. A decrease, rather than the expected increase, in affected sons of affected males with an affected father makes this hypothesis untenable. No matter which grandparent was affected, mothers with the gene had equal numbers of affected and unaffected offspring of both sexes, as expected for autosomal dominant inheritance; fathers with the gene had a decrease from the expected proportion of affected sons and an increase in unaffected sons with no distortion of the sex ratio. The hypotheses of preferential segregation and of a sex–linked dominant modifier gene have likewise been discredited. The findings fit the expectation for autosomal dominant inheritance, with reduced penetrance in the sons of affected fathers; it is suggested that the unfavourable intrauterine milieu of the affected mother increases the penetrance of the gene in her sons to that in her daughters. This is supported by a lower fr