RFLP analysis in families with sporadic hemophilia A. Estimate of the mutation ratio in male and female gametes

Abstract

To investigate the sporadic occurrence of hemophilia A and to estimate the sex ratio of mutation rates directly, 17 families with isolated cases of the disorder were studied by RFLP analysis and by clotting assays. Three RFLPs, one intragenic and two with close linkage to hemophilia A, were used. In eight families the RFLP study excluded the carrier status of the maternal grandmothers. Since hemostatic studies showed that the eight mothers of these propositi were hemophilia carriers, the origin of the newly mutated genes was inferred from the RFLP patterns: six hemophilic genes derived from the normal maternal grandfathers and two, from maternal grandmothers. The data indicate a higher mutation rate in males than in females, as previously suggested by segregation analysis and coagulation studies. However the sex ratio indicated by the RFLP analysis is lower than previously reported and could explain previous conflicting estimates.