Mutation Rates in Humans. I. Overall and Sex-Specific Rates Obtained from a Population Study of Hemophilia B

SummaryA population-based study of hemophilia B mutations was conducted in the United Kingdom in order to construct a national confidential database of mutations and pedigrees to be used for the provision of carrier and prenatal diagnoses based on mutation detection. This allowed the direct estimate of overall (μ), male (v), and female (u) mutation rates for hemophilia B. The values obtained per gamete per generation and the 95% confidence intervals are μ=7.73 (6.29–9.12)×10−6; v=18.8 (14.5–22.9)×10−6; and u=2.18 (1.44–3.16)×10−6. The ratio of male-to-female mutation rates is 8.64, with a 95% confidence interval of 5.46–14.5. The higher male rate was not caused by a much higher rate of transition at CpG sites in the male. Attempts to detect evidence of gonadal mosaicism for hemophilia B mutation in suitable families did not detect any instances of ovarian mosaicism in any of 47 available opportunities. This suggests that the risk of a noncarrier mother manifesting as a gonadal mosaic by transmitting the mutation to a second child should be