Proportions of spontaneous mutations in males and females with ornithine transcarbamylase deficiency

Abstract

We used specific mutation analysis to estimate the proportions of males and females with ornithine transcarbamylase (OTC) deficiency whose mutations occurred in the germ cells of one of the parents. The mutations were identified in the probands, and subsequently carrier testing was performed on their mothers and some of the grandmothers. Of 28 OTC deficient males, only 2 (7%) had sporadic mutations (95% CI, 0.6-18.5%), whereas of 15 OTC deficient females, 12 (80%) had sporadic mutations (95% CI, 63-99%) (P < 0.001). Based on these results we estimated the male/female mutation rate ratio (nu/mu) in the OTC gene to be approximately 52. Assuming a fitness for males with OTC deficiency of 0 and the proportion of new female mutants at 0.80, the estimated fitness of heterozygous females is 0.4. Because of the difference in mutation rates between male and female germ cells, we suggest that 9/10 or higher, rather than the conventional 2/3 proportion, be applied when estimating prior risk of carrier status in a mother of one affected male. The prior risk of a mother of an affected female is much lower, approximately 2/10.