In families with a monogenic disorder, the causal mutation usually cosegregates with the disease phenotype. In rare cases, however, individuals carrying the same mutation within a family may show various phenotypes. This study aimed to analyze the discrepancy between genotype and phenotype in three families with moderate hemophilia A (HA) caused by missense mutation in the F8 gene. Among the 67 noninversion moderate HA families in our cohort, incomplete penetrance was found in three families. In these three families, the grandfathers were asymptomatic, whereas the probands had different clinical phenotypes. Apart from one mutation in the VWF gene (c.1330 G>A) found in one grandfather, only one missense mutation (c.5837A>T, c.6679G>A, and c.6506G>A, in the respective families) in the F8 gene was identified in each proband and their grandfathers. Subsequent Sanger sequencing results combined with bioinformatic analysis indicated that the three missense mutations in the F8 gene were the causative mutations. Our study demonstrated incomplete penetrance of missense mutation within HA families in China. Therefore, genetic counseling and management of such cases need to be reappraised.
Keywords: Chinese; F8; incomplete penetrance; moderate hemophilia A; next-generation sequencing; variable expressivity.