Somatic mosaicism in hemophilia A: A fairly common event

Mutations in the large gene of clotting factor VIII (FVIII) are the most co mmon events leading to severe human bleeding disorder. The high proportion of de novo mutations observed in this gene raises the possibility that a si gnificant proportion of such mutations does not derive from a single germ c ell but instead should be attributed to a germline or somatic mosaic origin ating from a mutation during early embryogenesis. The present study explore s this hypothesis by using allele-specific PCR to analyze 61 families that included members who had sporadic severe hemophilia A and known FVIII gene defects. The presence of somatic mosaicisms of varying degrees (0.2%-25%) c ould be shown in 8 (13%) of the 61 families and has been confirmed by a mut ation-enrichment procedure. All mosaics were found in families with point m utations (8 [25%] of 32 families). In the subgroup of 8 families with CpG t ransitions, the percentage with mosaicism increased to 50% (4 of 8 families ). In contrast, no mosaics were observed in 13 families with small deletion s/insertions or in 16 families with intron 22 inversions. Our data suggest that mosaicism may represent a fairly common event in hemophilia A. As a co nsequence, risk assessment in genetic counseling should include considerati on of the possibility of somatic mosaicism in families with apparently de n ovo mutations, especially families with the subtype of point mutations.