Somatic Mosaicism in Hemophilia A: A Fairly Common Event

Abstract

Mutations in the large gene of clotting factor VIII (FVIII) are the most common events leading to severe human bleeding disorder. The high proportion of de novo mutations observed in this gene raises the possibility that a significant proportion of such mutations does not derive from a single germ cell but instead should be attributed to a germline or somatic mosaic originating from a mutation during early embryogenesis. The present study explores 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%) could be shown in 8 (13%) of the 61 families and has been confirmed by a mutation-enrichment procedure. All mosaics were found in families with point mutations (8 [25%] of 32 families). In the subgroup of 8 families with CpG transitions, the percentage with mosaicism increased to 50% (4 of 8 families). In contrast, no mosaics were observed in 13 families with small deletions/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 consequence, risk assessment in genetic counseling should include consideration of the possibility of somatic mosaicism in families with apparently de novo mutations, especially families with the subtype of point mutations.

Somatic mosaicism for a MECP2 mutation associated with classic Rett syndrome in a boy

“…These include ornithine transcarbamylase deficiency, 17 Duchenne muscular dystrophy, 18 and hemophilia A. 19 Although it is not clear whether the single-gene mutation occurred as a postzygotic event or at the halfchromatid stage, before fertilisation, 20 somatic mosaicism should be considered when an X-linked dominant disease is observed in a male.…”

On a Break with the X: The Role of Repair of Double-Stranded DNA Breaks in X-Linked Disease

“…Partial or complete factor VIII gene deletions are found in about 5% of the families with severe hemophilia A, some of which include recombinations of repeated sequences of the line1 and Alu type (82,103). Family analysis shows that, similarly to the inversion with breakpoints in the 10 kb repeat in intron 22, the index patient carrying the rearrangement in Factor Viii gene is usually the first case in the family, born to a carrier mother (50), and that most (though not all) rearrangements occur in the male germline (10,64).…”

Genotype-Phenotype Interaction Analyses in Hemophilia

“…This mechanism, if minor, remains underestimated by routine analysis and originates predominantly from females in the case of somatic mosaicism. This may represent a frequent event in hemophilia that must be considered in genetic counseling of isolated cases that mainly involve point mutations (Leuer et al, 2001). In the case of factor IX gene, a considerably lower mutation rate than for factor VIII has been reported (3.2 x 10 9 ) (Koeberl et al, 1990).…”