Somatic mosaicism in hemophilia A: a fairly common event

Am J Hum Genet. 2001 Jul;69(1):75-87. doi: 10.1086/321285. Epub 2001 Jun 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Base Sequence
  • Chromosome Inversion
  • DNA Mutational Analysis
  • Embryo, Mammalian / embryology
  • Exons / genetics
  • Factor VIII / genetics
  • Female
  • Gene Frequency / genetics*
  • Genetic Counseling
  • Genetic Predisposition to Disease / genetics
  • Genetic Testing
  • Hemophilia A / genetics*
  • Humans
  • Introns / genetics
  • Male
  • Mosaicism / genetics*
  • Mutation / genetics*
  • Pedigree
  • Sequence Deletion / genetics
  • Sex Characteristics


  • Factor VIII