De novo factor VIII gene intron 22 inversion in a female carrier presents as a somatic mosaicism

The intron 22 inversion represents the most prevalent factor VIII gene defe ct in severe hemophilia A, accounting for about 40% of all mutations. It is hypothesized that the inversion mutations occur almost exclusively in germ cells during meiotic cell division by intrachromosomal recombination betwe en 1 of 2 telomeric copies of the Int22h region and its intragenic homologu e, The majority of inversion mutations originate in male germ cells, where the lack of bivalent formation may facilitate flipping of the telomeric end of the single X chromosome. This is the first intron 22 inversion that pre sents as a somatic mosaicism in a female, affecting only about 50% of lymph ocyte and fibroblast cells of the proposita, Supposing a postzygotic de nov o mutation as the usual cause of somatic mosaicism, the finding would imply that the intron 22 inversion mutation is not restricted to meiotic cell di visions but can also occur during mitotic cell divisions, either in germ ce ll precursors or in somatic cells. (C) 2000 by The American Society of Hema tology.