FACTOR-VIII GENE INVERSIONS CAUSING SEVERE HEMOPHILIA-A ORIGINATE ALMOST EXCLUSIVELY IN MALE GERM-CELLS

The factor VIII gene, which is defective in hemophilia A, is located i n the last megabase of the long arm of the X chromosome. Inversions du e to intrachromosomal homologous recombination between mispaired copie s of gene A located within intron 22 of the gene and about 500 kb telo meric to it account for nearly half of all cases of severe hemophilia A. We hypothesized that pairing of Xq with its homolog inhibits the in version process, and that, therefore, the event originates predominant ly in male germ cells. In all 20 informative cases in which the invers ion originated in a maternal grandparent, DNA polymorphism analysis de termined that it occurred in the male germline. In addition, all but o ne of 50 mothers of sporadic cases due to an inversion were carriers. Thus, these data support the hypothesis and indicate that factor VIII gene inversions leading to severe hemophilia A occur almost exclusivel y in male germ cells.