CLINICAL CORRELATES AMONG 49 FAMILIES WITH HEMOPHILIA-A AND FACTOR-VIII GENE INVERSIONS

Inversions between a gene A copy within intron 22 of the factor VIII g ene and additional copies outside the factor VIII gene were found in 4 9 families with hemophilia A. Inversion patterns were that of recombin ation with a distal gene A copy in 34, a proximal copy in 14, and a th ird (variant) copy in one, Baseline factor VIII clotting activity leve ls were <1% of normal in 43 and 1% in 6. No inversion was detected in 61 other families whose affected members had less than or equal to 1% activity levels nor in 42 families with moderately severe hemophilia A and 2-5% baseline levels. Both high titer and low level alloantibody inhibitors were found in patients with or without an inversion. Of 13 high titer inhibitors, 8 were persistent and 1 of these patients had a n inversion. Of 5 that responded to daily factor VIII infusions, 4 wer e in patients with gene inversions. Of the 49 families with an inversi on, the occurrence of hemophilia was isolated in 30 and the mother was a carrier in the 25 in which additional family members were informati ve. In three of these families with isolated occurrence, the maternal grandmother was a carrier whereas in three others a de novo mutation o ccurred in the maternal grandfather's factor VIII gene. Screening for gene inversions in patients with severe (or ''borderline'' severe) hem ophilia A provides a direct marker of the mutation in 45% of families. It is useful even if there is no living affected member and in predic ting the likely severity of an infant in which there are no reliable b aseline clotting activities, including 70% of families with isolated o ccurrences of hemophilia A. (C) 1996 Wiley-Liss, Inc.