Inversions between a gene A copy within intron 22 of the factor Vlll gene and additlonal copies outside the factor Vlll gene were found In 49 families with hemophilia A. Inversion patterns were that of recombination with a distal gene A copy in 34, a proximal copy In 14, and a third (variant) copy in one. Baseline factor Vlll clotting activity levels were 1 1 % of normal in 43 and 1% in 6. No inversion was detected in 61 other families whose affected members had 51% activity levels nor in 42 familles with moderately severe hemophllia A and 2-5% baseline levels. Both high titer and low level alloantibody lnhibltors were found in patients with or without an inversion. Of 13 high titer inhlbltors, 8 were perslstent and 1 of these patients had an inversion. Of 5 that responded to daily factor Vlll infusions, 4 were in patients with gene inversions. Of the 49 families with an inversion, the occurrence of hemophilla was Isolated in 30 and the mother was a carrier in the 25 In which addltlonal family members were informatlve. In three of these families with Isolated occurrence, the maternal grandmother was a carrier whereas in three others a de now mutatlon occurred in the maternal grandfather's factor Vlll gene. Screening for gene Inversions in patlents with severe (or "borderline" severe) hemo-philia 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 predicting the likely severity of an infant in which there are no reliable baseline clotting activities, including 70% of families with isolated occurrences of hemophilia A.

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Heteroduplex screening of amplified fragments containing sequences of all known small haemophilic mutations in the factor IX gene localized mutations in 18 new families: 12 were at common recurrent sites; three were novel. Carriers and/or patients from each of 41 families with mutations in 7 exons and 5' and 3' non-coding regions were positive.