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Screening for inversions in the factor VIII (F8) gene causing severe haemophilia A

A total of 164 unrelated patients with severe haemophilia A were screened for partial in versions of the factor VIII (F8) gene resulting from recombination between the intronic F8A gene and one or other of two homologous upstream A gene sequences. Inversions were found in 69 (42%) patients. Most inversions (90%) involved the distal rather than the proximal A gene. This unique mutational mechanism is estimated to occur with a frequency of 7.2 × 106 per gene per gamete per generation. Although two patients with an inversion possessed inhibitors (antibodies) against factor VIII, possession of inhibitors did not appear to be associated disproportionately with inversion-type mutations.