Direct Detection of a Common Inversion Mutation in the Genetic Diagnosis

Two recent reports suggest that approximately 50 % of the cases of severe hemophilia A (factor VIII:C <0.01 U/mL) may be caused by a gross rearrangement of the factor Vlll gene. The mutation involves genomic sequence from exon 1 to within intron 22 of the gene in an inversion event. This re-arrangement can be detected on a Southern blot using a probe that is complementary t o sequence from within intron 22. In this report, we describe the analysis of 71 severe he-mophilia A patients for the presence of this mutation. Thirty-two of the patients (45%) showed evidence of the re-arrangement, a figure that confirms the initial reports on 28 patients. Five different patterns of rearrangement have been noted, although two of these patterns (pattern 1 [70%1 and pattern 2 I16%l) account for the majority of cases. The other patterns of rearrangement appear to be confined to in