DIRECT-DETECTION OF A COMMON INVERSION MUTATION IN THE GENETIC DIAGNOSIS OF SEVERE HEMOPHILIA-A

Two recent reports suggest that approximately 50% of the cases of seve re hemophilia A (factor VIII:C <0.01 U/mL) may be caused by a gross re arrangement of the factor VIII gene. The mutation involves genomic seq uence from exon 1 to within intron 22 of the gene in an inversion even t. This rearrangement can be detected on a Southern blot using a probe that is complementary to sequence from within intron 22. In this repo rt, we describe the analysis of 71 severe hemophilia A patients for th e presence of this mutation. Thirty-two of the patients (45%) showed e vidence of the rearrangement, a figure that confirms the initial repor ts on 28 patients. Five different patterns of rearrangement have been noted, although two of these patterns (pattern 1 [70%] and pattern 2 [ 16%]) account for the majority of cases. The other patterns of rearran gement appear to be confined to individual families and may represent the result of additional sequence variation within the region of the g enome to which the proximal 22 exons of factor VIII are translocated. Analysis of this patient population for the factor VIII inversion muta tion has been extremely useful in a molecular diagnostic sense. In 23 of the cases studied (72%), the affected individual was the only docum ented hemophiliac in the family and, thus, previous linkage analysis h ad been limited to the provision of exclusion testing only. In conclus ion, it appears that testing for the factor VIII inversion mutation wi ll be positive in approximately 45% of severe hemophiliacs and as such should constitute the initial stage in the genetic testing protocol f or these patients' families. (C) 1994 by The American Society of Hemat ology.