Inversions in the factor VIII gene: Improvement of carrier detection and prenatal diagnosis in Dutch haemophilia A families

Abstract

Haemophilia A is an X linked bleeding disorder caused by a heterogeneous spectrum of mutations in the factor VIII gene. It has recently been reported that about 50% of severe haemophilia A cases are the result of an inversion in the factor VIII gene. The inversion results from homologous recombination between the A gene located in intron 22 of the FVIII gene and one of the two distal A genes, thus disrupting the coding sequence of the factor VIII gene. The inversion can be detected by conventional Southern blotting and hybridisation techniques. Here we present an analysis of 177 unrelated Dutch haemophilia A cases for the presence of an inversion. In 57% of the patients with severe disease an inversion was found and also in at least one of the 26 patients with moderately severe disease. The majority of inversions (85%) involved the most distal A gene, while in a minority (15%) the more proximal A gene was involved. We show that direct mutation detection greatly improves the assessment of carrier status and prenatal diagnosis for haemophilia A, especially in families with an isolated patient. The inversion is predominantly of grandpaternal origin.