Factor VIII gene inversions in severe hemophilia A: results of an international consortium study

Abstract

Twenty-two molecular diagnostic laboratories from 14 countries participated in a consortium study to estimate the impact of Factor VIII gene inversions in severe hemophilia A. A total of 2,093 patients with severe hemophilia A were studied; of those, 740 (35%) had a type 1 (distal) factor VIII inversion, and 140 (7%) showed a type 2 (proximal) inversion. In 25 cases, the molecular analysis showed additional abnormal or polymorphic patterns. Ninety-eight percent of 532 mothers of patients with inversions were carriers of the abnormal factor VIII gene; when only mothers of nonfamilial cases were studied, 9 de novo inversions in maternal germ cells were observed among 225 cases (approximately 1 de novo maternal origin of the inversion in 25 mothers of sporadic cases). When the maternal grandparental origin was examined, the inversions occurred de novo in male germ cells in 69 cases and female germ cells in 1 case. The presence of factor VIII inversions is not a major predisposing factor for the development of factor VIII inhibitors; however, slightly more patients with severe hemophilia A and factor VIII inversions develop inhibitors (130 of 642 [20%]) than patients with severe hemophilia A without inversions (131 of 821 [16%]).

Mutation analysis in 51 patients with haemophilia A: report of 10 novel mutations and correlations between genotype and clinical phenotype

“…for approximately 45% of severe cases [4,10]. The incidence of the intron 22 inversion in our study is lower than predicted (eight of the 27 families with severe haemophilia), this could be a reflection of the small numbers tested, however, the overall incidence of FVIII intron 22 inversion at this centre is relatively low at 26% of severe cases.…”

Haemophilia management: time to get personal?

“…at the wild-type exon-22/-23 junction region, were recognized as foreign by their immune systems. This hypothesis is consistent with clinical observations indicating that only about one in five patients with the I22-inv develop inhibitory antibodies [39], whereas inhibitor frequencies of close to 90% have been observed in patients with large deletions involving multiple exons, whose plasma also tests antigenically negative for FVIII-cross-reactive material (CRM)) [28]. However, tolerance could be broken (or not achieved in the first place) if I22-inv patients were infused with a FVIII protein containing an immunogenic sequence variation, e.g.…”

Factor VIII gene intron 1 inversion: lower than expected prevalence in Italian haemophiliac severe patients

“…We have analysed 327 severe patients referred to our haemophilia centre for invint22 by Long PCR [8] and we have found 137 patients with this mutation. Among the investigated patients, 293 were unrelated and the invint22 accounts for 121 haemophiliacs, with a prevalence of 41%, according to previously published studies [9]. Among the remaining severe unrelated haemophiliacs, we have analysed 71 patients for the causative mutation by using conformation sensitive gel electrophoresis (CSGE), an heteroduplex based method for screening the regulatory and coding gene regions of the F8 gene, followed by sequencing of any DNA fragments suspected to contain a mutation [10].…”