Common large partial VWF gene deletion does not cause alloantibody formation in the Hungarian type 3 von Willebrand disease population

Abstract

Summary. Background: Type 3 von Willebrand disease (VWD) is an autosomal recessive bleeding disorder, characterized by virtually undetectable plasma von Willebrand factor (VWF) and consequently reduced plasma factor VIII levels. Genetic mutations responsible for type 3 VWD are very heterogeneous, scattered throughout the VWF gene and show high variability among different populations. Methods: Twenty‐five severe VWD patients were studied by direct sequencing of the 51 coding exons of the VWF gene. The total number of VWD type 3 families in Hungary is 24, of which 23 were investigated. Results: Fifteen novel mutations were identified in 31 alleles, five being nonsense mutations (p.Q1238X, p.Q1898X, p.Q1931X, p.S2505X and p.S2568X), four small deletions and insertions resulting in frame shifts (c.1992insC, c.3622delT, c.5315insGA and c.7333delG), one a large partial deletion (delExon1‐3) of the 5′‐region, four candidate missense mutations (p.C35R, p.R81G, p.C295S, p.C623T) and one a candidate splice site mutation (c.1730–10C>A). Six previously described mutations were detected in 17 alleles, including the repeatedly found c.2435delC, p.R1659X and p.R1853X. Only one patient developed alloantibodies to VWF, carrying a homozygous c.3622delT. Conclusion: We report the genetic background of the entire Hungarian type 3 VWD population. A large novel deletion, most probably due to a founder effect, seems to be unique to Hungarian type 3 VWD patients with high allele frequency. In contrast to previous reports, none of the five patients homozygous for the large partial deletion developed inhibitors to VWF. This discrepancy raises the possibility of selection bias in some of the reports.

The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles

“…In the majority of type 3 VWD studies, pathogenic mutations are identified in 80–90% of patients . In this study we were able to identify both pathogenic mutations in 85% of IC (62 of 68 [91%] mutant alleles identified).…”

Principles of care for the diagnosis and treatment of von Willebrand disease

“…The risk of alloantibody formation in patients with large deletions may not be as high as previously thought at least for some deletions. 51 These patients can be effectively treated with recombinant FVIII, administered by continuous intravenous infusion, or with recombinant activated factor VII.…”

Alloantibodies in von Willebrand disease

“…26 Furthermore, not all cases of type 3 VWD caused by partial gene deletions develop alloantibodies against VWF. Mohl et al 32 described 25 Hungarian type 3 VWD patients of which 5 were homozygous for a large partial gene deletion. None of these 5 patients developed anti-VWF antibodies as a complication of treatment, raising unanswered questions about additional genetic or environmental modifiers.…”

“…None of these 5 patients developed anti-VWF antibodies as a complication of treatment, raising unanswered questions about additional genetic or environmental modifiers. 32 …”