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

Abstract

Summary Background Type 3 von Willebrand disease (VWD) is the most severe form of the disease and is classically inherited in an autosomal recessive fashion. Objectives The aim of the current study was to investigate the molecular pathogenesis of a Canadian cohort of type 3 VWD patients. Patients/Methods 34 families comprised of 100 individuals were investigated. Phenotypic data, including bleeding scores (BS), von Willebrand factor (VWF) laboratory values, and anti-VWF inhibitor status were included as well as sequence analysis. Results We identified 31 different mutations (20 novel): 8 frameshift, 5 splice site, 9 nonsense, 1 gene conversion, 6 missense, and 2 partial gene deletion mutations. The majority of mutations identified were in the propeptide (42%); index cases (IC) with these mutations exhibited more severe bleeding (BS=22) than those with mutations elsewhere in VWF (BS=13). 62 of 68 (91%) mutant alleles were identified. Twenty-nine IC (85%) had a VWF null genotype identified; 17 homozygous, 12 compound heterozygous. In five IC (15%), two mutant VWF alleles were not identified to explain the type 3 VWD phenotype. In four ICs only one mutant VWF allele was identified and in one IC no mutant VWF alleles were identified. Conclusions We have investigated the molecular pathogenesis of a Canadian cohort of type 3 VWD patients. Obligate carriers are not phenotypically silent in the Canadian population; 48% have been diagnosed with type 1 VWD. In ~50% of families in this study the inheritance pattern for type 3 VWD is co-dominant and not recessive.

Current issues in diagnosis and treatment of von Willebrand disease

“…With regard to type 3 VWD, some have used this category to include those with minimal residual VWF levels (ie, <5 IU/dL) 6. Others consider any detectable VWF to represent type 1 VWD, albeit a more severe phenotype, and reserve the label of type 3 VWD for those with completely undetectable VWF levels 2, 7.…”

von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy

“…20 The disease is transmitted as either a recessive trait (normal parents) or through the inheritance of 2 mutant codominant alleles (both parents have type 1 VWD). 21 The .110 type 3 VWD cases that have been genetically characterized show a range of VWF mutations, from large VWF deletions through a miscellany of null mutations to missense mutations that prevent VWF biosynthesis and secretion. Although initial studies of the infrequent cases of type 3 VWD developing alloantibodies to VWF showed an association with VWF deletion mutations, 22,23 there has been no systematic confirmation of this observation.…”

Characterization of aberrant splicing of von Willebrand factor in von Willebrand disease: an underrecognized mechanism

“…The severity of these patients' bleeding symptoms was evaluated using the Condensed MCMDM-1VWD BAT where a BS of $4 denotes abnormal bleeding. 9 Peripheral blood samples were taken to obtain plasma, genomic DNA, and BOECs from these patients. Putative splicing mutations were confirmed though Sanger DNA sequencing (supplemental Table 1, available on the Blood Web site).…”

“…by guest www.bloodjournal.org From VWF:Ag and VWF:RCo levels lower than 0.5 IU/mL, and abnormal BS $4 using the MCMDM-1VWD BAT (Table 1). 9 The first family (with patients V69 and V70) exhibited significant mucocutaneous bleeding with positive BSs and correspondingly low VWF and FVIII plasma levels ( Table 1). Both patients were heterozygous for the exonic mutation c.3538G.A in exon 26 of VWF.…”