Type 3 von Willebrand disease (VWD) is a severe autosomal recessive inherited
bleeding disorder. In affected individuals the underlying
von Willebrand factor gene (VWF) mutations frequently remain uncharacterized. The aim of this study was to investigate the molecular basis of
type 3 VWD in patients (11 Caucasians and 9 of Asian origin) attending the
haemophilia centres at Central Manchester NHS Trust. A combination of
DNA sequencing of VWF genomic and
complementary DNA was performed to identify mutations in the patient cohort. Fifteen different VWF mutations were identified at the genomic
DNA level: two gene conversion events, three nonsense, three frameshift, one missense, two splice site, one insertion-deletion and three deletion mutations. Homozygosity or compound heterozygosity for mutations was present in 15 of the 20 patients. In the remaining five individuals, heterozygosity for a single VWF mutation was identified in four cases and one patient had no detectable VWF mutation. Analysis of platelet-derived VWF
RNA from these five individuals revealed heterozygosity for a deletion of exons 4 and 5 in four cases. The remaining patient was heterozygous for a three base deletion which had already been identified at the
DNA level. Overall the observed VWF genotype explained the phenotype in 18 of the 20 patients investigated. In genetic studies in
type 3 VWD, if VWF mutations are not detected at the
DNA level,
RNA analysis should be performed to search for intronic mutations, heterozygous deletions or aberrant splicing/post-transcriptional events. However, this may still not explain all cases of previously phenotypically diagnosed
type 3 VWD.