A novel family with recessive von Willebrand disease due to compound heterozygosity for a splice site mutation and a missense mutation in the von Willebrand factor gene

Abstract

We report a new family with autosomal recessive von Willebrand disease (VWD) in which the propositus was compound heterozygous for a missense mutation in exon 42 (G7085T, C2362F) and a C→A splice site mutation in intron 13 of the von Willebrand factor (VWF) gene. The propositus had factor VIII:C ≈20 IU/dl, VWF antigen 5–7 IU/dl and ristocetin cofactor activity <3–7 IU/dl. The bleeding time (BT) was markedly prolonged (>15 min). Haplotype analysis and mutation screening were conducted by polymerase chain reaction (PCR)-based methodology. Each mutation appeared to be linked to a haplotype that was identical to the haplotype previously detected in subjects in the Veneto region carrying these mutations, suggesting a founder effect. In the propositus' family six subjects were heterozygotes for the C2362F mutation and five were heterozygotes for the splice site mutation. None of the heterozygotes had suffered from significant bleeding. The mutation C2362F and the splice site mutation in intron 13 are commonly observed in subjects with recessive von Willebrand disease in the Veneto region. These mutations are truly recessive and cause bleeding only in the compound heterozygous or homozygous state.