Von Willebrand disease—Phenotype versus genotype: Deficiency versus disease

Abstract 

Von Willebrand disease (VWD) is classified into three primary subtypes; type 1 includes partial quantitative deficiency, type 2 (A, B, M and N) includes qualitative defects and type 3 includes virtually complete deficiency of von Willebrand factor (VWF). Type 2A includes variants with decreased platelet adhesion caused by selective deficiency of high molecular weight VWF multimers. Type 2B includes variants with increased affinity for platelet glycoprotein Ib. Type 2M includes variants with markedly defective platelet adhesion despite normal sized VWF multimers. Finally, type 2N includes variants with markedly decreased affinity for factor VIII (FVIII). Studies have begun to address the association between particular genetic variants of VWF and the disease phenotype. For example, the recessive type 3 disease appears to be due to a variety of mutations that result in a null phenotype, while type 2N disease results from a group of recessive missense mutations that interfere with FVIII binding. Recently, the molecular pathogenesis of type 1 VWD has begun to be characterised revealing a diverse spectrum of genetic changes. In two large studies, patients with type 1 VWD were found to be heterozygous for a variety of missense, splice site and transcriptional mutations. In some patients, more than one variant sequence was present, and in a significant number of individuals no changes were evident in the VWF gene. These results suggest that the molecular correlates for type 1 VWD are complex and, in addition to a wide array of changes at the VWF locus, are likely to involve mutations in other genes.

Keywords: Classification of disease, Genetics, Molecular pathology, Mutations, Von Willebrand disease, VWD, Von Willebrand factor, VWF