New insights into genotype and phenotype of VWD

Abstract

Recent advances in VWD research have improved our understanding of the genotype and phenotype of VWD. The VWF gene is highly polymorphic, with a large number of sequence variations reported in healthy individuals. This can lead to some difficulty when attempting to discern genotype-phenotype correlations because sequence variations may not represent disease. In type 1 VWD, mutations can be found throughout the VWF gene, but likely pathogenic sequence variations are found in only ∼2/3 of type 1 VWD patients. Sequence variations in type 2 VWD are located in the region corresponding to the defect in the VWF protein found in each type 2 variant. In type 3 VWD, sequence variations are not confined to a specific region of the VWF gene and also include large deletions that may not be picked up using conventional sequencing techniques. Use of genetic testing may be most helpful in diagnosis of type 2 VWD, in which a larger number of known, well characterized mutations are present and demonstration of one of these may help to confirm the diagnosis. Bleeding symptoms in general are more severe with decreasing VWF levels and more severe in type 2 and type 3 VWD compared with type 1 VWD. Prediction of phenotype for an individual patient, however, is still difficult, and the addition of genetic data will be most helpful in ascertaining the correct diagnosis for VWD patients.