Genotypic classification of von Willebrand disease

Many mutations in the von Willebrand factor (VWF) gene associated with von Willebrand disease (VWD) have been reported. To examine the profile of mutations reported for each VWD type, two sources of information were consulted. The International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee (SSC) on von Willebrand factor has an electronic database to list VWF mutations; www.shef.ac.uk/vwf to which all researchers are invited to submit mutations that they have identified. The 307 mutations submitted to the database were classified by VWD type, VWF location, and by mutation type to seek common features within each disease type and characteristics discriminating the different disease types. Type 2 VWD subtypes are characterized by missense mutations in discrete areas of VWF, whereas 80% of type 3 VWD mutations are predicted to result in non-expressed alleles located throughout VWF. Remaining type 3 mutations are missense and these are predominantly located in the D1 and D4-CK domains, none are to date reported in the A domains. Few mutations associated with type 1 VWD have been submitted to the database. The European Union collaborative study on type 1 von Willebrand disease; Molecular and Clinical Markers for the Diagnosis and Management of type 1 VWD (MCMDM-1VWD) has investigated 153 index cases originally classified as having type 1 VWD for mutations in the VWF gene. 80% of the mutations are missense, these are located throughout VWF. Common features of mutation type and location in each VWD type can therefore be identified and may be useful for directed mutation analysis.