Genetic characterization of families with von Willebrand disease

Abstract: von Willebrand disease (VWD) is the most common hereditary bleeding disorder. It is caused by quantitative and/or qualitative defects of the von Willebrand factor (VWF). The severity of the disease can vary considerably, as can the hereditary patterns. The variable phenotypes of VWD have given rise to a classification scheme that divides the disease into three types according to how it is manifested and inherited. The genetics of, especially type 1, VWD is relatively complicated and many aspects of it remain to be elucidated. The purpose of these studies was therefore to investigate and clarify certain genetic mechanisms that underlie VWD. When we investigated to what extent co-segregation exists in type 1 VWD, we found that the disease is linked to the VWF gene in a majority (27 of 31) of Swedish type 1 VWD families. Several common disease haplotypes probably exist for type 1 VWD in Sweden, which suggests founder effects. The Y1584C variation is not as common in the Swedish type 1 VWD population as it is in some other populations. We confirmed that blood group O is over-represented among type 1 VWD patients in Sweden. Apart from certain misunderstandings, the participants in the linkage study were found to have a satisfying level of knowledge of the genetics of the disease. In general, patients, younger individuals, and women have a higher knowledge about the genetics causing type 1 VWD than do healthy relatives, older individuals, and men, respectively. Inherited recessively, the C570S mutation causes a distinct subtype of type 2A VWD characterized by very low plasma FVIII and VWF levels and the exclusive presence of the dimeric form of VWF in plasma. The findings define a structural element that is indispensable for VWF multimerization. Inherited dominantly, the N1421K mutation causes type 2M VWD characterized by moderately decreased plasma FVIII and VWF levels, disproportionately low plasma VWF:RCo levels, and an apparently normal multimeric pattern. The findings indicate a structural element in the A1 domain that is necessary for proper GPIb binding.