Molecular genetic testing in von Willebrand disease: past, present, and beyond

The gene for von Willebrand factor (VWF) was among the earliest genomic discoveries in the mid-1980s. It became feasible to use this new knowledge to better understand the genetic mechanisms responsible for von Willebrand disease (VWD) and to utilize the information to generate molecular genetic diagnostic testing strategies. Following initial studies demonstrating large structural variants in type 3 VWD patients, investigations focused on the genetic basis of the various type 2 forms of VWD, demonstrating that the pathogenic variants were localized to regions of the gene encoding functionally distinct domains of the VWF glycoprotein. These observations have resulted in increasing use of molecular genetic diagnosis as either the primary strategy for diagnosing type 2 forms of VWD or, more often, as confirmatory tests to substantiate the results of prior phenotypic analysis. In the meantime, genetic studies of type 3 were demonstrating that a wide range of pathogenic variants located throughout the VWF coding sequence were responsible for this severe phenotype. These studies also showed that ~15% of pathogenic variants responsible for type 3 were missense substitutions and that in ~25% of families this severe phenotype, classically thought to be recessive in nature, was transmitted as a semi-dominant trait. Finally, the most prevalent form of VWD, type 1/Low VWF, has proven to be the most challenging for routine molecular genetic testing, with VWF coding sequence variants identified in only ~65% of index cases. This review explores various aspects of molecular genetic testing for VWF, commemorating the 100th anniversary of VWD and the 40th anniversary of VWF cloning.