Comparison of genotypes and phenotypes for von Willebrand factor gene variants using Japanese genome database

• Analysis of the Japanese genome database showed no firm association between VWF pathogenic variants and phenotypic expression.

• Estimating VWD prevalence directly based on the variant allele frequencies risks overestimation.

von Willebrand disease (VWD) is a common inherited bleeding disorder. The aim of this study was to determine the predicted disease states associated with various pathogenic VW factor (VWF) variants and their phenotypes using the largest Japanese whole-genome database. Of the 5,857 VWF gene variants registered in the Japanese Multi-Omics Reference Panel (jMorp), variants with the following criteria were extracted; 1) caused protein abnormalities due to genetic alterations, 2) have already been detected and included in a database, including known association with VWD, and 3) highly-likely pathogenic by in silico analysis. We measured VWF activity, antigen, propeptide, and collagen binding activity in stored plasma samples obtained from heterozygous carriers of the selected variants. A total of 29 VWF variants (26 single nucleotide and 3 small insertions/deletions) were detected and six of these were found in Leiden Open Mutation Database. We obtained 43 plasma samples from individuals carrying these 29 variants as heterozygous. For the 43 variant-carriers, their mean age was 43.0 and blood group was type O in 17 (39.5%). Analysis of these plasma samples showed low VWF levels (<50%) in 6 (14.0%). Low VWF levels were found in 2/8 (25%) of the nonsense and 4/31 (12.9%) of the missense variants. Taking into consideration the limitation of using stored plasma samples, analysis of the jMorp indicated that most VWF gene variants with predicted pathogenic potential did not correlate with phenotypic expression. Our results supported incomplete penetrance and variable expressivity of the VWF gene variants.