OC 60.2 - Population-based prevalence and mutational landscape of von Willebrand disease using large-scale genetic databases

Background: Von Willebrand disease (VWD) is a common bleeding disorder caused by mutations in the von Willebrand factor gene (VWF). The true global prevalence of VWD has not been accurately established.

Aims: To estimate the worldwide and within-population prevalence of inherited VWD and to explore the global mutational landscape of VWF.

Methods: We obtained and analyzed VWF variants of 141,456 unrelated subjects from gnomAD population and results were compared to the Human-Gene-Mutation-Database(HGMD) and Leiden-Open-Variation-Database(LOVD). The following gnomAD variants were considered pathogenic: nonsense, frameshift, inframe deletion or insertion; splice-site variants affecting the first or last three intronic nucleotides; splicing variants affecting the first or last eight intronic nucleotides or missense variants predicted deleterious by three and seven algorithms, respectively and all variants found in the gnomAD being associated with VWD in HGMD/LOVD.

Results: 4,313 different genetic variants were identified within VWF in the gnomAD population. Of these, 505 variants were predicted pathogenic(i.e. novel, n=287) or reported to be associated with VWD(n=218), with 244 being identified in only one subject. Among the 282,912 alleles analyzed, 31,785 were affected by the aforementioned variants. The population-based prevalence of dominant VWD was established to be 7.7% for type 1, 0.3% for 2A, 0.3% for 2B and 0.6% for 2M. For recessive forms, the prevalence was 0.003% for 2N and 0.3% for type 3(Table 1). This comprehensive analysis provided a global mutational landscape of VWD with 927 so-far reported (in the HGMD/LOVD) and 287 novel variants identified in the gnomAD.

Conclusion(s): For the first time, we attempted to estimate the worldwide and within-population prevalence of VWD using genome/exome sequencing data of 141,456 individuals in the gnomAD. Our results reveal a considerably higher than-expected prevalence of putative disease alleles and variants associated with VWD and suggest that a large number of VWD patients are undiagnosed.