Updated global prevalence and ethnic diversity of von Willebrand disease based on population genetics analysis.

von Willebrand disease (VWD) is known as the most common inherited bleeding disorder. Despite this, some uncertainty remains regarding its prevalence and the distribution of different phenotypes worldwide and across ethnic groups. By leveraging genetic epidemiology approaches that enable population-scale estimates, the prevalence of VWD and its diverse phenotypes can be assessed more precisely. We estimated the global VWD prevalence and its distribution across distinct ethnic groups using the largest and most widely used publicly available genetic database. Available exome/genome sequencing data of 807,162 (730,947 exomes, 76,215 genomes) subjects from the Genome Aggregation Database (gnomAD-v4.1) were used. Based on the allele frequencies of 321 previously reported VWF pathogenic variants identified in the gnomAD population, the estimated worldwide prevalence of VWD per 1,000 individuals was 10.6 for type 1, 1.3 for type 2A, 1.7 for type 2B, and 1.5 for type 2 M. For the recessive forms of VWD, the global prevalence was estimated to be 33.9 cases per million for type 2N and 1.3 cases per million for type 3 VWD. Once structural variants and copy number variants from gnomAD that result in loss of function were included, the estimated prevalence of type 3 slightly increased to 1.8 per million. Additionally, VWD prevalence was found to vary significantly across different ethnic groups. This updated population-based genetic prevalence indicates a substantially higher than expected frequency of VWD. Our novel finding suggests that a large number of patients remain undiagnosed.