OC 60.1 - Delineating von Willebrand factor genetic variants in patients with a von Willebrand disease diagnosis

Background: Von Willebrand disease (VWD) is a common inherited bleeding disorder often caused by variants within the von Willebrand factor (VWF) gene.

Aims: To characterize candidate VWF variants in type 1, 2 and 3 VWD and elucidate pathogenicity using clinical, computational, familial segregation and functional data.

Methods: Index cases had thorough phenotypic laboratory and bleeding analysis and VWF genotyping. Candidate VWF variants were investigated in all family members. Variants were characterized using predictive programs (CADD, SpliceAI) and gnomAD allele frequencies. Available variant functional expression data were included to provide further evidence of pathogenicity.

Results: 540 VWD index cases, 692 affected and 868 unaffected family members enrolled in the Zimmerman Program with complete phenotypic and genotypic testing were analyzed. Candidate VWF variants were identified in 57% type 1/low VWF, 94% type 1C, 100% type 1-Severe, 90-100% type 2s and 100% type 3 patients (Table 1). Type 1 consisted of missense, frameshift, nonsense and intronic variants spread throughout the gene with variable population frequencies and CADD scores. The majority of type 1C variants were missense variants in the D’D3, A1 and D4 domains. In contrast, both type 1-Severe and type 3 predominantly involved frameshift, nonsense, splice and deletion variants resulting in null alleles. Not surprisingly, type 2A and 2B consisted of missense variants causing either interference with multimer formation, storage and secretion (A1/A2 domain) or enhanced platelet binding (A1) with high CADD scores and complete genetic segregation. Most type 2M variants responsible for reduced binding to platelets or collagen were A1 missense changes, and all 2N missense variants were located in the D’D3 FVIII binding region (Figure 1).

Conclusion(s): Our data illustrates how incorporating multiple methods for variant characterization can provide further insight into VWF variant pathogenicity, genotype-phenotype correlations, and segregation in VWD families which is critical for classification and guiding future clinical care and recurrence risks.