Rare VWF Gene Variants Predict von Willebrand Factor Antigen Levels Beyond Known Pathogenic Mutations
In a study of 527 patients with low VWF or von Willebrand disease and 210 controls, the burden of rare nonsynonymous VWF coding variants was a strong predictor of VWF antigen levels, even after controlling for known pathogenic variants. Type 1 VWD patients carried eight times more rare variants than healthy subjects. The findings suggest that next-generation sequencing of the full VWF gene can improve diagnostic yield in the approximately 35% of type 1 VWD patients without an identified pathogenic variant.
The original study
von Willebrand factor antigen levels are associated with burden of rare nonsynonymous variants in the VWF gene.
- Authors
- Sadler B, Christopherson PA, Haller G, Montgomery RR, Di Paola J
- Journal
- Blood
- Type
- Clinical Trial, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural
- PMID
- 33556167
Original abstract
Approximately 35% of patients with type 1 von Willebrand disease (VWD) do not have a known pathogenic variant in the von Willebrand factor (VWF) gene. We aimed to understand the impact of VWF coding variants on VWD risk and VWF antigen (VWF:Ag) levels, studying 527 patients with low VWF and VWD and 210 healthy controls. VWF sequencing was performed and VWF:Ag levels assayed. A combined annotation-dependent depletion (CADD) score >20 was used as a predicted pathogenicity measure. The number of rare nonsynonymous VWF variants significantly predicted VWF:Ag levels (P = 1.62 × 10-21). There was an association between average number of rare nonsynonymous VWF variants with VWD type 1 (P = 2.4 × 10-13) and low VWF (P = 1.6 × 10-27) compared with healthy subjects: type 1 subjects possessed on average >2 times as many rare variants as those with low VWF and 8 times as many as healthy subjects. The number of rare nonsynonymous variants significantly predicts VWF:Ag levels even after controlling for presence of a variant with a CADD score >20 or a known pathogenic variant in VWF (P = 2.7 × 10-14). The number of rare nonsynonymous variants in VWF as well as the presence of a variant with CADD >20 are both significantly associated with VWF levels. The association with rare nonsynonymous variants holds even when controlling for known pathogenic variants, suggesting that additional variants, in VWF or elsewhere, are associated with VWF:Ag levels. Patients with higher VWF:Ag levels with fewer rare nonsynonymous VWF gene variants could benefit from next-generation sequencing to find the cause of their bleeding.