Faculty Collaboration Database

von Willebrand factor antigen levels are associated with burden of rare nonsynonymous variants in the VWF gene. Blood 2021 Jun 10;137(23):3277-3283

Date

02/09/2021

Pubmed ID

33556167

Pubmed Central ID

PMC8351900

DOI

10.1182/blood.2020009999

Scopus ID

2-s2.0-85107840652 (requires institutional sign-in at Scopus site)   10 Citations

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.

Author List

Sadler B, Christopherson PA, Haller G, Montgomery RR, Di Paola J

Author

Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Female
Genetic Variation
Hemorrhage
Humans
Male
von Willebrand Disease, Type 1
von Willebrand Factor