Characterization of copy-number variants in a large cohort of patients with von Willebrand disease reveals a relationship between disrupted regions and disease type

Brooke Sadler; Pamela A Christopherson; Crystal L Perry; Daniel B Bellissimo; Sandra L Haberichter; Gabe Haller; Lilian Antunes; Veronica H Flood; Jorge Di Paola; Robert R Montgomery; Zimmerman Program Investigators

doi:10.1016/j.rpth.2023.102232

Characterization of copy-number variants in a large cohort of patients with von Willebrand disease reveals a relationship between disrupted regions and disease type

Res Pract Thromb Haemost. 2023 Oct 14;7(7):102232. doi: 10.1016/j.rpth.2023.102232. eCollection 2023 Oct.

Authors

Affiliations

¹ Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
² Versiti Blood Research Institute, Milwaukee, Wisconsin, USA.
³ Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
⁴ Division of Pediatric Hematology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
⁵ Department of Neurosurgery, Washington University, St. Louis, Missouri, USA.

Abstract

Background: Genetic analysis for von Willebrand disease (VWD) commonly utilizes DNA sequencing to identify variants in the von Willebrand factor (VWF) gene; however, this technique cannot always detect copy-number variants (CNVs). Additional mapping of CNVs in patients with VWD is needed.

Objectives: This study aimed to characterize CNVs in a large sample of VWF mutation-negative VWD patients.

Methods: To determine the role of CNVs in VWD, a VWF high-resolution comparative genomic hybridization array was custom-designed to avoid multiple sequence variations, repeated sequences, and the VWF pseudogene. This was performed on 204 mutation-negative subjects for whom clinical variables were also available.

Results: Among the 204 patients, 7 unique CNVs were found, with a total of 24 CNVs (12%). Of the 7 unique CNVs, 1 was novel, 1 was found in a VWF database, and 5 were previously reported. All patients with type 1C VWD and a CNV had the same exon 33 and 34 in-frame deletion. Certain clinical variables were also significantly different between those with and without CNVs.

Conclusion: The in-frame deletion in patients with type 1C VWD exactly matches the D4N module of the D4 domain, a region where mutations and deletions are known to affect clearance. We observed significantly higher VWF-to-ristocetin cofactor levels in patients with type 1C VWD and a CNV than in patients without a CNV, suggesting a relationship between CNVs and the increased clearance observed in patients with type 1C VWD. Glycoprotein IbM activity was significantly lower in patients with type 1 VWD and a CNV than in patients without a CNV, suggesting that platelet binding is more affected by CNVs than single base pair mutations. This work elucidates some of the underlying genetic mechanisms of CNVs in these patients.

Keywords: bleeding score; comparative genomic hybridization; copy number variants; ristocetin cofactor; von Willebrand disease; von Willebrand factor.

Abstract

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