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Characterization of copy-number variants in a large cohort of patients with von Willebrand disease reveals a relationship between disrupted regions and disease type.
Sadler, Brooke; Christopherson, Pamela A; Perry, Crystal L; Bellissimo, Daniel B; Haberichter, Sandra L; Haller, Gabe; Antunes, Lilian; Flood, Veronica H; Di Paola, Jorge; Montgomery, Robert R.
Afiliación
  • Sadler B; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
  • Christopherson PA; Versiti Blood Research Institute, Milwaukee, Wisconsin, USA.
  • Perry CL; Versiti Blood Research Institute, Milwaukee, Wisconsin, USA.
  • Bellissimo DB; Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
  • Haberichter SL; Versiti Blood Research Institute, Milwaukee, Wisconsin, USA.
  • Haller G; Division of Pediatric Hematology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
  • Antunes L; Department of Neurosurgery, Washington University, St. Louis, Missouri, USA.
  • Flood VH; Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
  • Di Paola J; Versiti Blood Research Institute, Milwaukee, Wisconsin, USA.
  • Montgomery RR; Division of Pediatric Hematology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Res Pract Thromb Haemost ; 7(7): 102232, 2023 Oct.
Article en En | MEDLINE | ID: mdl-38077814
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Res Pract Thromb Haemost Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Res Pract Thromb Haemost Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos