OC 13.5 - Whole-genome characterization of low-VWF and VWD Type 1 Patients with no Known Pathogenic VWF Variant Reveals Novel Genetic Associations

Sunday, June 25, 2023

11:45 – 12:00 ET

Room: 710B

Session Available As: On-Demand

Presenting Author(s)

Brooke Sadler, PhD, MA

Assistant Professor in Pediatrics, Hematology and Oncology
Department of Pediatrics, School of Medicine, Washington University
St. Louis, Missouri, United States

Co-Author(s)

Pamela A. Christopherson

Research Program Coordinator
Versiti Blood Research Institute
Milwaukee, Wisconsin, United States
GH

Gabe Haller

Assistant Professor
Washington University School of Medicine
St. Louis, Missouri, United States
LA

Lilian Antunes

Postdoctoral Scholar
Washington University School of Medicine
St. Louis, Missouri, United States
CC

Carlos Cruchaga

Professor
Washington University School of Medicine
St. Louis, Missouri, United States
AP

Andrew Paterson

Senior Scientist
Hospital for Sick Children
Toronto, Ontario, Canada
Paula James, MD

Professor
Department of Medicine, Queen's University, Kingston, ON, Canada
Kingston, Ontario, Canada
David Lillicrap, MD

Professor
Department of Pathology and Molecular Medicine, Queen's University
Kingston, Ontario, Canada
JO

James S. O'Donnell, MB, PhD

Professor of Haematology
Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland,Dublin, Ireland
Dublin, Dublin, Ireland
RM

Robert Montgomery

Senior Investigator
Medical College of Wisconsin, Versiti Blood Research Institute, Children's Research Institute
Milwaukee, Wisconsin, United States
Jorge Di Paola, MD (he/him/his)

Professor of Pediatrics and Molecular Genetics & Genomics
Washington University School of Medicine, United States

Background: Approximately 35% of VWD type 1 patients do not have a known pathogenic variant in the VWF gene, and this figure is even lower in low-VWF patients.

Aims: To elucidate the underlying genetic mechanisms of low-VWF and VWD outside of the VWF gene by performing Whole Genome Sequencing (WGS) on patients with no known VWF variant as well as control genomes.

Methods: We performed 30x WGS on 227 low-VWF and VWD type 1 patients with no known VWF variant and 90 family members, both affected and unaffected, using the Illumina NovaSeq. 625 control genomes were run on the same platform. Age, sex and principal components were used as covariates. Case/control GWAS were performed, as well as de novo analyses on trios, rare recessive analyses and copy-number variant analyses.

Results: We find genome-wide significant signals at ABO and VWF and two new GWAS signals that surpassed exome-wide significance: MAN2A1, a gene involved in the n-glycan maturation pathway and an eQTL for PLPP3, a gene involved in aortic endothelial cell function (Figure 1). Additionally, we find 3 de novo variants (2 missense, 1 frameshift) in genes involved in autoimmune thrombocytopenia and 1 de novo frameshift variant in GALNT17, a galactosaminyltransferase involved in membrane trafficking. Rare recessive analyses on trios revealed multiple compound heterozygotes in genes relevant to hemostasis, and CNV analyses revealed rare CNVs in genes involved in hematological phenotypes.

Conclusion(s): Here we report the initial results of our WGS data in low-VWF and VWD type 1 patients with no known pathogenic VWF variant. Our findings are indicative of a complex disorder with multiple genetic risk factors. Future replications and functionalization of variants will allow for a better characterization of these patients.

Learning Objectives:

Understand the importance of whole-genome sequencing in low-VWF and VWD patients with no known pathogenic VWF sequence variant.
Describe approaches for analyzing whole-genome sequence data and what was discovered in the sample of low-VWF/VWD patents.
Identify what makes low-VWF/VWD a complex genetic disorder with multiple genetic risk factors.