PB0821 - Data mining for profiling the mutational landscape of von Willebrand disease

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

Omid Seidizadeh, MSc, Phd student

Phd Student
Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
Milan, Lombardia, Italy

Co-Author(s)

Andrea Cairo

Biologist
Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
Milan, Lombardia, Italy
Luciano Baronciani

Biologist
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
Milan, Lombardia, Italy
MP

Maria Teresa Pagliari

Researcher
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
Milan, Lombardia, Italy
SS

Simona Maria Siboni

Hematologist
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
Milan, Lombardia, Italy
Eugenia Biguzzi, MD

Hematologist
Hematology clinic, Oncology Institute of Southern Switzerland, EOC
Bellinzona, Ticino, Switzerland
Flora Peyvandi, MD, PhD

Professor of Internal Medicine; Director of the Angelo Bianchi Bonomi Hemophilia & Thrombosis Center
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
Milan, Lombardia, Italy

Background: Von Willebrand disease (VWD) with a population prevalence of 1% is caused by mutations in the von Willebrand factor (VWF). However, its exact prevalence is not yet established. More than 900 distinct mutations have been found in the VWF so far.

Aims: To explore the VWF mutational burden and to estimate VWD prevalence in the general population using the genome Aggregation Database (gnomAD).

Methods: VWF variants were obtained from the gnomAD (v2.1.1; 141,456 subjects) and were compared to the Human-Gene-Mutation-Database (HGMD) and Leiden-Open-Variation-Database (LOVD v.2.0 and v.3.0). The following variants were considered pathogenic: nonsense and frame-shift; splicing (+2/-2); splicing (+8/-8) and missense predicted deleterious by 3/3 and 7/7 tools respectively or being associated with VWD in HGMD and LOVD2/3. All identified pathogenic variants were used to evaluate the VWF mutational burden and VWD prevalence.

Results: Using gnomAD, we identified 505 distinct VWF pathogenic variants (244 unique): 287 not reported (novel) and 218 already reported. 138 of 218 gnomAD variants were not predicted as pathogenic by all in-silico tools but were reported to be associated with VWD in HGMD and/or LOVD databases. Thirteen variants had a minor-allele-frequency (MAF) >0.01 in at least one population. In particular, 3 variants (p.Arg2185Gln, p.Met740Ile, p.His817Gln) were very frequent in Africans/Africans American (MAF: 0.11-0.18, Table 1). Due to these variants, the African population was excluded from the calculation of VWD prevalence in the general population and was analyzed standalone (Table 2). This analysis revealed a heterozygote frequency of 0.13 among all populations with a prevalence of 0.45 and 13.4 for recessively-inherited and autosomal-dominant, respectively among 100 individuals.

Conclusion(s): Through our systematic analysis of>140,000 individual exome/genome data from the gnomAD database, we found 287 novel VWF variants predicted as pathogenic. Our results demonstrated that the “true” worldwide prevalence of VWD is more than 10 times higher than that reported so far.