PB0272 - Novel insight into the genetic background of Low VWF using whole exome sequencing

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

Omid Seidizadeh, MSc, PhD

University of Milan, Department of Pathophysiology and Transplantation, Milan, Italy
Milan, Lombardia, Italy

Co-Author(s)

Andrea Cairo

Professional research collaborator
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
Milan, Lombardia, Italy
Alessandro Ciavarella

Clinician
Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
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
GC

Giovanna Cozzi

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

Paola Colpani

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

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

Hadi Eidgah

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

Cristina Novembrino

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

Francesco Ballardini

Clinician
Department of Oncology and Onco-Hematology, University of Milan, Milan, Italy
Milan, Lombardia, Italy
Pasquale Agosti, MD, PhD

Assistant Professor Clinician
Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.
Milan, Lombardia, Italy
SS

Simona Maria Siboni

Physician
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
Milan, Lombardia, Italy
Flora Peyvandi, MD, PhD

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

Background: Low von Willebrand factor(VWF) refers to subjects with plasma levels of 30-50 IU/dL. The genetic background of Low VWF is poorly understood, with most cases not possessing VWF pathogenic variants.

Aims: To investigate the genetic background of Low VWF using whole-exome sequencing(WES).

Methods: Of 250 patients from the Low VWF Milan Cohort (LOVMIC), we have performed so far WES for 71 patients and 140 healthy controls. Genetic association for common variants was performed using PLINK. For rare variants, a cumulative test using KGGseq (Burden, SKAT, and SKATO tests) was performed. Previously reported common variants associated with VWF levels were assessed by linear regression. Copy number variation(CNV) was performed by custom pipeline using CNVkit.

Results: VWF pathogenic variants(n=18) were found in only 19 patients(27%) however, 73% did not carry pathogenic variants. In the remaining 52 cases, 14 other genes known to be associated with VWF levels were investigated(UFM1, AVPR2, LRP1, ST3GAL4, SCARA5, ABO, ACE, FUT1, STX2, CLEC4M, FUT2, ADGRB3, STXBP5, and STAB2). We found 114 rare variants in these/and VWF genes with CADD score>15, affecting 116 alleles(26-cases, 90-controls) and the cumulative test indicated 2 significant genes(UFM1 and AVPR2;Table 1). We found 16 common variants in VWF and other genes with a significant distribution between patients and controls (p < 0.05, ABO-adjusted;Table 2). Linear regression analysis on 6 previously reported variants (rs1063857, rs868875, rs2277998, rs1039084, rs9390459, and rs8176719) in 52 patients indicated that 3 of them have a significant association with VWF antigen levels (rs1063857:reduced level, rs868875 and rs2277998:increased level). CNV analysis identified 2 potential duplications in 2 patients and 2 deletions in other 4 patients.

Conclusion(s): These novel results show that genes outside the VWF could be involved in the underlying mechanism of Low VWF patients without VWF pathogenic variants. Our results newly indicate the relevant role of CNV in the genetic background of Low VWF.