PB0277 - Discrepancy between variant interpretation and phenotypes in von Willebrand disease (VWD): Insights from a study on Japanese genetic variants in VWD

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

Takafumi Akimoto, MSc, MBA, Pharmacist

Graduate Student
Department of Laboratory Medicine, Tokyo Medical University
Shinjuku-ku, Tokyo, Japan

Co-Author(s)

Hiroshi Inaba

Associate Professor
Department of Laboratory Medicine, Tokyo Medical University
Shinjuku, Tokyo, Japan
EK

Eiichi N. Kodama

Professor
Graduate School of Medicine, Tohoku University International Research Institute of Disaster Science, Tohoku University
Sendai, Miyagi, Japan
SO

Soichi Ogishima

Professor
Department of Informatics for Genomic Medicine, Group of Integrated Database Systems, Tohoku Medical Megabank Organization, Tohoku University
Sendai, Miyagi, Japan
KK

Kazuki Kumada

Professor
Department of Biobank, Group of Biobank, Tohoku Medical Megabank Organization, Tohoku University
Sendai, Miyagi, Japan
AM

Ayano Mitsuhashi

Endowed researcher
Department of Laboratory Medicine, Tokyo Medical University
Shinjuku, Tokyo, Japan
Keiko Shinozawa, PhD

Assistant Professor
Department of Laboratory Medicine, Tokyo Medical University/Japan
Shinjuku-ku, Tokyo, Japan
KA

Kagehiro Amano

Professor
Department of Laboratory Medicine, Tokyo Medical University
Shinjuku, Tokyo, Japan
EK

Ei Kinai

Professor
Department of Laboratory Medicine, Tokyo Medical University
Shinjuku, Tokyo, Japan

Background: VWD is one of the most common inherited bleeding disorders. Despite the incomplete penetrance and variable expressivity of VWF gene variants, detailed information is scarce due to lack of population-based evaluation of gene expressivity.

Aims: To clarify penetrance and expressivity of multiple VWF gene variants by comparing variant interpretations with phenotypes using the Japanese gene variant database (the Japanese Multi-Omics Reference Panel (jMorp) in the Tohoku Medical Megabank Organization (ToMMo)) and preserved plasma.

Methods: Using the genomic analysis data from approximately 8,300 general population Japanese (8.3KJPN) available on the jMorp as a data source, we picked up possible pathogenic variants by in silico analyses and by checking for registration in the LOVD. Then we obtained plasma samples of individuals with these variants from ToMMo and measured VWF:RCo, VWF:Ag, VWF:pp, and VWF:CB to confirm the pathogenicity of these variants. This investigation was approved by the ethical committees at Tokyo Medical University and ToMMo.

Results: Screening of 5,857 VWF gene variants revealed 29 variants as potential pathogenic. Three of these showed low VWF levels, i.e., VWF:RCo or VWF:Ag less than 30 IU/dl, that allowed for the diagnosis of VWD. The other three samples showed VWF:RCo or VWF:Ag between 30 and 50 IU/dl, indicating “low VWF”. In addition, one other sample showed only low levels of VWF:CB/VWF:Ag, indicating a possible VWF abnormality. However, despite the suggested pathogenicity, the remaining samples showed no abnormalities in VWF. Additionally, the same variant was observed to have different VWF levels.

Conclusion(s): Of 29 potentially pathogenic variants, only 7 variants exhibited abnormal VWF, and some variants presented various range of VWF levels. It supported the incomplete penetrance and variable expressivity of VWF gene variants. To clarify their etiology, other multiple factors for VWF expression or metabolism should be evaluated.