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Genetic Study for Idiopathic Venous Thromboembolism in Japanese Using Short-Read and Long Read Sequencers: A Pilot Study of Japanese Group of Idiopathic Thromboembolism

1National Cerebral and Cardiovascular Center, Department of Cardiovascular Medicine, Suita, Japan, 2National Cerebral and Cardiovascular Center, Suita, Japan, 3Mie University Graduate School of Medicine, Department of Molecular and Laboratory Medicine, Tsu, Japan, 4Kanazawa University Graduate School of Medical Science, Department of Clinical Laboratory Science, Kanazawa, Japan, 5Mie University Graduate School of Medicine, Department of Cardiology and Nephrology, Tsu, Japan, 6Nara Medical University, Department of Pediatrics, Kashihara, Japan, 7Nagoya University Graduate School of Medicine, Department of Pathophysiological Laboratory Sciences, Nagoya, Japan, 8Nagoya University Hospital, Department of Transfusion Medicine, Nagoya, Japan, 9Kuwana City Medical Center, Kuwana, Japan

Abstract Number: PB2182

Meeting: ISTH 2020 Congress

Theme: Venous Thromboembolism and Cardioembolism » Genetic Risk Factors of Thrombosis

Background: Idiopathic venous thromboembolism (VTE) is characterized with family history of thrombosis, thrombosis at a young age (< 40 years), recurrent thrombosis, or thrombosis in unusual vascular territories. Short-read DNA sequencer facilitates the genetic analysis in patients with VTE. However, long-read sequencer has never been utilized for patients with idiopathic VTE.

Aims: We collected patients with idiopathic VTE consecutively. Using short-read and long-read sequencers, we identified small genetic variations and large structural variations in patients with VTE.

Methods: We selected 10 VTE candidate genes, SERPIC1, PROC, PROS1, F2, F5, FGA, FGB, FGG, F9, and THBD, and established a long-read sequencing using PacBio RS II (Pacific Bio) and short-read sequencing using Miseq (Illumina) for the candidate gene approach.

Results: Targeted sequencing using short-read as well as long-read sequencers identified 8 loss of function (LOF) variations in anticoagulant proteins in 27 VTE patients, including 2 LOF variations in SERPINC1 in 2 families, 2 LOF variations in PROC in 3 families, and 4 LOF variations in PROS1 in 7 families. In addition, we identified a thrombophilic variation, p.Arg596Gln, in the F2 gene in three patients with two families that conveys antithrombin resistance. We also identified copy number variation in F2 intron 4 and translocation in FV intron 6, which functions remained to be analyzed.

Conclusions: Our study provided fundamental resources for idiopathic VTE in Japan. Targeted sequencing using both short- and long-read sequencings would open a new paradigm for diagnosis and treatment for idiopathic VTE.

To cite this abstract in AMA style:

Tsuji A, Sekine A, Wada H, Morishita E, Ogihara Y, Nogami K, Kojima T, Matsushita T, Yamada N, Ogo T, Neki R, Kokame K, Yasuda S, Miyata T. Genetic Study for Idiopathic Venous Thromboembolism in Japanese Using Short-Read and Long Read Sequencers: A Pilot Study of Japanese Group of Idiopathic Thromboembolism [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/genetic-study-for-idiopathic-venous-thromboembolism-in-japanese-using-short-read-and-long-read-sequencers-a-pilot-study-of-japanese-group-of-idiopathic-thromboembolism/. Accessed September 29, 2023.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/genetic-study-for-idiopathic-venous-thromboembolism-in-japanese-using-short-read-and-long-read-sequencers-a-pilot-study-of-japanese-group-of-idiopathic-thromboembolism/