Functionally validated <i>SCN5A</i> variants allow interpretation of pathogenicity and prediction of lethal events in Brugada syndrome
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- Taisuke Ishikawa
- Omics Research Center, National Cerebral and Cardiovascular Center , 6-1 Kishibe-Shimmachi, Suita 5648565, Japan
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- Hiroki Kimoto
- Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences , 1-12-4 Sakamoto, Nagasaki 8528523, Japan
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- Hiroyuki Mishima
- Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences , 1-12-4 Sakamoto, Nagasaki 8528523, Japan
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- Kenichiro Yamagata
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center , 6-1 Kishibe-Shimmachi, Suita 5648565, Japan
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- Soshiro Ogata
- Department of Preventive Medicine and Epidemiology, National Cerebral and Cardiovascular Center , 6-1 Kishibe-Shimmachi, Suita 5648565, Japan
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- Yoshiyasu Aizawa
- Department of Cardiovascular Medicine, International University of Health and Welfare , 4-3 Kozunomori, Narita 2860048, Japan
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- Kenshi Hayashi
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences , 13-1 Takaramachi, Kanazawa 9208641, Japan
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- Hiroshi Morita
- Department of Cardiovascular Therapeutics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 2-5-1 Shikata-cho, Okayama 7008558, Japan
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- Tadashi Nakajima
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine , 3-39-22 Showamachi, Maebashi 3710034, Japan
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- Yukiko Nakano
- Department of Cardiovascular Medicine, Hiroshima University , 1-2-3 Kasumi, Hiroshima 7348551, Japan
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- Satoshi Nagase
- Department of Advanced Arrhythmia and Translational Medical Science, National Cerebral and Cardiovascular Center , 6-1 Kishibe-Shimmachi, Suita 5648565, Japan
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- Nobuyuki Murakoshi
- Department of Cardiology, University of Tsukuba , 1-1-1 Tennodai, Tsukuba 3058575, Japan
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- Shinya Kowase
- Department of Heart Rhythm Management, Yokohama Rosai Hospital , 3211 Kozukue-Cho, Yokohama 2220036, Japan
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- Kimie Ohkubo
- Division of Cardiology, Department of Medicine, Nihon University School of Medicine , 30-1 Oyaguchi-kamimachi, Tokyo 1738610, Japan
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- Takeshi Aiba
- Department of Clinical Laboratory, National Cerebral and Cardiovascular Center , 6-1 Kishibe-Shimmachi, Suita 5648565, Japan
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- Shimpei Morimoto
- Innovation Platform & Office for Precision Medicine, Nagasaki University Graduate School of Biomedical Sciences , 1-7-1 Sakamoto, Nagasaki 8528501, Japan
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- Seiko Ohno
- Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center , 6-1 Kishibe-Shimmachi, Suita 5648565, Japan
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- Shiro Kamakura
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center , 6-1 Kishibe-Shimmachi, Suita 5648565, Japan
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- Akihiko Nogami
- Department of Cardiology, University of Tsukuba , 1-1-1 Tennodai, Tsukuba 3058575, Japan
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- Masahiko Takagi
- Division of Cardiac Arrhythmia, Kansai Medical University , 10-15 Fumizonomachi, Moriguchi 5708507, Japan
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- Matilde Karakachoff
- L'institut du Thorax, CHU Nantes , 1 Place Alexis-Ricordeau, Nantes 44007, France
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- Christian Dina
- L'institut du Thorax, INSERM, CNRS, UNIV Nantes , 8 Quai Moncousu, Nantes 44007, France
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- Jean-Jacques Schott
- L'institut du Thorax, INSERM, CNRS, UNIV Nantes , 8 Quai Moncousu, Nantes 44007, France
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- Koh-Ichiro Yoshiura
- Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences , 1-12-4 Sakamoto, Nagasaki 8528523, Japan
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- Minoru Horie
- Center for Epidemiologic Research in Asia, Shiga University of Medical Science , Setatsukiwa-cho, Ohtsu 5202192, Japan
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- Wataru Shimizu
- Department of Cardiovascular Medicine, Nippon Medical School , 1-1-5 Sendagi, Tokyo 1138603, Japan
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- Kunihiro Nishimura
- Department of Preventive Medicine and Epidemiology, National Cerebral and Cardiovascular Center , 6-1 Kishibe-Shimmachi, Suita 5648565, Japan
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- Kengo Kusano
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center , 6-1 Kishibe-Shimmachi, Suita 5648565, Japan
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- Naomasa Makita
- Omics Research Center, National Cerebral and Cardiovascular Center , 6-1 Kishibe-Shimmachi, Suita 5648565, Japan
抄録
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Aims</jats:title> <jats:p>The prognostic value of genetic variants for predicting lethal arrhythmic events (LAEs) in Brugada syndrome (BrS) remains controversial. We investigated whether the functional curation of SCN5A variations improves prognostic predictability.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and results</jats:title> <jats:p>Using a heterologous expression system and whole-cell patch clamping, we functionally characterized 22 variants of unknown significance (VUSs) among 55 SCN5A mutations previously curated using in silico prediction algorithms in the Japanese BrS registry (n = 415). According to the loss-of-function (LOF) properties, SCN5A mutation carriers (n = 60) were divided into two groups: LOF-SCN5A mutations and non-LOF SCN5A variations. Functionally proven LOF-SCN5A mutation carriers (n = 45) showed significantly severer electrocardiographic conduction abnormalities and worse prognosis associated with earlier manifestations of LAEs (7.9%/year) than in silico algorithm-predicted SCN5A carriers (5.1%/year) or all BrS probands (2.5%/year). Notably, non-LOF SCN5A variation carriers (n = 15) exhibited no LAEs during the follow-up period. Multivariate analysis demonstrated that only LOF-SCN5A mutations and a history of aborted cardiac arrest were significant predictors of LAEs. Gene-based association studies using whole-exome sequencing data on another independent SCN5A mutation-negative BrS cohort (n = 288) showed no significant enrichment of rare variants in 16 985 genes including 22 non-SCN5A BrS-associated genes as compared with controls (n = 372). Furthermore, rare variations of non-SCN5A BrS-associated genes did not affect LAE-free survival curves.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>In vitro functional validation is key to classifying the pathogenicity of SCN5A VUSs and for risk stratification of genetic predictors of LAEs. Functionally proven LOF-SCN5A mutations are genetic burdens of sudden death in BrS, but evidence for other BrS-associated genes is elusive.</jats:p> </jats:sec>
収録刊行物
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- European Heart Journal
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European Heart Journal 42 (29), 2854-2863, 2021-06-05
Oxford University Press (OUP)
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詳細情報 詳細情報について
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- CRID
- 1360294643721644288
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- ISSN
- 15229645
- 0195668X
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- データソース種別
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