Taisuke Ishikawa1, Hiroki Kimoto2, Hiroyuki Mishima3, Kenichiro Yamagata4, Soshiro Ogata5, Yoshiyasu Aizawa6, Kenshi Hayashi7, Hiroshi Morita8, Tadashi Nakajima9, Yukiko Nakano10, Satoshi Nagase11, Nobuyuki Murakoshi12, Shinya Kowase13, Kimie Ohkubo14, Takeshi Aiba15, Shimpei Morimoto16, Seiko Ohno17, Shiro Kamakura4, Akihiko Nogami12, Masahiko Takagi18, Matilde Karakachoff19, Christian Dina20, Jean-Jacques Schott20, Koh-Ichiro Yoshiura3, Minoru Horie21, Wataru Shimizu22, Kunihiro Nishimura5, Kengo Kusano4, Naomasa Makita1. 1. Omics Research Center, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita 5648565, Japan. 2. Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 8528523, Japan. 3. Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 8528523, Japan. 4. Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita 5648565, Japan. 5. Department of Preventive Medicine and Epidemiology, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita 5648565, Japan. 6. Department of Cardiovascular Medicine, International University of Health and Welfare, 4-3 Kozunomori, Narita 2860048, Japan. 7. Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, 13-1 Takaramachi, Kanazawa 9208641, Japan. 8. Department of Cardiovascular Therapeutics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 7008558, Japan. 9. Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showamachi, Maebashi 3710034, Japan. 10. Department of Cardiovascular Medicine, Hiroshima University, 1-2-3 Kasumi, Hiroshima 7348551, Japan. 11. Department of Advanced Arrhythmia and Translational Medical Science, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita 5648565, Japan. 12. Department of Cardiology, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 3058575, Japan. 13. Department of Heart Rhythm Management, Yokohama Rosai Hospital, 3211 Kozukue-Cho, Yokohama 2220036, Japan. 14. Division of Cardiology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamimachi, Tokyo 1738610, Japan. 15. Department of Clinical Laboratory, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita 5648565, Japan. 16. Innovation Platform & Office for Precision Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 8528501, Japan. 17. Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita 5648565, Japan. 18. Division of Cardiac Arrhythmia, Kansai Medical University, 10-15 Fumizonomachi, Moriguchi 5708507, Japan. 19. L'institut du Thorax, CHU Nantes, 1 Place Alexis-Ricordeau, Nantes 44007, France. 20. L'institut du Thorax, INSERM, CNRS, UNIV Nantes, 8 Quai Moncousu, Nantes 44007, France. 21. Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Setatsukiwa-cho, Ohtsu 5202192, Japan. 22. Department of Cardiovascular Medicine, Nippon Medical School, 1-1-5 Sendagi, Tokyo 1138603, Japan.
Abstract
AIMS: 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. METHODS AND RESULTS: 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: 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. METHODS AND RESULTS: 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Corey L Anderson; Saba Munawar; Louise Reilly; Timothy J Kamp; Craig T January; Brian P Delisle; Lee L Eckhardt Journal: Front Cardiovasc Med Date: 2022-07-04
Authors: Matthew J O'Neill; Ayesha Muhammad; Bian Li; Yuko Wada; Lynn Hall; Joseph F Solus; Laura Short; Dan M Roden; Andrew M Glazer Journal: Genet Med Date: 2022-03-16 Impact factor: 8.864
Authors: Hasina Masha Aziz; Michał P Zarzecki; Sebastian Garcia-Zamora; Min Seo Kim; Piotr Bijak; Gary Tse; Hong-Hee Won; Paweł T Matusik Journal: J Clin Med Date: 2022-03-30 Impact factor: 4.241