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Genotype-Phenotype Correlation of SCN5A Mutation for the Clinical and Electrocardiographic Characteristics of Probands With Brugada Syndrome: A Japanese Multicenter Registry.

From Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan (K.Y., T.A., K.K., S.K. S.Y., H.O., W.S.); Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Japan (M.H., S. Ohno); Department of Cardiovascular Medicine, University of Tokyo, Japan (K.Y.); Department of Cardiopulmonary Medicine, Keio University, Tokyo, Japan (S. Ogawa, K.F.); Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, Japan (Y.A., H.W.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan (T.O., H.M.); Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Ishikawa, Japan (M.Y., K.H.); Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Japan (N.M.); Department of Cardiology, Tokyo Metropolitan Hiroo Hospital, Japan (H.S.); Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan (T.T.); Division of Cardiology, Yamaguchi University Graduate School of Medicine, Japan (A.S.); Department of Cardiology, Tokyo Women's Medical University, Japan (N.H.); Department of Cardiology, St Marianna University of Medicine, Kanagawa, Japan (R.K.); Department of Cardiovascular Medicine, Hiroshima University, Japan (Y.N.); Department of Cardiovascular Medicine, Osaka City University, Japan (M.T.); Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan (T.M.); Laboratory of Molecular Genetics, National Cerebral and Cardiovascular Center, Osaka, Japan (Y.M.); Departments of Cardiovascular Diseases, Pediatrics, and Molecular Pharmacology & Experimental Therapeutics; Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN (J.D.K., M.J.A.); and Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan (W.S.). From Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan (K.Y., T.A., K.K., S.K. S.Y., H.O., W.S.); Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Japan (M.H., S. Ohno); Department of Cardiovascular Medicine, University of Tokyo, Japan (K.Y.); Department of Cardiopulmonary Medicine, Keio University, Tokyo, Japan (S. Ogawa, K.F.); Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, Japan (Y.A., H.W.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan (T.O., H.M.); Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Ishikawa, Japan (M.Y., K.H.); Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Japan (N.M.); Department of Cardiology, Tokyo Metropolitan Hiroo Hospital, Japan (H.S.); Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan (T.T.); Division of Cardiology, Yamaguchi University Graduate School of Medicine, Japan (A.S.); Department of Cardiology, Tokyo Women's Medical University, Japan (N.H.); Department of Cardiology, St Marianna University of Medicine, Kanagawa, Japan (R.K.); Department of Cardiovascular Medicine, Hiroshima University, Japan (Y.N.); Department of Cardiovascular Medicine, Osaka City University, Japan (M.T.); Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan (T.M.); Laboratory of Molecular Genetics, National Cerebral and Cardiovascular Center, Osaka, Japan (Y.M.); Departments of Cardiovascular Diseases, Pediatrics, and Molecular Pharmacology & Experimental Therapeutics; Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN (J.D.K., M.J.A.); and Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan (W.S.). wshimizu@nms.ac.jp.

Circulation. 2017;(23):2255-2270
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Abstract

BACKGROUND The genotype-phenotype correlation of SCN5A mutations as a predictor of cardiac events in Brugada syndrome remains controversial. We aimed to establish a registry limited to probands, with a long follow-up period, so that the genotype-phenotype correlation of SCN5A mutations in Brugada syndrome can be examined without patient selection bias. METHODS This multicenter registry enrolled 415 probands (n=403; men, 97%; age, 46±14 years) diagnosed with Brugada syndrome whose SCN5A gene was analyzed for mutations. RESULTS During a mean follow-up period of 72 months, the overall cardiac event rate was 2.5%/y. In comparison with probands without mutations (SCN5A (-), n=355), probands with SCN5A mutations (SCN5A (+), n=60) experienced their first cardiac event at a younger age (34 versus 42 years, P=0.013), had a higher positive rate of late potentials (89% versus 73%, P=0.016), exhibited longer P-wave, PQ, and QRS durations, and had a higher rate of cardiac events (P=0.017 by log-rank). Multivariate analysis indicated that only SCN5A mutation and history of aborted cardiac arrest were significant predictors of cardiac events (SCN5A (+) versus SCN5A (-): hazard ratio, 2.0 and P=0.045; history of aborted cardiac arrest versus no such history: hazard ratio, 6.5 and P<0.001). CONCLUSIONS Brugada syndrome patients with SCN5A mutations exhibit more conduction abnormalities on ECG and have higher risk for cardiac events.

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Publication Type : Multicenter Study

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