Genotype-Phenotype Correlation of SCN5A Genotype in Patients With Brugada Syndrome and Arrhythmic Events Insights From the SABRUS in 392 Probands
Por:
Milman A, Behr ER, Gray B, Johnson DC, Andorin A, Hochstadt A, Gourraud JB, Maeda S, Takahashi Y, Jm Juang J, Kim SH, Kamakura T, Aiba T, Postema PG, Mizusawa Y, Denjoy I, Giustetto C, Conte G, Huang Z, Sarquella-Brugada G, Mazzanti A, Jespersen CH, Arbelo E, Brugada R, Calo L, Corrado D, Casado-Arroyo R, Allocca G, Takagi M, Delise P, Brugada-Terradellas J, Tfelt-Hansen J, Priori SG, Veltmann C, Yan GX, Brugada P, Gaita F, Leenhardt A, Wilde AAM, Kusano KF, Nam GB, Hirao K, Probst V and Belhassen B
Publicada:
1 oct 2021
Ahead of Print:
31 ago 2021
Resumen:
Background: Brugada syndrome (BrS) is associated with mutations in the cardiac sodium channel gene, SCN5A. However, genetic studies of patients with BrS with arrhythmic events have been limited. We sought to compare various clinical, ECG, and electrophysiological parameters according to SCN5A genotype in a large cohort of BrS probands with first arrhythmic event. Methods: Survey on Arrhythmic Events in Brugada Syndrome is a survey of 10 Western and 4 Asian countries, gathering 678 patients with BrS with first arrhythmic event. Only probands were included, and SCN5A genotype adjudicated. Patients without appropriate genetic data were excluded. Associations of genotype with clinical features were analyzed. Results: The study group comprised 392 probands: 92 (23.5%) SCN5A+(44 pathogenic/likely pathogenic [P/LP] and 48 variants of unknown significance) and 300 (76.5%) SCN5A-. SCN5A missense variants and the patients hosting them were similar regardless of adjudication. A higher proportion of patients with P/LP were pediatric (<16 years) compared with SCN5A- (11.4% versus 3%, P=0.023). The proportion of females was higher among patients with P/LP compared with SCN5A- (18.2% versus 6.3%, P=0.013). P/LP probands were more likely to have a family history of sudden cardiac death compared with SCN5A- (41.9% versus 16.8%, P<0.001). A higher proportion of patients with P/LP were White compared with SCN5A- (87.5% versus 47%, P<0.001). Ethnicity (odds ratio, 5.41 [2.8-11.19], P<0.001) and family history of sudden cardiac death (odds ratio, 2.73 [1.28-5.82], P=0.009) were independent variables associated with P/LP genotype following logistic regression. Conclusions: The genetic basis of BrS has a complex relationship with gender, ethnicity, and age. Probands hosting a P/LP variant tended to experience their first arrhythmic event at a younger age and to have events triggered by fever compared with patients with SCN5A-. In addition, they were more likely to be White and to have family history of sudden cardiac death. Among females, a P/LP variant suggests an increased risk of being symptomatic. This association should be further studied on an ethnically specific basis in large prospectively collected international cohorts.
Filiaciones:
Milman A:
Leviev Heart Institute, The Chaim Sheba Medical Center, Tel Hashomer, Israel (A. Milman)
Sackler School of Medicine, Tel Aviv University, Israel (A. Milman, A.H., B.B.)
Behr ER:
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (E.R.B., D.C.J., A.A., J.-B.G., P.G.P., Y.M., A. Mazzanti, C.H.J., D.C., J.T.-H., S.G.P., A.A.M.W., V.P.)
Cardiovascular Clinical Academic Group, St George's, University of London & St. George's University Hospitals NHS Foundation Trust, United Kingdom (E.R.B., B.G., D.C.J.)
Gray B:
Cardiovascular Clinical Academic Group, St George's, University of London & St. George's University Hospitals NHS Foundation Trust, United Kingdom (E.R.B., B.G., D.C.J.)
Johnson DC:
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (E.R.B., D.C.J., A.A., J.-B.G., P.G.P., Y.M., A. Mazzanti, C.H.J., D.C., J.T.-H., S.G.P., A.A.M.W., V.P.)
Cardiovascular Clinical Academic Group, St George's, University of London & St. George's University Hospitals NHS Foundation Trust, United Kingdom (E.R.B., B.G., D.C.J.)
Andorin A:
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (E.R.B., D.C.J., A.A., J.-B.G., P.G.P., Y.M., A. Mazzanti, C.H.J., D.C., J.T.-H., S.G.P., A.A.M.W., V.P.)
Service de Cardiologie, CHU de Nantes, France (A.A., J.-B.G., V.P.)
Hochstadt A:
Sackler School of Medicine, Tel Aviv University, Israel (A. Milman, A.H., B.B.)
Department of Cardiology, Tel-Aviv Sourasky Medical Center, Israel (A.H.)
Gourraud JB:
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (E.R.B., D.C.J., A.A., J.-B.G., P.G.P., Y.M., A. Mazzanti, C.H.J., D.C., J.T.-H., S.G.P., A.A.M.W., V.P.)
Service de Cardiologie, CHU de Nantes, France (A.A., J.-B.G., V.P.)
Maeda S:
Heart Rhythm Center, Tokyo Medical and Dental University, Tokyo, Japan (S.M., Y.T., K.H.)
Takahashi Y:
Heart Rhythm Center, Tokyo Medical and Dental University, Tokyo, Japan (S.M., Y.T., K.H.)
Jm Juang J:
Cardiovascular Center and Division of Cardiology, National Taiwan University Hospital & University College of Medicine, Taipei (J.J.M.J.)
Kim SH:
Division of Cardiology, College of Medicine, The Catholic University of Korea, Seoul, Korea (S.-H.K.)
Kamakura T:
Division of Arrhythmia and Electrophysiology, National Cerebral and Cardiovascular Center, Osaka, Japan (T.K., T.A., K.F.K.)
Aiba T:
Division of Arrhythmia and Electrophysiology, National Cerebral and Cardiovascular Center, Osaka, Japan (T.K., T.A., K.F.K.)
Postema PG:
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (E.R.B., D.C.J., A.A., J.-B.G., P.G.P., Y.M., A. Mazzanti, C.H.J., D.C., J.T.-H., S.G.P., A.A.M.W., V.P.)
Amsterdam UMC, University of Amsterdam, Heart Center
Department of Clinical & Experimental Cardiology, the Netherlands (P.G.P., Y.M., A.A.M.W.)
Mizusawa Y:
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (E.R.B., D.C.J., A.A., J.-B.G., P.G.P., Y.M., A. Mazzanti, C.H.J., D.C., J.T.-H., S.G.P., A.A.M.W., V.P.)
Amsterdam UMC, University of Amsterdam, Heart Center
Department of Clinical & Experimental Cardiology, the Netherlands (P.G.P., Y.M., A.A.M.W.)
Denjoy I:
Service de Cardiologie et CNMR Maladies Cardiaques Héréditaires Rares, Hôpital Bichat & Université Paris Diderot, Sorbonne, France (I.D., A.L.)
Giustetto C:
Division of Cardiology, University of Torino, Department of Medical Sciences, Città della Salute e della Scienza Hospital, Italy (C.G., F.G.)
Conte G:
Heart Rhythm Management Centre, UZ-VUB, Brussels, Belgium (G.C., P.B.)
Huang Z:
Department of Cardiology, the First Affiliated Hospital of Xiamen University, Fujian, China (Z.H.)
Sarquella-Brugada G:
Pediatric Arrhythmias, Electrophysiology and Sudden Death Unit Cardiology, Department Hospital Sant Joan de Déu, Barcelona - Universitat de Barcelona, Spain (G.S.-B.)
Mazzanti A:
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (E.R.B., D.C.J., A.A., J.-B.G., P.G.P., Y.M., A. Mazzanti, C.H.J., D.C., J.T.-H., S.G.P., A.A.M.W., V.P.)
Molecular Cardiology, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy (A. Mazzanti, S.G.P.)
Jespersen CH:
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (E.R.B., D.C.J., A.A., J.-B.G., P.G.P., Y.M., A. Mazzanti, C.H.J., D.C., J.T.-H., S.G.P., A.A.M.W., V.P.)
The Heart Centre, Copenhagen University Hospital, Denmark (C.H.J., J.T.-H.)
Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Denmark (C.H.J., J.T.-H.)
Arbelo E:
Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Denmark (C.H.J., J.T.-H.)
Brugada R:
Cardiovascular Institute, Hospital Clinic and IDIBAPS, Barcelona, Catalonia, Spain (E.A., J.B.)
Cardiovascular Genetics Center, University of Girona-IDIBGI, Spain (R.B.)
Medical Science Department, School of Medicine, University of Girona, Spain (R.B.)
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain (R.B.)
Calo L:
Division of Cardiology, Policlinico Casilino, Roma, Italy (L.C.)
Corrado D:
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (E.R.B., D.C.J., A.A., J.-B.G., P.G.P., Y.M., A. Mazzanti, C.H.J., D.C., J.T.-H., S.G.P., A.A.M.W., V.P.)
Department of Cardiac, Thoracic and Vascular Sciences University of Padova, Italy (D.C.)
Casado-Arroyo R:
Department of Cardiology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium (R.C.-A.)
Allocca G:
Division of Cardiology, Hospital of Peschiera del Garda, Veneto, Italy (G.A., P.D.)
Takagi M:
Division of Cardiac Arrhythmia, Kansai Medical University Medical Center, Moriguchi, Japan (M.T.)
Delise P:
Division of Cardiology, Hospital of Peschiera del Garda, Veneto, Italy (G.A., P.D.)
Brugada-Terradellas J:
Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Denmark (C.H.J., J.T.-H.)
Tfelt-Hansen J:
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (E.R.B., D.C.J., A.A., J.-B.G., P.G.P., Y.M., A. Mazzanti, C.H.J., D.C., J.T.-H., S.G.P., A.A.M.W., V.P.)
The Heart Centre, Copenhagen University Hospital, Denmark (C.H.J., J.T.-H.)
Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Denmark (C.H.J., J.T.-H.)
Priori SG:
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (E.R.B., D.C.J., A.A., J.-B.G., P.G.P., Y.M., A. Mazzanti, C.H.J., D.C., J.T.-H., S.G.P., A.A.M.W., V.P.)
Molecular Cardiology, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy (A. Mazzanti, S.G.P.)
Veltmann C:
Hannover Heart Rhythm Center, Department of Cardiology & Angiology, Hannover Medical School, Hannover, Germany (C.V.)
Yan GX:
Cardiovascular Institute, Hospital Clinic and IDIBAPS, Barcelona, Catalonia, Spain (E.A., J.B.)
Brugada P:
Heart Rhythm Management Centre, UZ-VUB, Brussels, Belgium (G.C., P.B.)
Gaita F:
Division of Cardiology, University of Torino, Department of Medical Sciences, Città della Salute e della Scienza Hospital, Italy (C.G., F.G.)
Leenhardt A:
Service de Cardiologie et CNMR Maladies Cardiaques Héréditaires Rares, Hôpital Bichat & Université Paris Diderot, Sorbonne, France (I.D., A.L.)
Wilde AAM:
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (E.R.B., D.C.J., A.A., J.-B.G., P.G.P., Y.M., A. Mazzanti, C.H.J., D.C., J.T.-H., S.G.P., A.A.M.W., V.P.)
Amsterdam UMC, University of Amsterdam, Heart Center
Department of Clinical & Experimental Cardiology, the Netherlands (P.G.P., Y.M., A.A.M.W.)
Kusano KF:
Division of Arrhythmia and Electrophysiology, National Cerebral and Cardiovascular Center, Osaka, Japan (T.K., T.A., K.F.K.)
Nam GB:
Division of Cardiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (G.-B.N.)
Hirao K:
Heart Rhythm Center, Tokyo Medical and Dental University, Tokyo, Japan (S.M., Y.T., K.H.)
Probst V:
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (E.R.B., D.C.J., A.A., J.-B.G., P.G.P., Y.M., A. Mazzanti, C.H.J., D.C., J.T.-H., S.G.P., A.A.M.W., V.P.)
Service de Cardiologie, CHU de Nantes, France (A.A., J.-B.G., V.P.)
Belhassen B:
Leviev Heart Institute, The Chaim Sheba Medical Center, Tel Hashomer, Israel (A. Milman)
Heart Institute, Hadassah University Hospital, Jerusalem, Israel (B.B.)
Green Submitted, Bronze
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