{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:43:21Z","timestamp":1783471401956,"version":"3.55.0"},"reference-count":200,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T00:00:00Z","timestamp":1696291200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Hundreds of thousands of people die each year as a result of sudden cardiac death, and many are due to heart rhythm disorders. One of the major causes of these arrhythmic events is Brugada syndrome, a cardiac channelopathy that results in abnormal cardiac conduction, severe life-threatening arrhythmias, and, on many occasions, death. This disorder has been associated with mutations and dysfunction of about two dozen genes; however, the majority of the patients do not have a definite cause for the diagnosis of Brugada Syndrome. The protein-coding genes represent only a very small fraction of the mammalian genome, and the majority of the noncoding regions of the genome are actively transcribed. Studies have shown that most of the loci associated with electrophysiological traits are located in noncoding regulatory regions and are expected to affect gene expression dosage and cardiac ion channel function. Noncoding RNAs serve an expanding number of regulatory and other functional roles within the cells, including but not limited to transcriptional, post-transcriptional, and epigenetic regulation. The major noncoding RNAs found in Brugada Syndrome include microRNAs; however, others such as long noncoding RNAs are also identified. They contribute to pathogenesis by interacting with ion channels and\/or are detectable as clinical biomarkers. Stem cells have received significant attention in the recent past, and can be differentiated into many different cell types including those in the heart. In addition to contractile and relaxational properties, BrS-relevant electrophysiological phenotypes are also demonstrated in cardiomyocytes differentiated from stem cells induced from adult human cells. In this review, we discuss the current understanding of noncoding regions of the genome and their RNA biology in Brugada Syndrome. We also delve into the role of stem cells, especially human induced pluripotent stem cell-derived cardiac differentiated cells, in the investigation of Brugada syndrome in preclinical and clinical studies.<\/jats:p>","DOI":"10.3390\/cells12192398","type":"journal-article","created":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T07:28:29Z","timestamp":1696318109000},"page":"2398","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Noncoding RNAs and Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Cardiac Arrhythmic Brugada Syndrome"],"prefix":"10.3390","volume":"12","author":[{"given":"Benjamin","family":"Theisen","sequence":"first","affiliation":[{"name":"Department of Biomedical and Anatomical Sciences, New York Institute of Technology College of Osteopathic Medicine at Arkansas State University, Jonesboro, AR 72401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9805-8838","authenticated-orcid":false,"given":"Austin","family":"Holtz","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Anatomical Sciences, New York Institute of Technology College of Osteopathic Medicine at Arkansas State University, Jonesboro, AR 72401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1334-502X","authenticated-orcid":false,"given":"Viswanathan","family":"Rajagopalan","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Anatomical Sciences, New York Institute of Technology College of Osteopathic Medicine at Arkansas State University, Jonesboro, AR 72401, USA"},{"name":"Arkansas Biosciences Institute, Jonesboro, AR 72401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/s41572-020-0188-7","article-title":"Inherited cardiac arrhythmias","volume":"6","author":"Schwartz","year":"2020","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Beckmann, B.M., Pfeufer, A., and Kaab, S. (2011). Inherited cardiac arrhythmias: Diagnosis, treatment, and prevention. Dtsch. Arztebl. Int., 108.","DOI":"10.3238\/arztebl.2011.0623"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.1056\/NEJMoa1510687","article-title":"A Prospective Study of Sudden Cardiac Death among Children and Young Adults","volume":"374","author":"Bagnall","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.hrthm.2020.10.010","article-title":"2020 APHRS\/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families","volume":"18","author":"Stiles","year":"2021","journal-title":"Heart Rhythm"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/s41569-019-0266-2","article-title":"Epidemiology of inherited arrhythmias","volume":"17","author":"Offerhaus","year":"2020","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"euad091","DOI":"10.1093\/europace\/euad091","article-title":"Spotlight on the 2022 ESC guideline management of ventricular arrhythmias and prevention of sudden cardiac death: 10 novel key aspects","volume":"25","author":"Konemann","year":"2023","journal-title":"Europace"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3997","DOI":"10.1093\/eurheartj\/ehac262","article-title":"2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death","volume":"43","author":"Zeppenfeld","year":"2022","journal-title":"Eur. Heart J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/j.1365-2796.2005.01587.x","article-title":"Amplification of spatial dispersion of repolarization underlies sudden cardiac death associated with catecholaminergic polymorphic VT, long QT, short QT and Brugada syndromes","volume":"259","author":"Antzelevitch","year":"2006","journal-title":"J. Intern. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.jacep.2021.12.001","article-title":"Brugada Syndrome","volume":"8","author":"Krahn","year":"2022","journal-title":"JACC Clin. Electrophysiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"149","DOI":"10.3389\/fcvm.2018.00149","article-title":"Recent Advances in Short QT Syndrome","volume":"5","author":"Campuzano","year":"2018","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Coll, M., Perez-Serra, A., Mates, J., Del Olmo, B., Puigmule, M., Fernandez-Falgueras, A., Iglesias, A., Pico, F., Lopez, L., and Brugada, R. (2017). Incomplete Penetrance and Variable Expressivity: Hallmarks in Channelopathies Associated with Sudden Cardiac Death. Biology, 7.","DOI":"10.3390\/biology7010003"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.trsl.2012.08.005","article-title":"Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes","volume":"161","author":"Giudicessi","year":"2013","journal-title":"Transl. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.jacasi.2022.03.011","article-title":"Brugada Syndrome as a Major Cause of Sudden Cardiac Death in Asians","volume":"2","author":"Nakano","year":"2022","journal-title":"JACC Asia"},{"key":"ref_14","first-page":"267","article-title":"Worldwide Prevalence of Brugada Syndrome: A Systematic Review and Meta-Analysis","volume":"34","author":"Vutthikraivit","year":"2018","journal-title":"Acta Cardiol. Sin."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.ejim.2017.06.019","article-title":"Brugada syndrome: A general cardiologist\u2019s perspective","volume":"44","author":"Polovina","year":"2017","journal-title":"Eur. J. Intern. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9","DOI":"10.3389\/fcvm.2016.00009","article-title":"The Brugada Syndrome: A Rare Arrhythmia Disorder with Complex Inheritance","volume":"3","author":"Gourraud","year":"2016","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Monasky, M.M., Micaglio, E., Ciconte, G., and Pappone, C. (2020). Brugada Syndrome: Oligogenic or Mendelian Disease?. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051687"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.1161\/CIRCULATIONAHA.107.711689","article-title":"Inherited arrhythmias: A National Heart, Lung, and Blood Institute and Office of Rare Diseases workshop consensus report about the diagnosis, phenotyping, molecular mechanisms, and therapeutic approaches for primary cardiomyopathies of gene mutations affecting ion channel function","volume":"116","author":"Lehnart","year":"2007","journal-title":"Circulation"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1016\/j.jacc.2008.07.052","article-title":"Gender differences in clinical manifestations of Brugada syndrome","volume":"52","author":"Benito","year":"2008","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1016\/j.jacc.2018.01.031","article-title":"The Diagnostic Yield of Brugada Syndrome After Sudden Death With Normal Autopsy","volume":"71","author":"Papadakis","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e005222","DOI":"10.1161\/CIRCEP.117.005222","article-title":"Age of First Arrhythmic Event in Brugada Syndrome: Data From the SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) in 678 Patients","volume":"10","author":"Milman","year":"2017","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1093\/eurheartj\/ehm116","article-title":"Role of programmed ventricular stimulation in patients with Brugada syndrome: A meta-analysis of worldwide published data","volume":"28","author":"Paul","year":"2007","journal-title":"Eur. Heart J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/j.jacc.2016.05.073","article-title":"Long-Term Trends in Newly Diagnosed Brugada Syndrome: Implications for Risk Stratification","volume":"68","author":"Berne","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1161\/CIRCULATIONAHA.109.887026","article-title":"Long-term prognosis of patients diagnosed with Brugada syndrome: Results from the FINGER Brugada Syndrome Registry","volume":"121","author":"Probst","year":"2010","journal-title":"Circulation"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1111\/j.1540-8159.2005.40020.x","article-title":"Prevalence and clinical course of the juveniles with Brugada-type ECG in Japanese population","volume":"28","author":"Oe","year":"2005","journal-title":"Pacing Clin. Electrophysiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1016\/j.hrthm.2013.07.030","article-title":"Fever-induced Brugada pattern: How common is it and what does it mean?","volume":"10","author":"Adler","year":"2013","journal-title":"Heart Rhythm"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1093\/europace\/eut009","article-title":"Alcohol-induced ventricular fibrillation in a case of Brugada syndrome","volume":"15","author":"Ohkubo","year":"2013","journal-title":"Europace"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1016\/j.hrthm.2009.07.002","article-title":"Drugs and Brugada syndrome patients: Review of the literature, recommendations, and an up-to-date website (www.brugadadrugs.org)","volume":"6","author":"Postema","year":"2009","journal-title":"Heart Rhythm"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1046\/j.1540-8167.2004.03601.x","article-title":"Vagal activity modulates spontaneous augmentation of ST elevation in the daily life of patients with Brugada syndrome","volume":"15","author":"Mizumaki","year":"2004","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1111\/j.1540-8167.2006.00424.x","article-title":"The full stomach test as a novel diagnostic technique for identifying patients at risk of Brugada syndrome","volume":"17","author":"Ikeda","year":"2006","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1111\/j.1540-8167.2007.00972.x","article-title":"Influence of meals on variations of ST segment elevation in patients with Brugada syndrome","volume":"19","author":"Nishizaki","year":"2008","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e003238","DOI":"10.1161\/CIRCGEN.120.003238","article-title":"Acacetin, a Potent Transient Outward Current Blocker, May Be a Novel Therapeutic for KCND3-Encoded Kv4.3 Gain-of-Function-Associated J-Wave Syndromes","volume":"15","author":"Ye","year":"2022","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1136\/heartjnl-2020-318258","article-title":"Brugada syndrome: Update and future perspectives","volume":"108","author":"Marsman","year":"2022","journal-title":"Heart"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e295","DOI":"10.1016\/j.hrthm.2016.05.024","article-title":"J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge","volume":"13","author":"Antzelevitch","year":"2016","journal-title":"Heart Rhythm"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1016\/j.jacc.2007.10.062","article-title":"Atrial fibrillation and Brugada syndrome","volume":"51","author":"Francis","year":"2008","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1016\/S0735-1097(02)02167-8","article-title":"Atrial fibrillation and atrial vulnerability in patients with Brugada syndrome","volume":"40","author":"Morita","year":"2002","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"15","DOI":"10.4037\/ccn2021499","article-title":"Brugada Syndrome: Fatal Consequences of a Must-Not-Miss Diagnosis","volume":"41","author":"Smith","year":"2021","journal-title":"Crit. Care Nurse"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1016\/0735-1097(92)90253-J","article-title":"Right bundle branch block, persistent ST segment elevation and sudden cardiac death: A distinct clinical and electrocardiographic syndrome. A multicenter report","volume":"20","author":"Brugada","year":"1992","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e222","DOI":"10.1111\/j.1540-8159.2010.02960.x","article-title":"Hypothyroid patient with Brugada electrocardiographic waveforms: Case report","volume":"35","author":"Zhao","year":"2012","journal-title":"Pacing Clin. Electrophysiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1507\/endocrj.K07E-024","article-title":"A case of hypothyroidism with brugada electrocardiographic waveforms","volume":"55","author":"Kitahara","year":"2008","journal-title":"Endocr. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e147","DOI":"10.1016\/j.jccase.2010.05.011","article-title":"Brugada-type electrocardiogram in a patient with hypothyroidism","volume":"2","author":"Taira","year":"2010","journal-title":"J. Cardiol. Cases"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"bcr2015212351","DOI":"10.1136\/bcr-2015-212351","article-title":"Sudden cardiac arrest as a presentation of Brugada syndrome unmasked by thyroid storm","volume":"2015","author":"Korte","year":"2015","journal-title":"BMJ Case Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"771349","DOI":"10.3389\/fcvm.2021.771349","article-title":"Brugada Syndrome: Warning of a Systemic Condition?","volume":"8","author":"Monasky","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1016\/j.repc.2017.06.015","article-title":"Induced Brugada syndrome: Possible sources of arrhythmogenesis","volume":"36","author":"Tome","year":"2017","journal-title":"Rev. Port. Cardiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1161\/CIRCEP.113.000927","article-title":"Brugada syndrome ECG is highly prevalent in schizophrenia","volume":"7","author":"Blom","year":"2014","journal-title":"Circ. Arrhythmia Electrophysiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.eplepsyres.2016.08.007","article-title":"The pathophysiology of cardiac dysfunction in epilepsy","volume":"127","author":"Ravindran","year":"2016","journal-title":"Epilepsy Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1111\/j.1540-8167.2006.00743.x","article-title":"Sex hormone and gender difference--role of testosterone on male predominance in Brugada syndrome","volume":"18","author":"Shimizu","year":"2007","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1016\/j.hrthm.2013.05.014","article-title":"HRS\/EHRA\/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: Document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013","volume":"10","author":"Priori","year":"2013","journal-title":"Heart Rhythm"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e91","DOI":"10.1016\/j.jacc.2017.10.054","article-title":"2017 AHA\/ACC\/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society","volume":"72","author":"Stevenson","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1161\/CIRCEP.115.003220","article-title":"Brugada Syndrome Phenotype Elimination by Epicardial Substrate Ablation","volume":"8","author":"Brugada","year":"2015","journal-title":"Circ. Arrhythmiaia Electrophysiol."},{"key":"ref_51","first-page":"e005053","article-title":"Electrical Substrate Elimination in 135 Consecutive Patients With Brugada Syndrome","volume":"10","author":"Pappone","year":"2017","journal-title":"Circ. Arrhythmiaia Electrophysiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1161\/CIRCULATIONAHA.122.063367","article-title":"Long-Term Outcomes of Brugada Substrate Ablation: A Report from BRAVO (Brugada Ablation of VF Substrate Ongoing Multicenter Registry)","volume":"147","author":"Nademanee","year":"2023","journal-title":"Circulation"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.33963\/KP.a2022.0193","article-title":"Fever-induced type-1 Brugada pattern: A sign of revealed Brugada syndrome or just a Brugada phenocopy? Author\u2019s reply","volume":"80","author":"Yalta","year":"2022","journal-title":"Kardiol. Pol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1093\/europace\/eux182","article-title":"First description of a Brugada phenocopy in the inferior leads in the context of an acute inferior myocardial infarction","volume":"19","author":"Alper","year":"2017","journal-title":"Europace"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.jelectrocard.2019.04.017","article-title":"Brugada phenocopy: Mechanisms, diagnosis, and implications","volume":"55","author":"Mastrocola","year":"2019","journal-title":"J. Electrocardiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"652027","DOI":"10.3389\/fcvm.2021.652027","article-title":"Evaluating the Use of Genetics in Brugada Syndrome Risk Stratification","volume":"8","author":"Monasky","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"L105","DOI":"10.1093\/eurheartj\/suaa146","article-title":"The omics of channelopathies and cardiomyopathies: What we know and how they are useful","volume":"22","author":"Pappone","year":"2020","journal-title":"Eur. Heart J. Suppl."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1161\/CIRCULATIONAHA.118.035954","article-title":"Beyond the One Gene-One Disease Paradigm: Complex Genetics and Pleiotropy in Inheritable Cardiac Disorders","volume":"140","author":"Cerrone","year":"2019","journal-title":"Circulation"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1161\/CIRCULATIONAHA.118.035070","article-title":"Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome","volume":"138","author":"Hosseini","year":"2018","journal-title":"Circulation"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1093\/eurheartj\/ehaa942","article-title":"Brugada syndrome genetics is associated with phenotype severity","volume":"42","author":"Ciconte","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Fernandez-Falgueras, A., Sarquella-Brugada, G., Brugada, J., Brugada, R., and Campuzano, O. (2017). Cardiac Channelopathies and Sudden Death: Recent Clinical and Genetic Advances. Biology, 6.","DOI":"10.3390\/biology6010007"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Martinez-Campelo, L., Cruz, R., Blanco-Verea, A., Moscoso, I., Ramos-Luis, E., Lage, R., Alvarez-Barredo, M., Sabater-Molina, M., Penafiel-Verdu, P., and Jimenez-Jaimez, J. (2022). Searching for genetic modulators of the phenotypic heterogeneity in Brugada syndrome. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0263469"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1161\/CIRCRESAHA.113.301565","article-title":"Reduced sodium channel function unmasks residual embryonic slow conduction in the adult right ventricular outflow tract","volume":"113","author":"Boukens","year":"2013","journal-title":"Circ. Res."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Lambiase, P.D., Ahmed, A.K., Ciaccio, E.J., Brugada, R., Lizotte, E., Chaubey, S., Ben-Simon, R., Chow, A.W., Lowe, M.D., and McKenna, W.J. (2009). High-density substrate mapping in Brugada syndrome: Combined role of conduction and repolarization heterogeneities in arrhythmogenesis. Circulation, 120.","DOI":"10.1161\/CIRCULATIONAHA.108.771401"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.cpcardiol.2015.06.002","article-title":"Brugada Syndrome: Clinical, Genetic, Molecular, Cellular, and Ionic Aspects","volume":"41","author":"Antzelevitch","year":"2016","journal-title":"Curr. Probl. Cardiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1016\/j.jacc.2021.08.010","article-title":"Biventricular Myocardial Fibrosis and Sudden Death in Patients With Brugada Syndrome","volume":"78","author":"Miles","year":"2021","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Popa, I.P., Serban, D.N., Maranduca, M.A., Serban, I.L., Tamba, B.I., and Tudorancea, I. (2023). Brugada Syndrome: From Molecular Mechanisms and Genetics to Risk Stratification. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043328"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1161\/CIRCEP.115.003366","article-title":"ST-Segment Elevation and Fractionated Electrograms in Brugada Syndrome Patients Arise From the Same Structurally Abnormal Subepicardial RVOT Area but Have a Different Mechanism","volume":"8","author":"Coronel","year":"2015","journal-title":"Circ. Arrhythmia Electrophysiol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1161\/CIRCEP.108.790543","article-title":"Slow and discontinuous conduction conspire in Brugada syndrome: A right ventricular mapping and stimulation study","volume":"1","author":"Postema","year":"2008","journal-title":"Circ. Arrhythmia Electrophysiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2769","DOI":"10.1161\/CIRCULATIONAHA.105.532614","article-title":"Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: A combined electrophysiological, genetic, histopathologic, and computational study","volume":"112","author":"Coronel","year":"2005","journal-title":"Circulation"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1016\/j.jacep.2023.03.009","article-title":"Functional Epicardial Conduction Disturbances Due to a SCN5A Variant Associated With Brugada Syndrome","volume":"9","author":"Renard","year":"2023","journal-title":"JACC Clin. Electrophysiol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1161\/CIRCULATIONAHA.122.061924","article-title":"Subepicardial Cardiomyopathy: A Disease Underlying J-Wave Syndromes and Idiopathic Ventricular Fibrillation","volume":"147","author":"Miles","year":"2023","journal-title":"Circulation"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.4022\/jafib.1554","article-title":"Hypothetical \u201canatomy\u201d of Brugada phenomenon: \u201cLong QT sine Long QT\u201d syndrome implicating morphologically undefined specific \u201cBrugada\u2019s myocells\u201d","volume":"9","author":"Stirbys","year":"2017","journal-title":"J. Atr. Fibrillation"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1161\/CIRCRESAHA.117.310959","article-title":"The Brugada Syndrome Susceptibility Gene HEY2 Modulates Cardiac Transmural Ion Channel Patterning and Electrical Heterogeneity","volume":"121","author":"Veerman","year":"2017","journal-title":"Circ. Res."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Scacchi, S., Colli Franzone, P., Pavarino, L.F., Gionti, V., and Storti, C. (2023). Epicardial Dispersion of Repolarization Promotes the Onset of Reentry in Brugada Syndrome: A Numerical Simulation Study. Bull. Math. Biol., 85.","DOI":"10.1007\/s11538-023-01124-9"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1161\/01.CIR.0000118467.53182.D1","article-title":"Delay in right ventricular activation contributes to Brugada syndrome","volume":"109","author":"Tukkie","year":"2004","journal-title":"Circulation"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.cardiores.2005.06.027","article-title":"Role of sequence variations in the human ether-a-go-go-related gene (HERG, KCNH2) in the Brugada syndrome","volume":"68","author":"Verkerk","year":"2005","journal-title":"Cardiovasc. Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1016\/j.jacep.2023.04.022","article-title":"Delayed Activation Due to Early Repolarization: A Combination of Hypotheses","volume":"9","author":"Boukens","year":"2023","journal-title":"JACC Clin. Electrophysiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3081","DOI":"10.1093\/eurheartj\/ehz308","article-title":"RRAD mutation causes electrical and cytoskeletal defects in cardiomyocytes derived from a familial case of Brugada syndrome","volume":"40","author":"Belbachir","year":"2019","journal-title":"Eur. Heart J."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Lloyd, K.C.K., Adams, D.J., Baynam, G., Beaudet, A.L., Bosch, F., Boycott, K.M., Braun, R.E., Caulfield, M., Cohn, R., and Dickinson, M.E. (2020). The Deep Genome Project. Genome Biol., 21.","DOI":"10.1186\/s13059-020-1931-9"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1161\/CIRCRESAHA.117.311802","article-title":"Long Noncoding RNA Discovery in Cardiovascular Disease: Decoding Form to Function","volume":"122","author":"Sallam","year":"2018","journal-title":"Circ. Res."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Rajagopalan, V., Chakraborty, S., and Lin, R. (2023). Novel Transcriptomic Interactomes of Noncoding RNAs in the Heart under Altered Thyroid Hormonal States. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076560"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1126\/science.1222794","article-title":"Systematic localization of common disease-associated variation in regulatory DNA","volume":"337","author":"Maurano","year":"2012","journal-title":"Science"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1101\/gr.136127.111","article-title":"Linking disease associations with regulatory information in the human genome","volume":"22","author":"Schaub","year":"2012","journal-title":"Genome Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature11247","article-title":"An integrated encyclopedia of DNA elements in the human genome","volume":"489","author":"Consortium","year":"2012","journal-title":"Nature"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41586-020-2449-8","article-title":"Perspectives on ENCODE","volume":"583","author":"Consortium","year":"2020","journal-title":"Nature"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Sakabe, N.J., Savic, D., and Nobrega, M.A. (2012). Transcriptional enhancers in development and disease. Genome Biol., 13.","DOI":"10.1186\/gb-2012-13-1-238"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e000062","DOI":"10.1161\/HCG.0000000000000062","article-title":"Noncoding RNAs in Cardiovascular Disease: Current Knowledge, Tools and Technologies for Investigation, and Future Directions: A Scientific Statement From the American Heart Association","volume":"13","author":"Das","year":"2020","journal-title":"Circ. Genom Precis. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/nrg1379","article-title":"MicroRNAs: Small RNAs with a big role in gene regulation","volume":"5","author":"He","year":"2004","journal-title":"Nat. Rev. Genet."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"402","DOI":"10.3389\/fendo.2018.00402","article-title":"Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation","volume":"9","author":"Hayder","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/nrm3838","article-title":"Regulation of microRNA biogenesis","volume":"15","author":"Ha","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/nrg3965","article-title":"Towards a molecular understanding of microRNA-mediated gene silencing","volume":"16","author":"Jonas","year":"2015","journal-title":"Nat. Rev. Genet."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.molcel.2016.09.004","article-title":"Pairing beyond the Seed Supports MicroRNA Targeting Specificity","volume":"64","author":"Broughton","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1016\/j.cell.2007.01.038","article-title":"AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2","volume":"128","author":"Vasudevan","year":"2007","journal-title":"Cell"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1016\/j.molcel.2016.02.013","article-title":"A Specialized Mechanism of Translation Mediated by FXR1a-Associated MicroRNP in Cellular Quiescence","volume":"61","author":"Bukhari","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1126\/science.1149460","article-title":"Switching from repression to activation: microRNAs can up-regulate translation","volume":"318","author":"Vasudevan","year":"2007","journal-title":"Science"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1101\/gr.082701.108","article-title":"Most mammalian mRNAs are conserved targets of microRNAs","volume":"19","author":"Friedman","year":"2009","journal-title":"Genome Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.trsl.2012.12.004","article-title":"MicroRNA regulation of cardiac conduction and arrhythmias","volume":"161","author":"Kim","year":"2013","journal-title":"Transl. Res."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Fu, J.D., Rushing, S.N., Lieu, D.K., Chan, C.W., Kong, C.W., Geng, L., Wilson, K.D., Chiamvimonvat, N., Boheler, K.R., and Wu, J.C. (2011). Distinct roles of microRNA-1 and -499 in ventricular specification and functional maturation of human embryonic stem cell-derived cardiomyocytes. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0027417"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1093\/cvr\/cvy019","article-title":"Integrated transcriptomic and regulatory network analyses identify microRNA-200c as a novel repressor of human pluripotent stem cell-derived cardiomyocyte differentiation and maturation","volume":"114","author":"Poon","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"D165","DOI":"10.1093\/nar\/gkaa1046","article-title":"NONCODEV6: An updated database dedicated to long non-coding RNA annotation in both animals and plants","volume":"49","author":"Zhao","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1161\/CIRCGENETICS.115.001264","article-title":"Systematic Characterization of Long Noncoding RNAs Reveals the Contrasting Coordination of Cis- and Trans-Molecular Regulation in Human Fetal and Adult Hearts","volume":"9","author":"He","year":"2016","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1002\/cphy.c180032","article-title":"Long Noncoding RNA: Genomics and Relevance to Physiology","volume":"9","author":"Kong","year":"2019","journal-title":"Compr. Physiol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e03058","DOI":"10.7554\/eLife.03058","article-title":"Considerations when investigating lncRNA function in vivo","volume":"3","author":"Bassett","year":"2014","journal-title":"Elife"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1016\/j.molcel.2011.08.018","article-title":"Molecular mechanisms of long noncoding RNAs","volume":"43","author":"Wang","year":"2011","journal-title":"Mol. Cell"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2995","DOI":"10.1113\/JP278131","article-title":"Non-coding RNAs: Key players in cardiac disease","volume":"598","author":"Kreutzer","year":"2020","journal-title":"J. Physiol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1161\/CIRCRESAHA.117.304156","article-title":"Lncing epigenetic control of transcription to cardiovascular development and disease","volume":"117","author":"Rizki","year":"2015","journal-title":"Circ. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/nature11993","article-title":"Natural RNA circles function as efficient microRNA sponges","volume":"495","author":"Hansen","year":"2013","journal-title":"Nature"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.canlet.2015.06.003","article-title":"Circular RNA: A new star of noncoding RNAs","volume":"365","author":"Qu","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s13287-019-1165-5","article-title":"Stem cells: Past, present, and future","volume":"10","author":"Zakrzewski","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_111","first-page":"481","article-title":"Brugada syndrome occurring after autologous peripheral blood stem cell transplantation for acute myeloid leukemia","volume":"45","author":"Matsubara","year":"2004","journal-title":"Rinsho Ketsueki"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"e024410","DOI":"10.1161\/JAHA.121.024410","article-title":"Brugada Syndrome: Different Experimental Models and the Role of Human Cardiomyocytes From Induced Pluripotent Stem Cells","volume":"11","author":"Li","year":"2022","journal-title":"J. Am. Heart Assoc."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.cell.2006.07.024","article-title":"Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors","volume":"126","author":"Takahashi","year":"2006","journal-title":"Cell"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1161\/CIRCRESAHA.119.315653","article-title":"RNA Sequencing Analysis of Induced Pluripotent Stem Cell-Derived Cardiomyocytes From Congenital Heart Disease Patients","volume":"126","author":"Kitani","year":"2020","journal-title":"Circ. Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/s11886-023-01852-3","article-title":"Induced Pluripotent Stem Cell-Based Modeling of Single-Ventricle Congenital Heart Diseases","volume":"25","author":"Parker","year":"2023","journal-title":"Curr. Cardiol. Rep."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1016\/j.stem.2022.03.003","article-title":"Uncompensated mitochondrial oxidative stress underlies heart failure in an iPSC-derived model of congenital heart disease","volume":"29","author":"Xu","year":"2022","journal-title":"Cell Stem Cell"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"e15696","DOI":"10.14814\/phy2.15696","article-title":"Inhibition of Wnt\/beta-catenin signaling upregulates Na(v) 1.5 channels in Brugada syndrome iPSC-derived cardiomyocytes","volume":"11","author":"Lu","year":"2023","journal-title":"Physiol. Rep."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Nijak, A., Saenen, J., Labro, A.J., Schepers, D., Loeys, B.L., and Alaerts, M. (2021). iPSC-Cardiomyocyte Models of Brugada Syndrome-Achievements, Challenges and Future Perspectives. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22062825"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"3071","DOI":"10.1093\/cvr\/cvab335","article-title":"Non-coding RNAs: Key regulators of reprogramming, pluripotency, and cardiac cell specification with therapeutic perspective for heart regeneration","volume":"118","author":"Hunkler","year":"2022","journal-title":"Cardiovasc. Res."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Schweiger, V., Hasimbegovic, E., Kastner, N., Spannbauer, A., Traxler, D., Gyongyosi, M., and Mester-Tonczar, J. (2021). Non-Coding RNAs in Stem Cell Regulation and Cardiac Regeneration: Current Problems and Future Perspectives. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179160"},{"key":"ref_122","first-page":"8842398","article-title":"Susceptibility to Ventricular Arrhythmias Resulting from Mutations in FKBP1B, PXDNL, and SCN9A Evaluated in hiPSC Cardiomyocytes","volume":"2020","author":"Smith","year":"2020","journal-title":"Stem Cells Int."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"e413","DOI":"10.1002\/ctm2.413","article-title":"A consistent arrhythmogenic trait in Brugada syndrome cellular phenotype","volume":"11","author":"Jouni","year":"2021","journal-title":"Clin. Transl. Med."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.gene.2015.08.062","article-title":"The cardiac sodium channel gene SCN5A and its gene product NaV1.5: Role in physiology and pathophysiology","volume":"573","author":"Veerman","year":"2015","journal-title":"Gene"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/s41588-021-01007-6","article-title":"Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility","volume":"54","author":"Barc","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1161\/CIRCULATIONAHA.111.055947","article-title":"Sudden cardiac death and genetic ion channelopathies: Long QT, Brugada, short QT, catecholaminergic polymorphic ventricular tachycardia, and idiopathic ventricular fibrillation","volume":"125","author":"Napolitano","year":"2012","journal-title":"Circulation"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.hrthm.2009.09.069","article-title":"An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing","volume":"7","author":"Kapplinger","year":"2010","journal-title":"Heart Rhythm"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"2026","DOI":"10.1161\/CIRCULATIONAHA.106.627489","article-title":"Compound heterozygous mutations P336L and I1660V in the human cardiac sodium channel associated with the Brugada syndrome","volume":"114","author":"Cordeiro","year":"2006","journal-title":"Circulation"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1161\/CIRCGENETICS.109.853374","article-title":"SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome","volume":"2","author":"Probst","year":"2009","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_130","first-page":"70","article-title":"Compound Heterozygous SCN5A Mutations in a Toddler\u2014Are they Associated with a More Severe Phenotype?","volume":"108","author":"Sacilotto","year":"2017","journal-title":"Arq. Bras. De Cardiol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1016\/j.hrthm.2018.06.019","article-title":"Gender differences in patients with Brugada syndrome and arrhythmic events: Data from a survey on arrhythmic events in 678 patients","volume":"15","author":"Milman","year":"2018","journal-title":"Heart Rhythm"},{"key":"ref_132","doi-asserted-by":"crossref","unstructured":"Monasky, M.M., Micaglio, E., Ciconte, G., Rivolta, I., Borrelli, V., Ghiroldi, A., D\u2019Imperio, S., Binda, A., Melgari, D., and Benedetti, S. (2021). Novel SCN5A p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094700"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1016\/j.hrthm.2012.02.023","article-title":"Genetic variants in SCN5A promoter are associated with arrhythmia phenotype severity in patients with heterozygous loss-of-function mutation","volume":"9","author":"Park","year":"2012","journal-title":"Heart Rhythm"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.cardiores.2003.09.030","article-title":"Cloning and initial characterization of the human cardiac sodium channel (SCN5A) promoter","volume":"61","author":"Yang","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1161\/CIRCULATIONAHA.105.580811","article-title":"Common sodium channel promoter haplotype in asian subjects underlies variability in cardiac conduction","volume":"113","author":"Bezzina","year":"2006","journal-title":"Circulation"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"e003644","DOI":"10.1161\/JAHA.116.003644","article-title":"Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes","volume":"5","author":"Yagihara","year":"2016","journal-title":"J. Am. Heart Assoc."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"113","DOI":"10.5603\/CJ.a2017.0104","article-title":"Novel and heteroplasmic mutations in mitochondrial tRNA genes in Brugada syndrome","volume":"25","author":"Tafti","year":"2018","journal-title":"Cardiol. J."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.bj.2019.03.003","article-title":"Role of SCN5A coding and non-coding sequences in Brugada syndrome onset: What\u2019s behind the scenes?","volume":"42","author":"Daimi","year":"2019","journal-title":"Biomed J."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1016\/j.hrthm.2015.02.018","article-title":"Regulation of SCN5A by microRNAs: miR-219 modulates SCN5A transcript expression and the effects of flecainide intoxication in mice","volume":"12","author":"Daimi","year":"2015","journal-title":"Heart Rhythm"},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Matsumura, H., Nakano, Y., Ochi, H., Onohara, Y., Sairaku, A., Tokuyama, T., Tomomori, S., Motoda, C., Amioka, M., and Hironobe, N. (2017). H558R, a common SCN5A polymorphism, modifies the clinical phenotype of Brugada syndrome by modulating DNA methylation of SCN5A promoters. J. Biomed Sci., 24.","DOI":"10.1186\/s12929-017-0397-x"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"e005009","DOI":"10.1161\/JAHA.116.005009","article-title":"SCN5A Genetic Polymorphisms Associated With Increased Defibrillator Shocks in Brugada Syndrome","volume":"6","author":"Makarawate","year":"2017","journal-title":"J. Am. Heart Assoc."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1016\/j.bbadis.2015.07.016","article-title":"Post-transcriptional regulation of cardiac sodium channel gene SCN5A expression and function by miR-192-5p","volume":"1852","author":"Zhao","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"2086","DOI":"10.1016\/j.jacc.2016.07.779","article-title":"Patient-Specific and Genome-Edited Induced Pluripotent Stem Cell-Derived Cardiomyocytes Elucidate Single-Cell Phenotype of Brugada Syndrome","volume":"68","author":"Liang","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.yjmcc.2017.10.002","article-title":"Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient","volume":"114","author":"Selga","year":"2018","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"11246","DOI":"10.1038\/s41598-018-29574-5","article-title":"Identification of an I(Na)-dependent and I(to)-mediated proarrhythmic mechanism in cardiomyocytes derived from pluripotent stem cells of a Brugada syndrome patient","volume":"8","author":"Ma","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Penttinen, K., Prajapati, C., Shah, D., Rajan, D.K., Cherian, R.M., Swan, H., and Aalto-Setala, K. (2023). HiPSC-derived cardiomyocyte to model Brugada syndrome: Both asymptomatic and symptomatic mutation carriers reveal increased arrhythmogenicity. BMC Cardiovasc. Disord., 23.","DOI":"10.1186\/s12872-023-03234-7"},{"key":"ref_147","doi-asserted-by":"crossref","unstructured":"Li, W., Stauske, M., Luo, X., Wagner, S., Vollrath, M., Mehnert, C.S., Schubert, M., Cyganek, L., Chen, S., and Hasheminasab, S.M. (2020). Disease Phenotypes and Mechanisms of iPSC-Derived Cardiomyocytes From Brugada Syndrome Patients With a Loss-of-Function SCN5A Mutation. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.592893"},{"key":"ref_148","doi-asserted-by":"crossref","unstructured":"Salvarani, N., Peretto, G., Silvia, C., Villatore, A., Thairi, C., Santoni, A., Galli, C., Carrera, P., Sala, S., and Benedetti, S. (2023). Functional Characterisation of the Rare SCN5A p.E1225K Variant, Segregating in a Brugada Syndrome Familial Case, in Human Cardiomyocytes from Pluripotent Stem Cells. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24119548"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"e1130","DOI":"10.1002\/ctm2.1130","article-title":"Novel insights in the pathomechanism of Brugada syndrome and fever-related type 1 ECG changes in a preclinical study using human-induced pluripotent stem cell-derived cardiomyocytes","volume":"13","author":"Li","year":"2023","journal-title":"Clin. Transl. Med."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"euad154","DOI":"10.1093\/europace\/euad154","article-title":"Beneficial effects of chronic mexiletine treatment in a human model of SCN5A overlap syndrome","volume":"25","author":"Nasilli","year":"2023","journal-title":"Europace"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"103153","DOI":"10.1016\/j.scr.2023.103153","article-title":"Generation of an induced pluripotent stem cell line from a patient with conduction disease and recurrent ventricular fibrillation with a sodium voltage-gated channel alpha subunit 5 (SCN5A) gene c.392 + 3A > G splice-site variant","volume":"71","author":"Li","year":"2023","journal-title":"Stem Cell Res."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"102605","DOI":"10.1016\/j.scr.2021.102605","article-title":"Generation of two induced pluripotent stem cell lines from Brugada syndrome affected patients carrying SCN5A mutations","volume":"57","author":"Belbachir","year":"2021","journal-title":"Stem Cell Res."},{"key":"ref_153","doi-asserted-by":"crossref","unstructured":"Sun, Y., Su, J., Wang, X., Wang, J., Guo, F., Qiu, H., Fan, H., Cai, D., Wang, H., and Lin, M. (2023). Patient-specific iPSC-derived cardiomyocytes reveal variable phenotypic severity of Brugada syndrome. EBioMedicine, 95.","DOI":"10.1016\/j.ebiom.2023.104741"},{"key":"ref_154","doi-asserted-by":"crossref","unstructured":"El-Battrawy, I., Muller, J., Zhao, Z., Cyganek, L., Zhong, R., Zhang, F., Kleinsorge, M., Lan, H., Li, X., and Xu, Q. (2019). Studying Brugada Syndrome With an SCN1B Variants in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Front. Cell Dev. Biol., 7.","DOI":"10.3389\/fcell.2019.00261"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.scr.2017.11.003","article-title":"Ajmaline blocks I(Na) and I(Kr) without eliciting differences between Brugada syndrome patient and control human pluripotent stem cell-derived cardiac clusters","volume":"25","author":"Miller","year":"2017","journal-title":"Stem Cell Res."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1093\/europace\/euz122","article-title":"A cellular model of Brugada syndrome with SCN10A variants using human-induced pluripotent stem cell-derived cardiomyocytes","volume":"21","author":"Albers","year":"2019","journal-title":"Europace"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1172\/JCI62613","article-title":"Genetic variation in T-box binding element functionally affects SCN5A\/SCN10A enhancer","volume":"122","author":"Wong","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.1172\/JCI73140","article-title":"A common genetic variant within SCN10A modulates cardiac SCN5A expression","volume":"124","author":"Smemo","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1038\/ng.2712","article-title":"Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death","volume":"45","author":"Bezzina","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/ng.516","article-title":"Genetic variation in SCN10A influences cardiac conduction","volume":"42","author":"Chambers","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/ng.511","article-title":"Several common variants modulate heart rate, PR interval and QRS duration","volume":"42","author":"Holm","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/ng.517","article-title":"Genome-wide association study of PR interval","volume":"42","author":"Pfeufer","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1038\/ng.716","article-title":"Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction","volume":"42","author":"Sotoodehnia","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1093\/cvr\/cvv042","article-title":"Role of common and rare variants in SCN10A: Results from the Brugada syndrome QRS locus gene discovery collaborative study","volume":"106","author":"Behr","year":"2015","journal-title":"Cardiovasc. Res."},{"key":"ref_165","doi-asserted-by":"crossref","unstructured":"(2016). Corrigendum to: Role of common and rare variants in SCN10A: Results from the Brugada syndrome QRS locus gene discovery collaborative study. Cardiovasc. Res., 110, 3.","DOI":"10.1093\/cvr\/cvw038"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1161\/CIRCULATIONAHA.121.054083","article-title":"Variant Intronic Enhancer Controls SCN10A-short Expression and Heart Conduction","volume":"144","author":"Man","year":"2021","journal-title":"Circulation"},{"key":"ref_167","doi-asserted-by":"crossref","unstructured":"Hartmann, N., Knierim, M., Maurer, W., Dybkova, N., Hasenfuss, G., Sossalla, S., and Streckfuss-Bomeke, K. (2023). Molecular and Functional Relevance of Na(V)1.8-Induced Atrial Arrhythmogenic Triggers in a Human SCN10A Knock-Out Stem Cell Model. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241210189"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1253\/circj.CJ-12-0995","article-title":"Novel SCN3B mutation associated with brugada syndrome affects intracellular trafficking and function of Nav1.5","volume":"77","author":"Ishikawa","year":"2013","journal-title":"Circ. J."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"34198","DOI":"10.1038\/srep34198","article-title":"Embryonic type Na(+) channel beta-subunit, SCN3B masks the disease phenotype of Brugada syndrome","volume":"6","author":"Okata","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"3306","DOI":"10.1172\/JCI27167","article-title":"The L-type calcium channel in the heart: The beat goes on","volume":"115","author":"Bodi","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1161\/CIRCULATIONAHA.106.668392","article-title":"Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death","volume":"115","author":"Antzelevitch","year":"2007","journal-title":"Circulation"},{"key":"ref_172","doi-asserted-by":"crossref","unstructured":"Zhong, R., Schimanski, T., Zhang, F., Lan, H., Hohn, A., Xu, Q., Huang, M., Liao, Z., Qiao, L., and Yang, Z. (2022). A Preclinical Study on Brugada Syndrome with a CACNB2 Variant Using Human Cardiomyocytes from Induced Pluripotent Stem Cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23158313"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"e646","DOI":"10.1002\/ctm2.646","article-title":"Deciphering the pathogenic role of a variant with uncertain significance for short QT and Brugada syndromes using gene-edited human-induced pluripotent stem cell-derived cardiomyocytes and preclinical drug screening","volume":"11","author":"Lan","year":"2021","journal-title":"Clin. Transl. Med."},{"key":"ref_174","unstructured":"Jin, X., Ma, W., Zhang, Y., Gao, H., Yin, D., Song, J., Li, D., Shi, L., Li, J., and Ma, J. (2023, July 20). Available online: https:\/\/www.researchsquare.com\/article\/rs-2171528\/v1."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1038\/s41598-017-01517-6","article-title":"A Systems Genetics Approach Identified GPD1L and its Molecular Mechanism for Obesity in Human Adipose Tissue","volume":"7","author":"He","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1253\/circj.CJ-08-0508","article-title":"Mutation analysis of the glycerol-3 phosphate dehydrogenase-1 like (GPD1L) gene in Japanese patients with Brugada syndrome","volume":"72","author":"Makiyama","year":"2008","journal-title":"Circ. J."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1161\/CIRCULATIONAHA.113.003077","article-title":"Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype","volume":"129","author":"Cerrone","year":"2014","journal-title":"Circulation"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"e003436","DOI":"10.1161\/CIRCEP.115.003436","article-title":"Common Variant Near HEY2 Has a Protective Effect on Ventricular Fibrillation Occurrence in Brugada Syndrome by Regulating the Repolarization Current","volume":"9","author":"Nakano","year":"2016","journal-title":"Circ. Arrhythmia Electrophysiol."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"100250","DOI":"10.1016\/j.xcrm.2021.100250","article-title":"Analysis of Brugada syndrome loci reveals that fine-mapping clustered GWAS hits enhances the annotation of disease-relevant variants","volume":"2","author":"Mates","year":"2021","journal-title":"Cell Rep. Med."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"e44","DOI":"10.5808\/gi.22047","article-title":"Metagenomic analysis of viral genes integrated in whole genome sequencing data of Thai patients with Brugada syndrome","volume":"20","author":"Chitcharoen","year":"2022","journal-title":"Genom. Inform."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1007\/s00414-019-02127-9","article-title":"Whole genome and transcriptome sequencing of post-mortem cardiac tissues from sudden cardiac death victims identifies a gene regulatory variant in NEXN","volume":"133","author":"Andersen","year":"2019","journal-title":"Int. J. Legal Med."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"2878","DOI":"10.1093\/eurheartj\/ehaa383","article-title":"An autoantibody profile detects Brugada syndrome and identifies abnormally expressed myocardial proteins","volume":"41","author":"Chatterjee","year":"2020","journal-title":"Eur. Heart J."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"e1800065","DOI":"10.1002\/prca.201800065","article-title":"Integration of \u201cOmics\u201d Strategies for Biomarkers Discovery and for the Elucidation of Molecular Mechanisms Underlying Brugada Syndrome","volume":"12","author":"Scumaci","year":"2018","journal-title":"Proteom. Clin. Appl."},{"key":"ref_184","doi-asserted-by":"crossref","unstructured":"Ikeuchi, Y., Ochi, H., Motoda, C., Tokuyama, T., Okubo, Y., Okamura, S., Miyauchi, S., Miyamoto, S., Uotani, Y., and Onohara, Y. (2022). Plasma MicroRNAs as noninvasive diagnostic biomarkers in patients with Brugada syndrome. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0261390"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"euad145","DOI":"10.1093\/europace\/euad145","article-title":"Leucocyte-derived micro-RNAs as candidate biomarkers in Brugada syndrome","volume":"25","author":"Steinberg","year":"2023","journal-title":"Europace"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.hrthm.2023.01.008","article-title":"A systematic review of global autopsy rates in all-cause mortality and young sudden death","volume":"20","author":"Paratz","year":"2023","journal-title":"Heart Rhythm"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.joa.2016.07.012","article-title":"Genetics of Brugada syndrome","volume":"32","author":"Juang","year":"2016","journal-title":"J. Arrhythmia"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1016\/j.jacc.2012.04.037","article-title":"Spectrum and prevalence of mutations involving BrS1- through BrS12-susceptibility genes in a cohort of unrelated patients referred for Brugada syndrome genetic testing: Implications for genetic testing","volume":"60","author":"Crotti","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"920390","DOI":"10.3389\/fgene.2022.920390","article-title":"Incomplete Penetrance and Variable Expressivity: From Clinical Studies to Population Cohorts","volume":"13","author":"Kingdom","year":"2022","journal-title":"Front. Genet."},{"key":"ref_190","doi-asserted-by":"crossref","unstructured":"Morales, M.A., Piacenti, M., Nesti, M., Solarino, G., Pieragnoli, P., Zucchelli, G., Del Ry, S., Cabiati, M., and Vozzi, F. (2021). The BrAID study protocol: Integration of machine learning and transcriptomics for brugada syndrome recognition. BMC Cardiovasc. Disord., 21.","DOI":"10.1186\/s12872-021-02280-3"},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"30967","DOI":"10.1038\/srep30967","article-title":"hiPSC-derived cardiomyocytes from Brugada Syndrome patients without identified mutations do not exhibit clear cellular electrophysiological abnormalities","volume":"6","author":"Veerman","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1038\/d41573-020-00078-0","article-title":"RNA therapeutics on the rise","volume":"19","author":"Wang","year":"2020","journal-title":"Nat. Rev. Drug. Discov."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/j.jacbts.2022.02.003","article-title":"Utilization and Potential of RNA-Based Therapies in Cardiovascular Disease","volume":"7","author":"Robinson","year":"2022","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/s41573-021-00219-z","article-title":"Noncoding RNA therapeutics\u2014Challenges and potential solutions","volume":"20","author":"Winkle","year":"2021","journal-title":"Nat. Rev. Drug. Discov."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/s12276-022-00757-5","article-title":"RNA therapy: Rich history, various applications and unlimited future prospects","volume":"54","author":"Kim","year":"2022","journal-title":"Exp. Mol. Med."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1038\/s41419-022-05075-2","article-title":"RNA-based therapeutics: An overview and prospectus","volume":"13","author":"Zhu","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_197","doi-asserted-by":"crossref","unstructured":"Zogg, H., Singh, R., and Ro, S. (2022). Current Advances in RNA Therapeutics for Human Diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052736"},{"key":"ref_198","doi-asserted-by":"crossref","unstructured":"Garbo, S., Maione, R., Tripodi, M., and Battistelli, C. (2022). Next RNA Therapeutics: The Mine of Non-Coding. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23137471"},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"JC70","DOI":"10.7326\/J23-0031","article-title":"Genotype-guided drug prescribing vs. usual care reduced clinically relevant adverse drug reactions at 12 wk","volume":"176","author":"Holbrook","year":"2023","journal-title":"Ann. Intern. Med."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/S0140-6736(22)01841-4","article-title":"A 12-gene pharmacogenetic panel to prevent adverse drug reactions: An open-label, multicentre, controlled, cluster-randomised crossover implementation study","volume":"401","author":"Swen","year":"2023","journal-title":"Lancet"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/19\/2398\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:04:33Z","timestamp":1760130273000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/19\/2398"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,3]]},"references-count":200,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["cells12192398"],"URL":"https:\/\/doi.org\/10.3390\/cells12192398","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,3]]}}}