{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T16:30:52Z","timestamp":1770913852255,"version":"3.50.1"},"reference-count":54,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T00:00:00Z","timestamp":1685491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Education, University and Research","award":["2015583WMX"],"award-info":[{"award-number":["2015583WMX"]}]},{"name":"Italian Ministry of Education, University and Research","award":["GR-2011-02347743"],"award-info":[{"award-number":["GR-2011-02347743"]}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["2015583WMX"],"award-info":[{"award-number":["2015583WMX"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["GR-2011-02347743"],"award-info":[{"award-number":["GR-2011-02347743"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Brugada syndrome (BrS) is an inherited autosomal dominant cardiac channelopathy. Pathogenic rare mutations in the SCN5A gene, encoding the alpha-subunit of the voltage-dependent cardiac Na+ channel protein (Nav1.5), are identified in 20% of BrS patients, affecting the correct function of the channel. To date, even though hundreds of SCN5A variants have been associated with BrS, the underlying pathogenic mechanisms are still unclear in most cases. Therefore, the functional characterization of the SCN5A BrS rare variants still represents a major hurdle and is fundamental to confirming their pathogenic effect. Human cardiomyocytes (CMs) differentiated from pluripotent stem cells (PSCs) have been extensively demonstrated to be reliable platforms for investigating cardiac diseases, being able to recapitulate specific traits of disease, including arrhythmic events and conduction abnormalities. Based on this, in this study, we performed a functional analysis of the BrS familial rare variant NM_198056.2:c.3673G&gt;A (NP_932173.1:p.Glu1225Lys), which has been never functionally characterized before in a cardiac-relevant context, as the human cardiomyocyte. Using a specific lentiviral vector encoding a GFP-tagged SCN5A gene carrying the specific c.3673G&gt;A variant and CMs differentiated from control PSCs (PSC-CMs), we demonstrated an impairment of the mutated Nav1.5, thus suggesting the pathogenicity of the rare BrS detected variant. More broadly, our work supports the application of PSC-CMs for the assessment of the pathogenicity of gene variants, the identification of which is increasing exponentially due to the advances in next-generation sequencing methods and their massive use in genetic testing.<\/jats:p>","DOI":"10.3390\/ijms24119548","type":"journal-article","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T04:41:49Z","timestamp":1685508109000},"page":"9548","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Functional Characterisation of the Rare SCN5A p.E1225K Variant, Segregating in a Brugada Syndrome Familial Case, in Human Cardiomyocytes from Pluripotent Stem Cells"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3443-3221","authenticated-orcid":false,"given":"Nicol\u00f2","family":"Salvarani","sequence":"first","affiliation":[{"name":"Institute of Genetic and Biomedical Research (IRGB), UOS of Milan, National Research Council of Italy, 20138 Milan, Italy"},{"name":"IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1815-4000","authenticated-orcid":false,"given":"Giovanni","family":"Peretto","sequence":"additional","affiliation":[{"name":"Department of Cardiac Electrophysiology and Arrhythmology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"Faculty of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5537-7006","authenticated-orcid":false,"given":"Crasto","family":"Silvia","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2858-1404","authenticated-orcid":false,"given":"Andrea","family":"Villatore","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9332-7771","authenticated-orcid":false,"given":"Cecilia","family":"Thairi","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy"},{"name":"Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Santoni","sequence":"additional","affiliation":[{"name":"Genomic Unit for the Diagnosis of Human Pathologies, IRCCS San Raffaele Hospital, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8447-0389","authenticated-orcid":false,"given":"Camilla","family":"Galli","sequence":"additional","affiliation":[{"name":"IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7376-2119","authenticated-orcid":false,"given":"Paola","family":"Carrera","sequence":"additional","affiliation":[{"name":"Genomic Unit for the Diagnosis of Human Pathologies, IRCCS San Raffaele Hospital, 20132 Milan, Italy"},{"name":"Laboratory of Clinical Molecular Biology, IRCCS San Raffaele Hospital, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3303-8892","authenticated-orcid":false,"given":"Simone","family":"Sala","sequence":"additional","affiliation":[{"name":"Department of Cardiac Electrophysiology and Arrhythmology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Benedetti","sequence":"additional","affiliation":[{"name":"Genomic Unit for the Diagnosis of Human Pathologies, IRCCS San Raffaele Hospital, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2373-5635","authenticated-orcid":false,"given":"Elisa","family":"Di Pasquale","sequence":"additional","affiliation":[{"name":"Institute of Genetic and Biomedical Research (IRGB), UOS of Milan, National Research Council of Italy, 20138 Milan, Italy"},{"name":"IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2880-6631","authenticated-orcid":false,"given":"Chiara","family":"Di Resta","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy"},{"name":"Genomic Unit for the Diagnosis of Human Pathologies, IRCCS San Raffaele Hospital, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,31]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/j.jacc.2018.06.037","article-title":"Present Status of Brugada Syndrome: JACC State-of-the-Art Review","volume":"72","author":"Brugada","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Di Resta, C., Berg, J., Villatore, A., Maia, M., Pili, G., Fioravanti, F., Tomaiuolo, R., Sala, S., Benedetti, S., and Peretto, G. (2022). Concealed Substrates in Brugada Syndrome: Isolated Channelopathy or Associated Cardiomyopathy?. Genes, 13.","DOI":"10.3390\/genes13101755"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1002\/joa3.12717","article-title":"European Heart Rhythm Association (EHRA)\/Heart Rhythm Society (HRS)\/Asia Pacific Heart Rhythm Society (APHRS)\/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases","volume":"38","author":"Wilde","year":"2022","journal-title":"J. Arrhythmia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"E002911","DOI":"10.1161\/CIRCGEN.120.002911","article-title":"SCN5A Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in SCN5A Families","volume":"13","author":"Wijeyeratne","year":"2020","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/32675","article-title":"Genetic basis and molecular mechanism for idiopathic ventricular fibrillation","volume":"392","author":"Chen","year":"1998","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2920","DOI":"10.1111\/jce.14732","article-title":"Low rate of life-threatening events and limitations in predicting invasive and noninvasive markers of symptoms in a cohort of type 1 Brugada syndrome patients: Data and insights from the GenBra registry","volume":"31","author":"Sacilotto","year":"2020","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1111\/j.1540-8167.2006.00349.x","article-title":"Progressive cardiac conduction defect is the prevailing phenotype in carriers of a Brugada syndrome SCN5A mutation","volume":"17","author":"Probst","year":"2006","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1038\/ejhg.2012.289","article-title":"Genetics can contribute to the prognosis of Brugada syndrome: A pilot model for risk stratification","volume":"21","author":"Sommariva","year":"2013","journal-title":"Eur. J. Hum. Genet. EJHG"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1093\/europace\/euac144","article-title":"Searching for atrial fibrillation: Looking harder, looking longer, and in increasingly sophisticated ways. An EHRA position paper","volume":"25","author":"Kalarus","year":"2022","journal-title":"Eurospace"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/gim.2016.190","article-title":"Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): A policy statement of the American College of Medical Genetics and Genomics","volume":"19","author":"Kalia","year":"2017","journal-title":"Genet. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1093\/cvr\/cvr142","article-title":"A Brugada syndrome mutation (p.S216L) and its modulation by p.H558R polymorphism: Standard and dynamic characterization","volume":"91","author":"Marangoni","year":"2011","journal-title":"Cardiovasc. Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"My, I., and Di Pasquale, E. (2021). Genetic Cardiomyopathies: The Lesson Learned from hiPSCs. J. Clin. Med., 10.","DOI":"10.3390\/jcm10051149"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e2393","DOI":"10.1038\/cddis.2016.304","article-title":"Adeno-associated virus-mediated CASQ2 delivery rescues phenotypic alterations in a patient-specific model of recessive catecholaminergic polymorphic ventricular tachycardia","volume":"7","author":"Lodola","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2267","DOI":"10.1038\/s41467-019-09929-w","article-title":"The K219T-Lamin mutation induces conduction defects through epigenetic inhibition of SCN5A in human cardiac laminopathy","volume":"10","author":"Salvarani","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_16","first-page":"E000043","article-title":"Induced Pluripotent Stem Cells for Cardiovascular Disease Modeling and Precision Medicine: A Scientific Statement From the American Heart Association","volume":"11","author":"Musunuru","year":"2018","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3079","DOI":"10.1161\/CIRCULATIONAHA.111.066092","article-title":"Cardiomyocytes derived from pluripotent stem cells recapitulate electrophysiological characteristics of an overlap syndrome of cardiac sodium channel disease","volume":"125","author":"Davis","year":"2012","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/gt.2012.19","article-title":"Lentiviral vectors and cardiovascular diseases: A genetic tool for manipulating cardiomyocyte differentiation and function","volume":"19","author":"Latronico","year":"2012","journal-title":"Gene Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.ajhg.2020.05.015","article-title":"High-Throughput Reclassification of SCN5A Variants","volume":"107","author":"Glazer","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.jmoldx.2012.09.002","article-title":"Inherited cardiomyopathies: Molecular genetics and clinical genetic testing in the postgenomic era","volume":"15","author":"Teekakirikul","year":"2013","journal-title":"J. Mol. Diagn."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1111\/jce.14374","article-title":"Programmed ventricular stimulation in patients with active vs previous arrhythmic myocarditis","volume":"31","author":"Peretto","year":"2020","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_23","first-page":"e005053","article-title":"Electrical Substrate Elimination in 135 Consecutive Patients With Brugada Syndrome","volume":"10","author":"Pappone","year":"2017","journal-title":"Circulation"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1016\/j.jacc.2020.08.012","article-title":"Inflammation as a Predictor of Recurrent Ventricular Tachycardia After Ablation in Patients With Myocarditis","volume":"76","author":"Peretto","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"110","DOI":"10.5808\/GI.2012.10.2.110","article-title":"Genetic Analysis of SCN5A in Korean Patients Associated with Atrioventricular Conduction Block","volume":"10","author":"Park","year":"2012","journal-title":"Genom. Inform."},{"key":"ref_26","unstructured":"(2023, March 01). GnomAD. Available online: https:\/\/gnomad.broadinstitute.org\/about."},{"key":"ref_27","unstructured":"(2023, March 01). NCBI, Available online: https:\/\/www.ncbi.nlm.nih.gov."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: Predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1093\/nar\/gkg509","article-title":"SIFT: Predicting amino acid changes that affect protein function","volume":"31","author":"Ng","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: Mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat. Methods"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1101\/gr.3577405","article-title":"Distribution and intensity of constraint in mammalian genomic sequence","volume":"15","author":"Cooper","year":"2005","journal-title":"Genome Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1089\/hum.2019.211","article-title":"Optimized Pre-Clinical Grade Production of Two Novel Lentiviral Vector Pseudotypes for Lung Gene Delivery","volume":"31","author":"Domm","year":"2020","journal-title":"Hum. Gene Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/7651_2014_173","article-title":"Generation of Cardiomyocytes from Pluripotent Stem Cells","volume":"1353","author":"Nakahama","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1002\/humu.9144","article-title":"Sodium channel gene (SCN5A) mutations in 44 index patients with Brugada syndrome: Different incidences in familial and sporadic disease","volume":"21","author":"Eckardt","year":"2003","journal-title":"Hum. Mutat."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/BF00656997","article-title":"Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches","volume":"391","author":"Hamill","year":"1981","journal-title":"Pflug. Arch. Eur. J. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.pbiomolbio.2008.02.005","article-title":"Tensegrity-based mechanosensing from macro to micro","volume":"97","author":"Ingber","year":"2008","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"H2006","DOI":"10.1152\/ajpheart.00694.2011","article-title":"High purity human-induced pluripotent stem cell-derived cardiomyocytes: Electrophysiological properties of action potentials and ionic currents","volume":"301","author":"Ma","year":"2011","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_39","first-page":"665","article-title":"J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge","volume":"19","author":"Antzelevitch","year":"2017","journal-title":"Eurospace"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2854","DOI":"10.1093\/eurheartj\/ehab254","article-title":"Functionally validated SCN5A variants allow interpretation of pathogenicity and prediction of lethal events in Brugada syndrome","volume":"42","author":"Ishikawa","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1016\/j.gim.2022.02.010","article-title":"Dominant negative effects of SCN5A missense variants","volume":"24","author":"Muhammad","year":"2022","journal-title":"Genet. Med."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Kroncke, B.M., Smith, D.K., Zuo, Y., Glazer, A.M., Roden, D.M., and Blume, J.D. (2020). A Bayesian method to estimate variant-induced disease penetrance. PLoS Genet., 16.","DOI":"10.1371\/journal.pgen.1008862"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e002095","DOI":"10.1161\/CIRCGEN.118.002095","article-title":"SCN5A (NaV1.5) Variant Functional Perturbation and Clinical Presentation: Variants of a Certain Significance","volume":"11","author":"Kroncke","year":"2018","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1002\/humu.24128","article-title":"Relationship between sodium channel function and clinical phenotype in SCN5A variants associated with Brugada syndrome","volume":"41","author":"Pearman","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1161\/01.RES.0000052672.97759.36","article-title":"Compound heterozygosity for mutations (W156X and R225W) in SCN5A associated with severe cardiac conduction disturbances and degenerative changes in the conduction system","volume":"92","author":"Bezzina","year":"2003","journal-title":"Circ. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e003379","DOI":"10.1161\/JAHA.116.003379","article-title":"Further Insights in the Most Common SCN5A Mutation Causing Overlapping Phenotype of Long QT Syndrome, Brugada Syndrome, and Conduction Defect","volume":"5","author":"Veltmann","year":"2016","journal-title":"J. Am. Heart Assoc."},{"key":"ref_47","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_48","doi-asserted-by":"crossref","first-page":"11173","DOI":"10.1038\/s41598-019-47632-4","article-title":"Comparing human iPSC-cardiomyocytes versus HEK293T cells unveils disease-causing effects of Brugada mutation A735V of NaV1.5 sodium channels","volume":"9","author":"Angsutararux","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"I165","DOI":"10.1093\/eurheartjsupp\/suac088","article-title":"When Brugada syndrome is at risk of sudden death: Clinical and anatomical aspects","volume":"24","author":"Stazi","year":"2022","journal-title":"Eur. Heart J. Suppl."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1093\/europace\/euz186","article-title":"Comparable clinical characteristics in Brugada syndrome patients harboring SCN5A or novel SCN10A variants","volume":"21","author":"Monasky","year":"2019","journal-title":"Europace"},{"key":"ref_51","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_52","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/978-1-4419-6066-5_2","article-title":"Introduction to ion channels","volume":"674","author":"Becchetti","year":"2010","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_53","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_54","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."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/11\/9548\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:45:59Z","timestamp":1760125559000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/11\/9548"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,31]]},"references-count":54,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["ijms24119548"],"URL":"https:\/\/doi.org\/10.3390\/ijms24119548","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,31]]}}}