{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:44:02Z","timestamp":1792521842865,"version":"4.5.0"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"33","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>Brugada Syndrome (BrS) is an inherited arrhythmia disorder that causes an elevated risk of sudden cardiac death. Approximately 20% of patients with BrS have rare variants in SCN5A, which encodes the cardiac sodium channel NaV1.5. Genetic workup of BrS is often complicated by SCN5A variants of uncertain significance (VUS) and\/or incomplete penetrance. This study deployed an SCN5A-BrS functional assay at cohort scale to facilitate the implementation of genetic and precision medicine.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>All 252 missense and in-frame insertion\/deletion SCN5A variants from a previously published large cohort of BrS cases (n = 3335 patients) were analysed using a calibrated high-throughput automated patch-clamp (APC) assay. Variant functional Z-scores were assigned evidence levels ranging from BS3_moderate (normal function) to PS3_strong (loss-of-function), as defined by American College of Medical Genetics and Genomics criteria. Functional evidence was combined with population frequency, hotspot, case counts, protein-length changes, and in silico predictions. Odds ratios of BrS case\u2013control enrichment and penetrance for BrS were calculated from variant frequencies in the BrS cohort and in gnomAD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Most variants (146\/252) were functionally abnormal (Z \u2264 \u22122), with 100 having severe loss-of-function (Z \u2264 \u22124). Functional evidence enabled the reclassification of 110 of 225 VUS; 104 to likely pathogenic and 6 to likely benign. SCN5A variants with loss-of-function were mainly localized to the transmembrane domains, especially the regions comprising the central pore. SCN5A variant penetrance was proportional to the severity of loss-of-function; variants with Z \u2264 \u22126 had penetrance of 24.5% (15.9%\u201337.7% CI) and an odds ratio of 501 for BrS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This cohort-scale APC dataset stratifies SCN5A variants found in BrS patients into normal function \u2018bystander\u2019 variants that have a low risk of BrS and loss-of-function variants that have a high risk for BrS. Functional data can be integrated with other criteria to reclassify a substantial fraction of VUS. The dataset helps clarify the SCN5A\u2013BrS relationship and will improve the diagnosis and clinical management of BrS probands and their families.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/eurheartj\/ehaf874","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T09:57:47Z","timestamp":1763459867000},"page":"4679-4693","source":"Crossref","is-referenced-by-count":10,"title":["Automated patch clamp data improve variant classification and penetrance stratification for\n                    <i>SCN5A<\/i>\n                    \u2013Brugada syndrome"],"prefix":"10.1093","volume":"47","author":[{"given":"Matthew J","family":"O\u2019Neill","sequence":"first","affiliation":[{"name":"Department of Medicine, Brigham and Women\u2019s Hospital , Boston, MA ,","place":["USA"]},{"name":"Clinical Fellow in Medicine, Harvard Medical School , Boston, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1616-5681","authenticated-orcid":false,"given":"Joanne G","family":"Ma","sequence":"additional","affiliation":[{"name":"Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute , 405 Liverpool St, Darlinghurst, NSW ,","place":["Australia"]},{"name":"School of Clinical Medicine, St Vincent\u2019s Healthcare Clinical Campus, Faculty of Medicine and Health , University of New South Wales, Sydney ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6071-9581","authenticated-orcid":false,"given":"Jessa L","family":"Aldridge","sequence":"additional","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center , 2215B Garland Ave, 1235 Medical Research Building IV, Nashville, TN ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7432-9056","authenticated-orcid":false,"given":"Joseph F","family":"Solus","sequence":"additional","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center , 2215B Garland Ave, 1235 Medical Research Building IV, Nashville, TN ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevieve R","family":"Harvey","sequence":"additional","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center , 2215B Garland Ave, 1235 Medical Research Building IV, Nashville, TN ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paige H","family":"Roberson","sequence":"additional","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center , 2215B Garland Ave, 1235 Medical Research Building IV, Nashville, TN ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Barc","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CNRS, INSERM, l\u2019institut du thorax , IRS-UN, 8 Quai Moncousu, BP 70721, Nantes 44007, France"},{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0633-3514","authenticated-orcid":false,"given":"Connie R","family":"Bezzina","sequence":"additional","affiliation":[{"name":"European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart , Amsterdam ,","place":["The Netherlands"]},{"name":"Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6302-0389","authenticated-orcid":false,"given":"Dan M","family":"Roden","sequence":"additional","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center , 2215B Garland Ave, 1235 Medical Research Building IV, Nashville, TN ,","place":["USA"]},{"name":"Department of Pharmacology, Vanderbilt University Medical Center , Nashville, TN ,","place":["USA"]},{"name":"Department of Biomedical Informatics, Vanderbilt University Medical Center , Nashville, TN ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5092-8825","authenticated-orcid":false,"given":"Roddy","family":"Walsh","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC , Amsterdam ,","place":["The Netherlands"]},{"name":"Cardiovascular and Genomics Research Institute, City St. George\u2019s University of London , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3859-3716","authenticated-orcid":false,"given":"Jamie I","family":"Vandenberg","sequence":"additional","affiliation":[{"name":"Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute , 405 Liverpool St, Darlinghurst, NSW ,","place":["Australia"]},{"name":"School of 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