{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T07:02:27Z","timestamp":1791529347299,"version":"4.3.4"},"reference-count":14,"publisher":"American Medical Association (AMA)","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Cardiol"],"published-print":{"date-parts":[[2026,5,1]]},"abstract":"\n Importance<\/jats:title>\n \n Genetic diagnosis has become increasingly important to guide clinical decision-making for patients with dilated cardiomyopathy (DCM). Pathogenic or likely pathogenic (P\/LP) missense variants in the gene\n RBM20<\/jats:italic>\n cause a highly penetrant arrhythmogenic DCM, but the role of\n RBM20<\/jats:italic>\n truncating variants (\n RBM20<\/jats:italic>\n tvs) is unclear.\n <\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n To assess the contribution of\n RBM20<\/jats:italic>\n variants to arrhythmogenic DCM.\n <\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n \n In this cohort study, participants in the genome-first UK Biobank (UKB) and All of Us populations were evaluated to assess the etiologic fraction, natural history and penetrance of\n RBM20<\/jats:italic>\n variants. Retrospective data were collected from an international cohort of patients with DCM and\n RBM20<\/jats:italic>\n variants identified at centers of excellence for genetic heart disease and compared based on time to event. Study dates are not disclosed because the institutional review board did not authorize the sharing of this information.\n <\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n \n RBM20<\/jats:italic>\n variants were compared to known P\/LP variants and variants of uncertain significance in\n RBM20<\/jats:italic>\n as well as titin truncating variants (\n TTN<\/jats:italic>\n tvs).\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n Major ventricular arrhythmias, end-stage heart failure, and heart failure hospitalization as measured by medical record review (retrospective cohort) and diagnostic codes (UKB).<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Two main cohorts were studied for this project. In UK Biobank, a cohort of participants with\n RBM20<\/jats:italic>\n tvs,\n RBM20<\/jats:italic>\n synonymous variants, and\n TTN<\/jats:italic>\n tvs was studied. Of these 4249 participants, 1869 (44%) were male. The mean (SD) age at enrollment was 56 (8.2) years. In the RBM20 registry, of 179 patients, 105 (58.6%) were male, and the mean (SD) age at enrollment was 43.8 (19.1) years. A validation cohort from the All of Us biobank was also used. This consisted of 7002 participants, 4342 of whom (62.0%) were male, and the mean (SD) age was 52.7 (16.7) years. The etiologic fraction of\n RBM20<\/jats:italic>\n variants in arrhythmogenic DCM was 0.53 (95% CI, 0.32-0.67;\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001). In genome-first biobanks, lifetime incidence of cardiomyopathy, heart failure, or major ventricular arrhythmia diagnosis was lower in participants with\n RBM20<\/jats:italic>\n variants than in those with\n TTN<\/jats:italic>\n tvs (hazard ratio, 0.55; 95% CI, 0.36-0.84;\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001). Patients with\n RBM20<\/jats:italic>\n tvs and DCM presented to referral centers later in life than those with P\/LP\n RBM20<\/jats:italic>\n and DCM (mean [SD], 53 [10] vs 34 [18] years;\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001) and were less likely to have a family history of sudden cardiac arrest (2 of 10 [20%] vs 11 of 17 [65%];\n P<\/jats:italic>\n \u2009=\u2009.046) or cardiomyopathy (2 of 10 [20%] vs 14 of 18 [78%];\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001). There was no significant difference in age- and sex-adjusted incident major heart failure or arrhythmia events between patients with\n RBM20<\/jats:italic>\n tv and DCM or those with P\/LP\n RBM20<\/jats:italic>\n and DCM, though sex-adjusted lifetime hazard was reduced in those with\n RBM20<\/jats:italic>\n tv and DCM (hazard ratio, 0.13; 95% CI, 0.03-0.56;\n P<\/jats:italic>\n \u2009=\u2009.01).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n This study found that\n RBM20<\/jats:italic>\n variants contributed to arrhythmogenic DCM phenotypes but conferred reduced lifetime disease penetrance compared to\n TTN<\/jats:italic>\n tvs and milder disease severity alone than P\/LP\n RBM20<\/jats:italic>\n variants. Their potential for additive interactions with other damaging variants should be considered in patients with DCM and their families.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamacardio.2026.0401","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T15:00:29Z","timestamp":1775660429000},"page":"439","source":"Crossref","is-referenced-by-count":6,"title":["RBM20<\/i>\n Truncating Variants and Human Cardiomyopathy"],"prefix":"10.1001","volume":"11","author":[{"given":"Brendan J.","family":"Floyd","sequence":"first","affiliation":[{"name":"Stanford Center for Inherited Cardiovascular Disease and Department of Medicine, Stanford School of Medicine, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce N.","family":"Njoroge","sequence":"additional","affiliation":[{"name":"Stanford Center for Inherited Cardiovascular Disease and Department of Medicine, Stanford School of Medicine, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikki A.","family":"Krysov","sequence":"additional","affiliation":[{"name":"Stanford Center for Inherited Cardiovascular Disease and Department of Medicine, Stanford School of Medicine, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruna","family":"Gomes","sequence":"additional","affiliation":[{"name":"Stanford Center for Inherited Cardiovascular Disease and Department of Medicine, Stanford School of Medicine, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Murtha","sequence":"additional","affiliation":[{"name":"Stanford Center for Inherited Cardiovascular Disease and Department of Medicine, Stanford School of Medicine, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiaka","family":"Aribeana","sequence":"additional","affiliation":[{"name":"Stanford Center for Inherited Cardiovascular Disease and Department of Medicine, Stanford School of Medicine, Stanford, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Cannie","sequence":"additional","affiliation":[{"name":"Barts Heart Centre, London, United Kingdom, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Smith","sequence":"additional","affiliation":[{"name":"University of Michigan, Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Paldino","sequence":"additional","affiliation":[{"name":"University of Trieste, Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily E.","family":"Brown","sequence":"additional","affiliation":[{"name":"Johns Hopkins University, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Barth","sequence":"additional","affiliation":[{"name":"Johns Hopkins University, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erkan","family":"Ilhan","sequence":"additional","affiliation":[{"name":"Division of Cardiology, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renee","family":"Johnson","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia"},{"name":"School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julianne","family":"Wojciak","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Center, University of California, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad","family":"Alkhayat","sequence":"additional","affiliation":[{"name":"Center for Inherited Cardiovascular Diseases, Wellspan Health, York, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Graw","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus, Aurora"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Medo","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus, Aurora"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Haas","sequence":"additional","affiliation":[{"name":"Heidelberg University, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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