{"doi":"10.1101/2025.07.26.25332081","title":"The contribution of <i>RBM20</i> truncating variants to human cardiomyopathy","abstract":"Abstract Background Genetic diagnosis has become increasingly important to guide clinical decision making for patients with dilated cardiomyopathy (DCM). Disease-causing (P/LP) missense variants in the gene RBM20 cause a highly penetrant arrhythmogenic dilated cardiomyopathy (DCM), but the role of truncating RBM20 variants ( RBM20tvs ) is unclear. Objective Assess the contribution of RBM20tvs to DCM. Methods We assembled an international cohort of DCM patients with RBM20 variants and used data from the genome-first UK Biobank (UKB) to assess the etiologic fraction, natural history and penetrance of RBM20tvs . Results The etiologic fraction of RBM20tvs in arrhythmogenic DCM was modest (0.53[0.32,0.67], p=7.5×10 -5 ). RBM20tv DCM patients presented to referral centers later in life than RBM20 P/LP DCM patients (53±10 vs. 34±18 years, p=4×10 -3 ), and were less likely to have a family history of sudden cardiac arrest (20% vs. 65%, p= 0.046) or cardiomyopathy (20% vs. 78% p=5.4×10 -3 ). There was no significant difference in age- and sex-adjusted incident major heart failure or arrhythmia events between RBM20tv and RBM20 P/LP DCM patients, though sex-adjusted lifetime hazard was reduced in RBM20tv DCM (HR 0.15[0.03,0.66],p=0.009). In UKB, lifetime incidence of cardiomyopathy, heart failure, or major ventricular arrhythmia diagnosis was lower in participants with RBM20tvs than in those with TTNtvs (HR 0.55 [0.36,0.84], p=5.9×10 -3 ). Conclusions RBM20tvs contribute to arrhythmogenic DCM phenotypes, but confer milder disease severity alone than RBM20 P/LP variants, and reduced lifetime disease penetrance compared to TTNtvs . Their potential for additive interactions with other damaging variants should be considered in DCM patients and families.","journal":"medRxiv","year":2025,"id":555678,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9295,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":655618,"name":"Joyce Njoroge","orcid":"0000-0003-4379-5328","position":1,"is_corresponding":false},{"id":1454925,"name":"Vikki A. 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