{"doi":"10.1101/2022.06.27.22276949","title":"Screening for Pathogenic Variants in Cardiomyopathy Genes Predicts Mortality and Composite Outcomes in UK Biobank","abstract":"Abstract Background Inherited cardiomyopathies can present with broad variation of phenotype. Data are limited regarding genetic screening strategies and outcomes associated with putative pathogenic variants (PuPV) in cardiomyopathy-associated genes in the general population. Objective We aimed to determine the risk of mortality and cardiomyopathy-related outcomes associated with PuPV in cardiomyopathy-associated genes in UK Biobank. Methods Using whole exome sequencing data, variants in dilated, hypertrophic and arrhythmogenic cardiomyopathy-associated genes with at least limited evidence of disease causality according to ClinGen Expert Panel curations, were annotated using REVEL (≥0.65) and ANNOVAR (predicted loss of function) to identify PuPVs. Individuals with PuPV comprised the genotype-positive (G+) and those without PuPV the genotype-negative (G-) cohorts. Group comparisons were made using time-to-event analyses for the primary (all-cause mortality) and secondary outcomes (diagnosis of cardiomyopathy; composite outcome of diagnosis of cardiomyopathy, heart failure, arrhythmia, stroke, and death). Results Among 200,619 participants, 22,401 (11.2%) were found to host ≥1 PuPV in cardiomyopathy-associated genes (G+). After adjusting for age and sex, G+ individuals had increased all-cause mortality [HR 1.07 (95%CI 1.02-1.13; p=0.011)] and increased rates of diagnosis of cardiomyopathy later in life [HR 2.37 (95%CI 1.98-2.85; p<0.0001)], which further increased in those with PuPV in definitive/strong evidence ClinGen genes [3.25 (95%CI 2.63-4.00; p<0.0001)]. G+ individuals had a higher risk of developing the composite outcome [HR 1.11 (95%CI 1.06-1.15; p<0.0001)]. Conclusions Adults with PuPV in cardiomyopathy-associated genes have higher all-cause mortality and increased risk of developing cardiomyopathy-associated features and complications, compared to genotype-negative controls. Condensed Abstract Leveraging the UK Biobank prospective cohort, we analyzed whole exome sequencing data in dilated, hypertrophic and arrhythmogenic cardiomyopathy-associated genes using a population screening ‘genotype-first’ approach. Individuals with putative pathogenic variants in genes implicated in cardiomyopathies showed an increased risk of all-cause mortality, higher risk of developing clinical cardiomyopathy later in life, and higher risk of a composite outcome (cardiomyopathy, heart failure, arrhythmia, stroke, and death) compared to genotype-negative controls. These findings highlight the potential role of ‘genotype-first’ approach in elevating personalized medicine into population level precision health in the future.","journal":"medRxiv","year":2022,"id":309530,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.932,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1004820,"name":"Ravi A. Shah","orcid":null,"position":1,"is_corresponding":false},{"id":1004495,"name":"Ghaith Sharaf Dabbagh","orcid":"0000-0001-7090-1064","position":2,"is_corresponding":false},{"id":328412,"name":"Andrew P. Landstrom","orcid":"0000-0002-1878-9631","position":3,"is_corresponding":false},{"id":1049,"name":"Dawood Darbar","orcid":"0000-0002-4103-5977","position":4,"is_corresponding":false},{"id":108268,"name":"Mohammed Y Khanji","orcid":"0000-0002-5903-4454","position":5,"is_corresponding":false},{"id":851353,"name":"Luís R. Lopes","orcid":"0000-0002-6408-4667","position":6,"is_corresponding":false},{"id":780251,"name":"Stefan van Duijvenboden","orcid":"0000-0001-8897-558X","position":7,"is_corresponding":false},{"id":108265,"name":"Daniele Muser","orcid":"0000-0003-4323-5988","position":8,"is_corresponding":false},{"id":700294,"name":"Aaron M. Lee","orcid":"0000-0001-6008-5366","position":9,"is_corresponding":false},{"id":688442,"name":"Christopher M. Haggerty","orcid":"0000-0002-3227-4490","position":10,"is_corresponding":false},{"id":51222,"name":"Pankaj Arora","orcid":"0000-0003-2420-3550","position":11,"is_corresponding":false},{"id":244334,"name":"Christopher Semsarian","orcid":"0000-0001-6441-274X","position":12,"is_corresponding":false},{"id":477418,"name":"Tobias Reichlin","orcid":"0000-0002-7197-8415","position":13,"is_corresponding":false},{"id":297937,"name":"Virend K. Somers","orcid":"0000-0003-4045-4341","position":14,"is_corresponding":false},{"id":465189,"name":"Anjali Owens","orcid":"0000-0002-9669-8495","position":15,"is_corresponding":false},{"id":31229,"name":"Steffen E. Petersen","orcid":"0000-0003-4622-5160","position":16,"is_corresponding":false},{"id":108266,"name":"Rajat Deo","orcid":"0000-0002-8250-2607","position":17,"is_corresponding":false},{"id":21970,"name":"Patricia B. Munroe","orcid":"0000-0002-4176-2947","position":18,"is_corresponding":false},{"id":413739,"name":"Nay Aung","orcid":"0000-0001-5095-1611","position":19,"is_corresponding":false},{"id":108269,"name":"C. Anwar A. Chahal","orcid":"0000-0001-7825-8827","position":20,"is_corresponding":false},{"id":456558,"name":"Babken Asatryan","orcid":"0000-0002-0050-5717","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T00:33:11.579763Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}