Screening for Pathogenic Variants in Cardiomyopathy Genes Predicts Mortality and Composite Outcomes in UK Biobank

BackgroundInherited 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. ObjectiveWe aimed to determine the risk of mortality and cardiomyopathy-related outcomes associated with PuPV in cardiomyopathy-associated genes in UK Biobank. MethodsUsing 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 ([&ge;]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). ResultsAmong 200,619 participants, 22,401 (11.2%) were found to host [&ge;]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)]. ConclusionsAdults 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 AbstractLeveraging 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.