Abstract 9669: Association of Pathogenic DNA Variants for Cardiomyopathy With Cardiovascular Disease Outcomes and All-Cause Mortality

Abstract

Introduction: Pathogenic DNA variants associated with inherited cardiomyopathies are recognized as clinically important and actionable when identified, leading some clinicians to recommend population-wide genomic screening. The prevalence and clinical importance of such variants within the context of contemporary clinical care warrant further study. Methods: Using whole exome sequencing data from participants in Atherosclerosis Risk in Communities (ARIC) and the UK Biobank (UKBB), observed DNA sequence variants in any of 12 genes ( ACTC1, GLA, LMNA, MYBPC3, MYH7, MYL2, MYL3, PRKAG2, TNNI3, TNNT2, TPM1, and TTN ) known to be causative of inherited cardiomyopathies with accepted preventative or therapeutic interventions were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status per recommendations from the American College of Medical Genetics. The relationship of carrier status to risk of death or cardiovascular disease was assessed. Results: Among 9,667 ARIC participants (mean [SD] age 54 [5.7] years; 43.8% female) and 49,744 UKBB participants (mean [SD] age 57.1 [8.0] years; 54.6% female), 68 (0.70%) and 362 (0.73%) harbored an actionable pathogenic or likely pathogenic variant associated with cardiomyopathy, respectively. Carriers of these variants were not reliably identifiable by imaging or electrocardiography signatures. Presence of these variants was associated with 1.7- to 1.8-fold increased risk of heart failure, 2.1- to 2.9-fold increased risk of atrial fibrillation, and 1.6- to 1.8-fold increased risk of all-cause mortality across studies. Conclusions: The findings suggest that approximately 0.7% of middle-aged adult population in ARIC and the UKBB harbored a pathogenic variant associated with cardiomyopathy. Carriers of these variants would be difficult to identify within routine clinical practice but suffer from increased risk of cardiovascular disease and all-cause mortality.