Myopathic Cardiac Genotypes Increase Risk for Myocarditis

Abstract

Background: Acute myocarditis (AM) is an important cause of heart failure and cardiomyopathy in adults and children, but risk factors are poorly understood. Mutations in genes related to cardiomyopathies have been implicated in children, suggesting overlap with other genetic myocardial disorders. Objectives: This study aimed to assess the prevalence of mutations in cardiac genes, including those associated with cardiomyopathies and neuromuscular disorders, among predominantly adult patients with AM. Methods: Genomic DNAs were obtained or extracted from blood from AM subjects from three separate cohorts (N=117; AM1=26, AM2=72, AM3=19), and next generation sequencing performed. Sex- and ancestry-matched controls without AM or cardiac disease and with available exome sequencing data from the BioMe biobank were included (N=468). Rates of deleterious variants (DV) in 93 cardiac genes were compared for cases and controls. Associations between DV status and histologic, viral and clinical outcomes were analyzed as secondary endpoints. Results: Based on a pooled burden meta-analysis (random effects), cardiac DV were statistically enriched in cases (AM1 19.2%, AM2 11.1%, AM3 31.6%) vs. respectively matched controls (5.6%, 7.6%, 7.9%) (P=0.013). Thirteen genes were implicated; of these, three (DYSF, DSP and TTN) were the source of DV for > 1 AM subject. No statistical differences were found between DV+ vs. DV- subjects for histologic AM classification, viral status or clinical outcome. Conclusions: Putatively damaging variants in genes related to cardiomyocyte structural integrity, classically associated with cardiomyopathy or neuromuscular disorders affecting the heart, are associated with increased risk for AM. Understanding viral-host genetic interactions may improve mechanistic insights in AM and clinical genetic testing may identify at-risk individuals.