Myopathic Cardiac Genotypes Increase Risk for Myocarditis

Amy R Kontorovich, Nihir Patel, Arden Moscati, Felix Richter, Inga Peter, Enkhsaikhan Purevjav, Simina Ramona Selejan, Ingrid Kindermann, Jeffrey A Towbin, Michael Bohm, Karin Klingel, Bruce D Gelb, Amy R Kontorovich, Nihir Patel, Arden Moscati, Felix Richter, Inga Peter, Enkhsaikhan Purevjav, Simina Ramona Selejan, Ingrid Kindermann, Jeffrey A Towbin, Michael Bohm, Karin Klingel, Bruce D Gelb

Abstract

Impairments in certain cardiac genes confer risk for myocarditis in children. To determine the extent of this association, we performed genomic sequencing in predominantly adult patients with acute myocarditis and matched control subjects. Putatively deleterious variants in a broad set of cardiac genes were found in 19 of 117 acute myocarditis cases vs 34 of 468 control subjects (P = 0.003). Thirteen genes classically associated with cardiomyopathy or neuromuscular disorders with cardiac involvement were implicated, including >1 associated damaging variant in DYSF, DSP, and TTN. Phenotypes of subjects who have acute myocarditis with or without deleterious variants were similar, indicating that genetic testing is necessary to differentiate them.

Keywords: ACM, arrhythmogenic cardiomyopathy; AM, acute myocarditis; AM1, acute myocarditis registry 1; CMP, cardiomyopathy; DV, deleterious variant; EF, ejection fraction; ES, exome sequencing; NMD, neuromuscular disorder; OR, odds ratio; TGP, targeted gene panel; acute myocarditis; cardiomyopathy; genetics.

Conflict of interest statement

This study is supported in part by the National Heart Lung and Blood Institute of the National Institutes of Health (HL140083 [to Dr Kontorovich]) and (HL135742 [to Dr Gelb]), a grant from the Children’s Cardiomyopathy Foundation (to Dr Kontorovich), and the German Research Foundation (KL593 2-3 [to Dr Klingel]). Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health (S10OD026880). Funders had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

© 2021 The Authors.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Pooled Burden Analysis of Putatively DVs in Patients With AM (A) A pooled burden analysis of deleterious variant (DV) burden in 3 acute myocarditis (AM) cohorts (AM1, AM2, AM3) identified a statistically significant enrichment of DVs in patients with AM compared with in control subjects (logistic regression odds ratio and 95% CI shown as red diamond; P = 0.003). (B) In a supporting analysis, 10,000 simulations of resampling with replacement within each study based on study sample size (gray) also identified a statistically significant DV burden in patients with AM (odds ratio: 2.48 shown as red line, 95% CI: 1.31-4.54; P = 0.004).
Figure 2
Figure 2
AM Genes and Traditional Associated Phenotypes The numbers1, 2, 3, and 8 indicate the DV frequencies. ACM = arrhythmogenic cardiomyopathy; AM = acute myocarditis; DCM = dilated cardiomyopathy; DV = deleterious variant; HCM = hypertrophic cardiomyopathy; NMD = neuromuscular disease.

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