Pathogenic Variants Associated With Dilated Cardiomyopathy Predict Outcome in Pediatric Myocarditis

Abstract

Background: Myocarditis is one of the most common causes leading to heart failure in children and a possible genetic background has been postulated. We sought to characterize the clinical and genetic characteristics in patients with myocarditis ≤18 years of age to predict outcome.

Methods: A cohort of 42 patients (Genetics in Pediatric Myocarditis) with biopsy-proven myocarditis underwent genetic testing with targeted panel sequencing of cardiomyopathy-associated genes. Genetics in Pediatric Myocarditis patients were divided into subgroups according to the phenotype of dilated cardiomyopathy (DCM) at presentation, resulting in 22 patients without DCM (myocarditis without phenotype of DCM) and 20 patients with DCM (myocarditis with phenotype of DCM).

Results: Myocarditis with phenotype of DCM patients (median age 1.4 years) were younger than myocarditis without phenotype of DCM patients (median age 16.1 years; P<0.001) and were corresponding to heart failure-like and coronary syndrome-like phenotypes, respectively. At least one likely pathogenic/pathogenic variant was identified in 9 out of 42 patients (22%), 8 of them were heterozygous, and 7 out of 9 were in myocarditis with phenotype of DCM. Likely pathogenic/pathogenic variants were found in genes validated for primary DCM (BAG3, DSP, LMNA, MYH7, TNNI3, TNNT2, and TTN). Rare variant enrichment analysis revealed significant accumulation of high-impact disease variants in myocarditis with phenotype of DCM versus healthy individuals (P=0.0003). Event-free survival was lower (P=0.008) in myocarditis with phenotype of DCM patients compared with myocarditis without phenotype of DCM and primary DCM.

Conclusions: We report heterozygous likely pathogenic/pathogenic variants in biopsy-proven pediatric myocarditis. Myocarditis patients with DCM phenotype were characterized by early-onset heart failure, significant enrichment of likely pathogenic/pathogenic variants, and poor outcome. These phenotype-specific and age group-specific findings will be useful for personalized management of these patients. Genetic evaluation in children newly diagnosed with myocarditis and DCM phenotype is warranted.

Keywords: biopsy, endomyocardial; cardiomyopathy, dilated; genetics; myocarditis.

Figure 1.

Study flow chart. Study design of the Genetics in Pediatric Myocarditis cohort, including only patients with biopsy-proven myocarditis, the performed diagnostics, and follow-up. CMR indicates cardiovascular magnetic resonance imaging; LV, left ventricular; NT-proBNP, N-terminal pro-brain natriuretic peptide; and PCR, polymerase chain reaction. *In 2 patients with a previous diagnosis of primary dilated cardiomyopathy, myocarditis was subsequently proven by endomyocardial biopsy (EMB).

Figure 2.

Accumulation of high-impact disease variants in pediatric myocarditis.A, Enrichment of high-impact disease variants with a Combined Annotation Dependent Depletion (CADD) score >30 was analyzed in myocarditis without phenotype of dilated cardiomyopathy (MYC-NonDCM), myocarditis with phenotype of dilated cardiomyopathy (MYC-DCM), RIKADA-DCM (DCM cohort of the study Risk Stratification in Children and Adolescents With Primary Cardiomyopathy) patients compared to healthy controls from the International Genome Sample Resource (IGSR) data respiratory. IGSR controls were of European descend. Genetic variants detected in 89 cardiomyopathy (CMP) disease genes were filtered with a minor allele frequency (MAF) of 0.0001%. B, Classification of automatically filtered heterozygous variants was performed according to their CADD score of MYC-NonDCM/MYC-DCM/RIKADA-DCM patients and IGSR control individuals. High-impact variants with a CADD score >30 are highlighted with a gray background. C, Enrichment of CADD >30 variants was tested for MYC-NonDCM, MYC-DCM, MYC-DCM/MYC-NonDCM, RIKADA-DCM, and MYC-DCM/RIKADA-DCM groups compared to the IGSR cohort with the Wilcoxon rank-sum test and Fisher exact test. Significant enrichment was observed in the MYC-DCM, MYC-DCM/MYC-NonDCM, and MYC-DCM/RIKADA-DCM subgroups.

Figure 3.

Outcome in a cohort of childhood biopsy-proven myocarditis (Genetics in Pediatric Myocarditis [MYCPEDIG]). Patients from the MYCPEDIG cohort were subdivided into myocarditis with phenotype of dilated cardiomyopathy (MYC-DCM) and myocarditis without phenotype of dilated cardiomyopathy (MYC-NonDCM) groups according to the phenotype at time of admission. Phenotype at follow-up was recorded, with DCM or without DCM (NonDCM). Patients receiving or heart transplantation (HTx) or died were listed separately (HTx/death).

Figure 4.

Event-free survival of the Genetics in Pediatric Myocarditis (MYCPEDIG) and RIKADA-DCM (DCM cohort of the study Risk Stratification in Children and Adolescents With Primary Cardiomyopathy) cohorts. Kaplan-Meier curves illustrate the event-free survival to the combined end point of death, heart transplantation, and mechanical circulatory support. Event-free survival (A) in the overall MYCPEDIG cohort, (B) between female (red) and male patients (blue; P=0.458, log-rank test), and (C) between the myocarditis without phenotype of dilated cardiomyopathy (MYC-NonDCM), RIKADA-DCM, and myocarditis with phenotype of dilated cardiomyopathy (MYC-DCM) subgroups (P=0.008, log-rank test).