Pathogenic Variants in Cardiomyopathy and Not Immune Disorder Genes Cause Pediatric Myocarditis with Dilated Cardiomyopathy Phenotype

Background: Myocarditis is an inflammatory entity of the myocardium that can lead to severe heart failure. Recently, we showed that pediatric myocarditis with dilated cardiomyopathy (DCM) phenotype is caused by pathogenic genetic variants in cardiomyopathy genes. The potential role of defects in immune disorder genes was not investigated.

Method: We analyzed five pediatric patients with biopsy-proven myocarditis and DCM phenotype and their family members with whole-exome sequencing (WES). The WES data were filtered for rare (minor allele frequency <10–4) pathogenic genetic defects in cardiomyopathy (n = 89) and immune disorder genes (n = 631). Immune disease genes cover entities such as autoinflammatory disease, bone marrow failure syndromes, complement disorders, and severe immunodeficiencies.

Results: We enrolled five children with a median age of 2.9 (1.0–6.8) years, four females. All had a DCM phenotype with a left ventricular ejection fraction of 28% (22–32%) and a chronic/healing myocarditis in the endomyocardial biopsy (EMB). In EMB of one patient mildly elevated copies of HHV6 DNA were detected. Four patients underwent implantation of a ventricular assist device and subsequently heart transplantation, none died. In three patients, we identified a pathogenic genetic variant in a known cardiac disease gene (MYH7, TNNI3, and DES) implicating primary cardiomyopathy. Two of these missense variants were de novo, one homozygous. Screening of immune disorder genes did not identify pathogenic rare, homozygous, truncating, or de novo variants. However, we identified 26 heterozygous rare missense variants (5.2 variants/patient) and one synonymous missense, splice region variant in DNAH9 within the genetic immune disorder screening.

Conclusion: This study supports that pediatric myocarditis with DCM phenotype is genetically caused by mutation of known cardiomyopathy genes. Piloting the idea that additional immune-related genetic defects promote myocarditis did not reveal any causative variants. Expanded analysis of WES data may identify immune-related genetic factors predisposing to myocardial inflammation.

Publication History

Article published online:
12 February 2022