Pathogenic Variants in Cardiomyopathy Disorder Genes Underlie Pediatric Myocarditis-Further Impact of Heterozygous Immune Disorder Gene Variants?

Abstract

Myocarditis is an inflammatory disease of the heart. Pediatric myocarditis with the dilated cardiomyopathy (DCM) phenotype may be caused by likely pathogenic or pathogenic genetic variants [(L)P] in cardiomyopathy (CMP) genes. Systematic analysis of immune disorder gene defects has not been performed so far. We analyzed 12 patients with biopsy-proven myocarditis and the DCM phenotype together with their parents using whole-exome sequencing (WES). The WES data were filtered for rare pathogenic variants in CMP (n = 89) and immune disorder genes (n = 631). Twelve children with a median age of 2.9 (1.0-6.8) years had a mean left ventricular ejection fraction of 28% (22-32%) and myocarditis was confirmed by endomyocardial biopsy. Patients with primary immunodeficiency were excluded from the study. Four patients underwent implantation of a ventricular assist device and subsequent heart transplantation. Genetic analysis of the 12 families revealed an (L)P variant in the CMP gene in 8/12 index patients explaining DCM. Screening of recessive immune disorder genes identified a heterozygous (L)P variant in 3/12 index patients. This study supports the genetic impact of CMP genes for pediatric myocarditis with the DCM phenotype. Piloting the idea that additional immune-related genetic defects promote myocarditis suggests that the presence of heterozygous variants in these genes needs further investigation. Altered cilium function might play an additional role in inducing inflammation in the context of CMP.

Keywords: dilated cardiomyopathy; genetic; immune; myocarditis; pathogenic variant.

Figure 1

Study flow chart of the genetic evaluation after whole-exome sequencing (WES), including only patients with biopsy-proven myocarditis and phenotype of dilated cardiomyopathy (DCM). Cardiomyopathy (CMP) disease genes and immune disease genes were filtered with minor allele frequency (MAF) of 10⁻⁴ for pathogenic and likely pathogenic, (L)P, variants. Filtering for cardiomyopathy and immune disease genes included all heterozygous (het), homozygous (hom), and hemizygous (hemi) variants. Analysis of cardiomyopathy disease genes included all missense, protein length changing, and splice effect variants. Analysis of immune disease genes included all protein length changing and splice effect variants, but only missense (L)P variants previously annotated in ClinVar.

Figure 2

Clinical and genetic evaluation of three selected families with CMP and myocarditis. (A) Pedigree of family #1 with the index patient 1-II:4 carrying a heterozygous titin truncating variant (TTN-tv), a splice variant in interferon regulatory factor 7 (IRF7), and a protein-truncating variant in coiled-coil domain containing 40 (CCDC40). The IRF7 and CCDC40 alleles are inherited from the father, while the TTN-tv allele is of maternal origin. (B′) Echocardiographic images of 4-chamber view and (B″) midventricular and short axis of individual 1-II:4 reveal severe left ventricular dilatation. (C) Pedigree of family #2 with the index patient 2-II:1 carrying a heterozygous de novo variant in troponin C1, slow skeletal and cardiac type (TNNC1), missense variants in fibrillin 1 (FBN1), as well as dystrophin (DMD), and a stop gain variant in dynein axonemal heavy chain 11 (DNAH11). All alleles are inherited from the mother. The DMD missense allele appears hemizygously. (D) Pedigree of family #3 with the index patient 3-II:2 exposes a homozygous missense variant in troponin I3, cardiac type (TNNI3), a stop gain variant in sperm-associated antigen 1 (SPAG1), and a splice variant in FA complementation group M (FANCM). The SPAG1 allele is inherited from the mother. The parents are consanguine.