[I-AEPCJS-02] Pathogenic Variants Associated with Dilated Cardiomyopathy Predict Outcome in Pediatric Myocarditis – Results from a MYKKE registry subgroup
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. MYKKE-registry is the world largest prospective cohort for patients ≤18 years with myocarditis, founded in 2013.
METHODS: From more than 740 patients from the MYKKE registry a subcohort 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 (N-DCM) and 20 patients with myocarditis with phenotype of (DCM).
RESULTS: Myocarditis with phenotype of DCM patients (median age 1.4 years) were younger than myocarditis without phenotype of (N-DCM) (median age 16.1 years; P<0.001) patients 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: MYKKE is the biggest registry with standardized clinical protocol and characterization of patients with myocarditis (≤18 years). We report for this pediatric subgroup (n=42) heterozygous likely pathogenic/pathogenic variants in biopsy-proven 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.
METHODS: From more than 740 patients from the MYKKE registry a subcohort 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 (N-DCM) and 20 patients with myocarditis with phenotype of (DCM).
RESULTS: Myocarditis with phenotype of DCM patients (median age 1.4 years) were younger than myocarditis without phenotype of (N-DCM) (median age 16.1 years; P<0.001) patients 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: MYKKE is the biggest registry with standardized clinical protocol and characterization of patients with myocarditis (≤18 years). We report for this pediatric subgroup (n=42) heterozygous likely pathogenic/pathogenic variants in biopsy-proven 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.