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.

中文翻译：

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与扩张型心肌病相关的致病变异可预测小儿心肌炎的预后

背景：心肌炎是导致儿童心力衰竭的最常见原因之一，并且可能存在遗传背景。我们试图描述 18 岁以下心肌炎患者的临床和遗传特征以预测结果。方法：一组 42 名经活检证实为心肌炎的患者（儿童心肌炎的遗传学）接受了基因检测，并对心肌病进行了靶向面板测序-相关基因。小儿心肌炎患者的遗传学根据就诊时扩张型心肌病（DCM）的表型分为亚组，其中无DCM（无DCM表型的心肌炎）22例和有DCM（有DCM表型的心肌炎）患者20例。 结果：具有 DCM 表型的心肌炎患者（中位年龄 1.P <0.001），分别对应于心力衰竭样和冠状动脉综合征样表型。在 42 名患者中的 9 名（22%）中至少发现了一种可能的致病/致病变异，其中 8 人是杂合子，9 人中有 7 人患有具有 DCM 表型的心肌炎。在原发性 DCM 验证的基因（ BAG3、DSP、LMNA、MYH7、TNNI3、TNNT2和TTN）中发现了可能的致病/致病变异。罕见变异富集分析显示，与健康个体相比，具有 DCM 表型的心肌炎中高影响疾病变异的显着积累（P = 0.0003）。无事件生存期较低（P= 0.008）在具有 DCM 表型的心肌炎患者中与没有 DCM 表型的心肌炎和原发性 DCM 患者相比。结论：我们报告了经活检证实的儿童心肌炎中可能存在杂合的致病/致病变异。具有 DCM 表型的心肌炎患者的特征是早发性心力衰竭、可能的致病/致病变异显着富集以及预后不良。这些特定表型和特定年龄组的发现将有助于这些患者的个性化管理。有必要对新诊断为心肌炎和 DCM 表型的儿童进行基因评估。