Background:Acute myocarditis (AM) is a well-known cause of sudden death and heart failure, often caused by prevalent viruses. We previously showed that some pediatric AM correlates with putatively damaging variants in genes related to cardiomyocyte structure and function. We sought to evaluate whether deleterious cardiomyopathic variants were enriched among fatal pediatric AM cases in New York City compared with ancestry-matched controls.Methods:Twenty-four children (aged 3 weeks to 20 years) with death due to AM were identified through autopsy records; histologies were reviewed to confirm that all cases met Dallas criteria for AM and targeted panel sequencing of 57 cardiomyopathic genes was performed. Controls without cardiovascular disease were identified from a pediatric database and matched by genetic ancestry to cases using principal components from exome sequencing. Rates of putative deleterious variations (DV) were compared between cases and controls. Where available, AM tissues underwent viral analysis by polymerase chain reaction.Results:DV were identified in 4 of 24 AM cases (16.7%), compared with 2 of 96 age and ancestry-matched controls (2.1%, P=0.014). Viral causes were proven for 6 of 8 AM cases (75%), including the one DV+ case where tissue was available for testing. DV+ cases were more likely to be female, have no evidence of chronic inflammation, and associate with sudden cardiac death than DV− cases.Conclusions:Deleterious variants in genes related to cardiomyocyte integrity are more common in children with fatal AM than controls, likely conferring susceptibility. Additionally, genetically mediated AM may progress more rapidly and be more severe.

中文翻译：

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致死性小儿心肌炎心肌病遗传变异的负担

背景：急性心肌炎 (AM) 是众所周知的猝死和心力衰竭原因，通常由流行的病毒引起。我们之前表明，一些儿科 AM 与假定的与心肌细胞结构和功能相关的基因中的破坏性变异相关。我们试图评估与血统匹配的对照相比，纽约市致命的儿科 AM 病例中有害的心肌病变异是否富集。方法：通过尸检记录确定了 24 名因 AM 死亡的儿童（3 周至 20 岁） ; 审查组织学以确认所有病例均符合达拉斯的 AM 标准，并进行了 57 个心肌病基因的靶向面板测序。从儿科数据库中识别出没有心血管疾病的对照，并通过遗传血统与使用外显子组测序的主要成分的病例进行匹配。在病例和对照之间比较了假定有害变异 (DV) 的发生率。在可用的情况下，AM 组织通过聚合酶链反应进行病毒分析。结果：DV 在 24 例 AM 病例中的 4 例 (16.7%) 中发现，而 96 例年龄和血统匹配的对照组中有 2 例 (2.1%,P = 0.014）。8 AM 病例中有 6 例 (75%) 证实了病毒原因，包括 1 例 DV+ 病例，其中组织可用于测试。与 DV- 病例相比，DV+ 病例更可能是女性，没有慢性炎症的证据，并且与心源性猝死相关。结论：与心肌细胞完整性相关的基因中的有害变异在致死性 AM 的儿童中比对照组更常见，可能赋予敏感性。此外，基因介导的 AM 可能进展更快且更严重。