Zena and Michael A. Weiner Cardiovascular Institute (A.R.K.), Icahn School of Medicine at Mount Sinai, New York.
Institute for Genomic Health (A.R.K.), Icahn School of Medicine at Mount Sinai, New York.
Circ Genom Precis Med. 2021 Aug;14(4):e003426. doi: 10.1161/CIRCGEN.121.003426. Epub 2021 Jul 6.
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.
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.
DV were identified in 4 of 24 AM cases (16.7%), compared with 2 of 96 age and ancestry-matched controls (2.1%, =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.
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.
急性心肌炎（AM）是导致猝死和心力衰竭的常见原因，通常由流行病毒引起。我们之前的研究表明，一些儿科 AM 与可能导致心肌细胞结构和功能损伤的变体有关。我们试图评估与纽约市的匹配对照相比，致命性儿科 AM 病例中是否存在有害的心肌病变体。
通过尸检记录确定了 24 例因 AM 而死亡的儿童（年龄 3 周至 20 岁）；通过组织学检查确认所有病例均符合达拉斯 AM 标准，并对 57 个心肌病基因进行靶向面板测序。从儿科数据库中确定无心血管疾病的对照，并使用外显子组测序的主成分对病例进行遗传背景匹配。比较病例和对照之间假定有害变异（DV）的发生率。在有条件的情况下，对 AM 组织进行聚合酶链反应的病毒分析。
24 例 AM 病例中有 4 例（16.7%）存在 DV，而 96 例年龄和遗传背景匹配的对照中仅有 2 例（2.1%，=0.014）。对 8 例 AM 病例中的 6 例（75%）进行了病毒病因检测，其中 1 例有 DV 的病例进行了组织检测。与 DV-病例相比，DV+病例更可能为女性，无慢性炎症证据，与心源性猝死相关。
与对照相比，致命性 AM 患儿中与心肌细胞完整性相关的基因中存在更多的有害变体，可能导致易感性。此外，遗传介导的 AM 可能进展更快且更严重。
