Background

Multisystem inflammatory syndrome in children (MIS-C) is a pediatric complication of severe acute respiratory syndrome coronavirus 2 infection that is characterized by multiorgan inflammation and frequently by cardiovascular dysfunction. It occurs predominantly in otherwise healthy children. We previously reported haploinsufficiency of suppressor of cytokine signaling 1 (SOCS1), a negative regulator of type I and II interferons, as a genetic risk factor for MIS-C.

Objectives

We aimed to identify additional genetic mechanisms underlying susceptibility to severe acute respiratory syndrome coronavirus 2–associated MIS-C.

Methods

In a single-center, prospective cohort study, whole exome sequencing was performed on patients with MIS-C. The impact of candidate variants was tested by using patients’ PBMCs obtained at least 7 months after recovery.

Results

We enrolled 18 patients with MIS-C (median age = 8 years; interquartile range = 5-12.25 years), of whom 89% had no conditions other than obesity. In 2 boys with no significant infection history, we identified and validated hemizygous deleterious defects in XIAP, encoding X-linked inhibitor of apoptosis, and CYBB, encoding cytochrome b-245, beta subunit. Including the previously reported SOCS1 haploinsufficiency, a genetic diagnosis was identified in 3 of 18 patients (17%). In contrast to patients with mild COVID-19, patients with defects in SOCS1, XIAP, or CYBB exhibit an inflammatory immune cell transcriptome with enrichment of differentially expressed genes in pathways downstream of IL-18, oncostatin M, and nuclear factor κB, even after recovery.

Conclusions

Although inflammatory disorders are rare in the general population, our cohort of patients with MIS-C was enriched for monogenic susceptibility to inflammation. Our results support the use of next-generation sequencing in previously healthy children who develop MIS-C.

中文翻译：

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儿童多系统炎症综合征遗传易感性的机制（MIS-C）

背景

儿童多系统炎症综合征 (MIS-C) 是严重急性呼吸综合征冠状病毒 2 感染的一种儿科并发症，其特征是多器官炎症和心血管功能障碍。它主要发生在其他方面健康的儿童中。我们之前报道过细胞因子信号传导抑制因子 1 (SOCS1)（I 型和 II 型干扰素的负调节因子）的单倍体不足，是 MIS-C 的遗传危险因素。

目标

我们的目的是确定与严重急性呼吸综合征冠状病毒 2 相关的 MIS-C 易感性的其他遗传机制。

方法

在一项单中心前瞻性队列研究中，对 MIS-C 患者进行了全外显子组测序。通过使用患者康复后至少 7 个月获得的 PBMC 来测试候选变异的影响。

结果

我们招募了 18 名 MIS-C 患者（中位年龄 = 8 岁；四分位数范围 = 5-12.25 岁），其中 89% 除肥胖外没有其他疾病。在 2 名没有明显感染史的男孩中，我们鉴定并验证了XIAP（编码 X 连锁凋亡抑制剂）和CYBB（编码细胞色素 b-245、β 亚基）的半合子有害缺陷。包括之前报道的 SOCS1 单倍体不足在内，18 名患者中有 3 名 (17%) 被确诊为基因诊断。与轻度 COVID-19 患者相比，SOCS1、XIAP 或 CYBB 缺陷的患者表现出炎症免疫细胞转录组，其中 IL-18、制瘤素 M 和核因子 κB 下游通路中的差异表达基因富集，即使在恢复。

结论

尽管炎症性疾病在普通人群中很少见，但我们的 MIS-C 患者队列富含对炎症的单基因易感性。我们的结果支持在患有 MIS-C 的既往健康儿童中使用新一代测序。