Mechanisms underlying genetic susceptibility to multisystem inflammatory syndrome in children (MIS-C).
Mechanisms underlying genetic susceptibility to multisystem inflammatory syndrome in children (MIS-C).
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儿童多系统炎症综合征遗传易感性的潜在机制（MIS-C）。
DOI：
10.1016/j.jaci.2021.06.024
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Taking on COVID-19 Together Study Investigators
中科院分区：
文献类型：
--
作者：
Chou J;Platt CD;Habiballah S;Nguyen AA;Elkins M;Weeks S;Peters Z;Day-Lewis M;Novak T;Armant M;Williams L;Rockowitz S;Sliz P;Williams DA;Randolph AG;Geha RS;Taking on COVID-19 Together Study Investigators
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。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。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。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 缺陷的患者即使在康复后也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。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。
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. We aimed to identify additional genetic mechanisms underlying susceptibility to severe acute respiratory syndrome coronavirus 2–associated MIS-C. 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. 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. 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.
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影响因子：
3.4
作者：
Marsh, Rebecca A.;Villanueva, Joyce;Zhang, Kejian;Snow, Andrew L.;Su, Helen C.;Madden, Lisa;Mody, Rajen;Kitchen, Brenda;Marmer, Dan;Jordan, Michael B.;Risma, Kimberly A.;Filipovich, Alexandra H.;Bleesing, Jack J.
通讯作者：
Bleesing, Jack J.
影响因子：
15.9
作者：
van de Geer, Annemarie;Nieto-Patlan, Alejandro;Bustamante, Jacinta
通讯作者：
Bustamante, Jacinta
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
DOI：
10.1126/science.abc6261
发表时间：
2020-09-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Arunachalam PS;Wimmers F;Mok CKP;Perera RAPM;Scott M;Hagan T;Sigal N;Feng Y;Bristow L;Tak-Yin Tsang O;Wagh D;Coller J;Pellegrini KL;Kazmin D;Alaaeddine G;Leung WS;Chan JMC;Chik TSH;Choi CYC;Huerta C;Paine McCullough M;Lv H;Anderson E;Edupuganti S;Upadhyay AA;Bosinger SE;Maecker HT;Khatri P;Rouphael N;Peiris M;Pulendran B
通讯作者：
Pulendran B
影响因子：
3.8
作者：
Wada, Taizo;Kanegane, Hirokazu;Yachie, Akihiro
通讯作者：
Yachie, Akihiro