Presence of Genetic Variants Among Young Men With Severe COVID-19
Presence of Genetic Variants Among Young Men With Severe COVID-19
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DOI：
10.1001/jama.2020.13719
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发表时间：
2020-08-18
影响因子：
120.7
通讯作者：
Hoischen, Alexander
中科院分区：
文献类型：
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作者：
van der Made, Caspar I.;Simons, Annet;Hoischen, Alexander
本病例系列描述了荷兰 4 名因 2019 年严重冠状病毒病 (COVID-19) 住院的年轻男性患者中与外周单核血细胞干扰素信号受损相关的罕见假定 X 染色体功能丧失变异。问题 年轻男性患者中的遗传变异是否与 2019 年严重冠状病毒病 (COVID-19) 相关？结果 在一个病例系列中，包括来自 2 个家庭的 4 名患有严重 COVID-19 的年轻男性患者，发现了 X 染色体 TLR7 的罕见功能丧失变异，以及 I 型和 II 型干扰素产生的免疫缺陷。意义 这些发现为了解 COVID-19 的发病机制提供了见解。 重要性 2019 年重症冠状病毒病 (COVID-19) 可能发生在没有既往病史的年轻患者（主要是男性）中。有些人可能患有原发性免疫缺陷，容易感染严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 引起的严重感染。目的 探讨年轻 COVID-19 患者中是否存在与原发性免疫缺陷相关的遗传变异。设计、背景和参与者 符合年轻人选择标准（年龄 T；p.[Val795Phe]）的无病史兄弟对系列病例。在患者的原代外周血单核细胞中，下游 I 型干扰素 (IFN) 信号转导转录下调，与家庭成员和对照相比，TLR7 激动剂咪喹莫特刺激后 IRF7、IFNB1 和 ISG15 的 mRNA 表达显着降低。患者对咪喹莫特的刺激产生的 IFN-γ（一种 II 型干扰素）的产生减少。结论和相关性 在这个由 4 名患有严重 COVID-19 的年轻男性患者组成的病例系列中，发现了 X 染色体 TLR7 的罕见假定功能丧失变异，这些变异与 I 型和 II 型 IFN 反应受损相关。这些初步发现为了解 COVID-19 的发病机制提供了见解。
This case series describes rare putative X-chromosomal loss-of-function variants associated with impaired peripheral mononuclear blood cell interferon signaling in 4 young male patients hospitalized with severe coronavirus disease 2019 (COVID-19) in the Netherlands.Question Are genetic variants associated with severe coronavirus disease 2019 (COVID-19) in young male patients? Findings In a case series that included 4 young male patients with severe COVID-19 from 2 families, rare loss-of-function variants of the X-chromosomal TLR7 were identified, with immunological defects in type I and II interferon production. Meaning These findings provide insights into the pathogenesis of COVID-19.Importance Severe coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objective To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19. Design, Setting, and Participants Case series of pairs of brothers without medical history meeting the selection criteria of young (age T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7, IFNB1, and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-gamma, a type II IFN, was decreased in patients in response to stimulation with imiquimod. Conclusions and Relevance In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.