Background: COVID-19 clinical presentation ranges from asymptomatic to fatal outcome. This variability is due in part to host genome specific mutations. Recently, two families in which COVID-19 segregates like an X-linked recessive monogenic disorder environmentally conditioned by SARS-CoV-2 have been reported leading to identification of loss-of-function variants in TLR7. Objective: We sought to determine whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients. Methods: We compared male subjects with extreme phenotype selected from the Italian GEN-COVID cohort of 1178 SARS-CoV-2-infected subjects (<60y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on the young male subset, picking up TLR7 as the most important susceptibility gene. Results: Rare TLR7 missense variants were predicted to impact on protein function in severely affected males and in none of the asymptomatic subjects. We then investigated a similar white European cohort in Spain, confirming the impact of TRL7 variants. A gene expression profile analysis in peripheral blood mononuclear cells after stimulation with TLR7 agonist demonstrated a reduction of mRNA level of TLR7, IRF7, ISG15, IFN-ɑ and IFN-γ in COVID-19 patients compared with unaffected controls demonstrating an impairment in type I and II INF responses. Conclusion: Young males with TLR7 loss-of-function mutations and severe COVID-19 in the two reported families represent only a fraction of a broader and complex host genome situation. Specifically, missense mutations in the X-linked recessive TLR7 disorder may significantly contribute to disease susceptibility in up to 4% of severe COVID-19.

中文翻译：

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Toll样受体7变异与男性威胁生命的COVID-19疾病的关联

背景：COVID-19的临床表现范围从无症状到致命。这种可变性部分归因于宿主基因组特异性突变。近来，已经报道了两个家族，其中COVID-19像由SARS-CoV-2环境调节的X连锁隐性单基因疾病一样分离，导致鉴定TLR7中功能丧失的变异。目的：我们试图确定这两个家族是否代表部分COVID-19男性患者的冰山一角。方法：我们比较了来自意大利GEN-COVID队列中1178名SARS-CoV-2感染受试者的极端表型的男性受试者（<60y，79例严重病例与77例对照病例）。我们应用了LASSO Logistic回归分析，仅考虑了年轻男性子集上的罕见变体，选择TLR7作为最重要的易感基因。结果：罕见的TLR7错义变体预计会在受严重影响的男性中和没有症状的受试者中影响蛋白质功能。然后，我们在西班牙调查了一个类似的欧洲白人队列，确认了TRL7变体的影响。对TLR7激动剂刺激后外周血单核细胞的基因表达谱分析表明，与未受影响的对照组相比，COVID-19患者的TLR7，IRF7，ISG15，IFN-γ和IFN-γmRNA水平降低，表明I型受损和II INF反应。结论：两个报告的家族中具有TLR7功能丧失突变和严重COVID-19的年轻男性仅代表更广泛和复杂的宿主基因组情况的一小部分。特别，