Zhang, QianDorgham, KarimSchlüter, AgathaQuiros Roldan, EugeniaNovelli, GiuseppePlanas Serra, LauraRodríguez Palmero, AgustíCOVID-STORM CliniciansCOVID CliniciansImagine COVID GroupFrench COVID Cohort Study GroupCoV-Contact CohortAmsterdam UMC Covid-19 BiobankCOVID Human Genetic EffortNIAID-USUHS/TAGC COVID Immunity Group2021-02-092021-02-092020-10-23https://hdl.handle.net/2445/173758Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3-and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.14 p.application/pdfengcc by (c) Zhang et al., 2020http://creativecommons.org/licenses/by/3.0/es/SARS-CoV-2COVID-19SARS-CoV-2COVID-19info:eu-repo/semantics/article2021-02-08info:eu-repo/semantics/openAccess32972995