Genotype count for all coding variants in type I IFN genes investigated in 659 life-threatening COVID-19 patients and 534 asymptomatic/mild infected controls

Clinical outcome upon infection with SARS-CoV-2 ranges from silent
infection to lethal 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 TLR3- and 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 define
LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying
autosomal recessive or dominant deficiencies. We show that human
fibroblasts with mutations affecting this pathway 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.