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X-linked COVID-19 risk factor: Age and male sex are two prominent risk factors for developing life-threatening COVID-19 after SARS-CoV-2 infection. Asano et al. analyzed 1202 critical male COVID-19 patients to examine whether non-synonymous variants in genes on the X chromosome are a risk factor for developing COVID-19 pneumonia. Toll-like receptor 7 (TLR7) variants resulting in TLR7 deficiency occurred in 16 unrelated males, most of which were under age 60. Plasmacytoid dendritic cells (pDCs), primary producers of type I interferon (IFN-I), from TLR7-deficient patients were unresponsive to TLR7 stimulation and displayed impaired production of IFN-I in response to SARS-CoV-2. These results identify X-linked recessive TLR7 deficiency as a genetic risk factor for COVID-19 pneumonia in males and demonstrate a key role for intact pDC IFN-I in protective immunity against SARS-CoV-2. Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean, 36.7 years) from a cohort of 1202 male patients aged 0.5 to 99 years (mean, 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean, 38.7 years) tested carry such TLR7 variants (P = 3.5 × 10−5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n = 2) or moderate (n = 1), severe (n = 1), or critical (n = 1) pneumonia. Two patients from a cohort of 262 male patients with severe COVID-19 pneumonia (mean, 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is <6.5 × 10−4. We show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7. The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract. [ABSTRACT FROM AUTHOR]