biostudies-literatureAsano TIntramural NIH HHSNCATS NIH HHSHoward Hughes Medical InstituteNIAID NIH HHSMedical Research CouncilNHGRI NIH HHSeabl4348https://www.ebi.ac.uk/biostudies/studies/S-EPMC8532080biostudies-literatureUnknown6(62)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 <i>TLR7</i> variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 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 <i>TLR7</i> variants (<i>p</i> = 3.5 × 10^-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (<i>n</i>=2, 5 and 38 years), or moderate (<i>n</i>=1, 5 years), severeScience immunologyX-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19.PMC8532080ZIA AI001265ZIA AI001270R01 AI0883641Z1 AA1001265UL1 TR001866R01 AI163029MR/S032304/1UL1 TR001863U24 HG008956UM1 HG006504Foti GSancho-Shimizu VArquero MFvan der Poll TAccordino GCarrabba MHraiech SWouters DGagro ABulle EBarzagh FKlocperk AGervais ARodriguez-Gallego CHorn JBilguvar KChristele KSaks KHorcajada JPTaupin JLSukumar GVught LARedin CSpaan ANDesguerre ISchluter AStepanovskiy YOlyaei NACiterio GLevi HBehilill SJimeno MTDe Munter PLaine FSeeleuthner YTipu IMeyts IAnnereau JPReyes LFHeath JRUddin MJKouakam CColobran RSchrauwen FAPHeppekcan DRebillat ASMontagne Svan Vugt MMunoz-Barrera AHalwani RAngoulvant FMogensen THSlabbynck HPalabiyik FMircher CVincent ABeudel 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life-threatening COVID-19.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 <i>TLR7</i> variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 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 <i>TLR7</i> variants (<i>p</i> = 3.5 × 10^-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (<i>n</i>=2, 5 and 38 years), or moderate (<i>n</i>=1, 5 years), severe2021-01-01T00:00:00Z2021 Aug2025-05-18T12:35:36.008Z2025-04-07T10:43:22.612ZS-EPMC85320803441314010.1126/sciimmunol.abl4348