Matuozzo D.Talouarn E.Marchal A.Zhang P.Manry J.Seeleuthner Y.Zhang Y.Bolze A.Chaldebas M.Milisavljevic B.Gervais A.Bastard P.Asano T.Bizien L.Barzaghi F.Abolhassani H.Tayoun A.A.Aiuti A.Darazam I.A.Allende L.M.Alonso-Arias R.Arias A.A.Aytekin G.Bergman P.Bondesan S.Bryceson Y.T.Bustos I.G.Cabrera-Marante O.Carcel S.Carrera P.Casari G.Chaïbi K.Colobran R.Condino-Neto A.Covill L.E.Delmonte O.M.Zein L.E.Flores C.Gregersen P.K.Gut M.Haerynck F.Halwani R.Hancerli S.Hammarström L.Hatipoğlu N.Karbuz A.Keles S.Kyheng C.Leon-Lopez R.Franco J.L.Mansouri D.Martinez-Picado J.Akcan O.M.Migeotte I.Morange P.-E.Morelle G.Martin-Nalda A.Novelli G.Novelli A.Özçelik TayfunPalabiyik F.Pan-Hammarström Q.de Diego R.P.Planas-Serra L.Pleguezuelo D.E.Prando C.Pujol A.Reyes L.F.Rivière J.G.Rodriguez-Gallego C.Rojas J.Rovere-Querini P.Schlüter A.Shahrooei M.Sobh A.Soler-Palacin P.Tandjaoui-Lambiotte Y.Tipu I.Tresoldi C.Troya J.van de Beek D.Zatz M.Zawadzki P.Al-Muhsen S.Z.Alosaimi M.F.Alsohime F.M.Baris-Feldman H.Butte M.J.Constantinescu S.N.Cooper M.A.Dalgard C.L.Fellay J.Heath J.R.Lau Y.-L.Lifton R.P.Maniatis T.Mogensen T.H.von Bernuth H.Lermine A.Vidaud M.Boland A.Deleuze J.-F.Nussbaum R.Kahn-Kirby A.Mentre F.Tubiana S.Gorochov G.Tubach F.Hausfater P.Meyts I.Zhang S.-Y.Puel A.Notarangelo L.D.Boisson-Dupuis S.Su H.C.Boisson B.Jouanguy E.Casanova J.-L.Zhang Q.Abel L.Cobat A.2024-03-142024-03-142023-04-05https://hdl.handle.net/11693/114738Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7 dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identifed in~80% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results No gene reached genome-wide signifcance. Under a recessive model, the most signifcant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P=1.1× 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 infuenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3–8.2], P=2.1× 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1–2635.4], P=3.4× 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3–8.4], P=7.7× 10−8). Finally, the patients with pLOF/ bLOF variants at these 15 loci were signifcantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68× 10−5). Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.EnglishRare variantsCOVID-19ImmunityType I interferonArticle10.1186/s13073-023-01173-81756-994X