Solanich, XavierVargas Parra, Gardenía MaríaVan Der Made, Caspar I.Simons, AnnetSchuurs Hoeijmakers, Janneke H.M.Antolí, ArnauValle, Jesús delRocamora Blanch, GemmaSetién, FernandoEsteller, Manel, 1968-Van Reijmersdal, Simon V.Riera Mestre, AntoniSabater Riera, JoanCapellá, G. (Gabriel)Van De Veerdonk, Frank L.Van Der Hoven, BenCorbella, XavierHoischen, AlexanderLázaro García, Conxi2021-09-102021-09-102021-07-23https://hdl.handle.net/2445/179929Introduction: Loss-of-function TLR7 variants have been recently reported in a small number of males to underlie strong predisposition to severe COVID-19. We aimed to determine the presence of these rare variants in young men with severe COVID-19. Methods: We prospectively studied males between 18 and 50 years-old without predisposing comorbidities that required at least high-flow nasal oxygen to treat COVID-19. The coding region of TLR7 was sequenced to assess the presence of potentially deleterious variants. Results: TLR7 missense variants were identified in two out of 14 patients (14.3%). Overall, the median age was 38 (IQR 30-45) years. Both variants were not previously reported in population control databases and were predicted to be damaging by in silico predictors. In a 30-year-old patient a maternally inherited variant [c.644A>G; p.(Asn215Ser)] was identified, co-segregating in his 27-year-old brother who also contracted severe COVID-19. A second variant [c.2797T>C; p.(Trp933Arg)] was found in a 28-year-old patient, co-segregating in his 24-year-old brother who developed mild COVID-19. Functional testing of this variant revealed decreased type I and II interferon responses in peripheral mononuclear blood cells upon stimulation with the TLR7 agonist imiquimod, confirming a loss-of-function effect. Conclusions: This study supports a rationale for the genetic screening for TLR7 variants in young men with severe COVID-19 in the absence of other relevant risk factors. A diagnosis of TLR7 deficiency could not only inform on treatment options for the patient, but also enables pre-symptomatic testing of at-risk male relatives with the possibility of instituting early preventive and therapeutic interventions.10 p.application/pdfengcc by (c) Solanich, Xavier et al., 2021http://creativecommons.org/licenses/by/3.0/es/COVID-19SARS-CoV-2Cribatge genèticImmunodeficiènciaCOVID-19SARS-CoV-2Genetic screeningImmunodeficiencyinfo:eu-repo/semantics/article7161202021-09-10info:eu-repo/semantics/openAccess34367187