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Título:	Genetic screening for TLR7 variants in young and previously healthy men with severe COVID-19
Autor/a:	Solanich, Xavier; Vargas-Parra, Gardenia; Van der Made, Caspar I.; Simons, Annet; Schuurs-Hoeijmakers, Janneke; Antolí, Arnau; Del Valle, Jesús; Rocamora-Blanch, Gemma; Setién, Fernando; Esteller, Manel; Van Reijmersdal, Simon V.; Riera-Mestre, Antoni; Sabater-Riera, Joan; Capellà, Gabriel; Van de Veerdonk, Frank L.; Van der Hoven, Ben; Corbella Virós, Xavier; Hoischen, Alexander; Lázaro, Conxi
Notas:	Introduction: 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.
Materia(s):	-COVID-19 (Malaltia) -Cribratge genètic -Tractament del pacient -Factors de risc -COVID-19 sever -COVID-19 -Cribado genético -Tratamiento del paciente -Factores de riesgo -COVID-19 severo -COVID-19 -Genetic screening -Patient treatment -Risk factors -COVID-19 severe -61 -616.9
Derechos:	© 2021 Solanich, Vargas-Parra, van der Made, Simons, Schuurs-Hoeijmakers, Antolí, del Valle, Rocamora-Blanch, Setién, Esteller, van Reijmersdal, Riera-Mestre, Sabater-Riera, Capellá, van de Veerdonk, van der Hoven, Corbella, Hoischen and Lázaro. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. https://creativecommons.org/licenses/by/4.0/
Tipo de documento:	Artículo Artículo - Versión publicada
Editor:	Frontiers Media S.A.
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