Genetic Screening for TLR7 Variants in Young and Previously Healthy Men With Severe COVID-19

Xavier Solanich*, Gardenia Vargas-Parra, Caspar I. van der Made, Annet Simons, Janneke Schuurs-Hoeijmakers, Arnau Antolí, Jesús del Valle, Gemma Rocamora-Blanch, Fernando Setién, Manel Esteller, Simon V. van Reijmersdal, Antoni Riera-Mestre, Joan Sabater-Riera, Gabriel Capellá, Frank L. van de Veerdonk, Ben van der Hoven, Xavier Corbella, Alexander Hoischen, Conxi Lázaro

*Corresponding author for this work

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Abstract

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.

Original languageEnglish
Article number719115
JournalFrontiers in Immunology
Volume12
DOIs
Publication statusPublished - 23 Jul 2021

Bibliographical note

Funding Information:
We sincerely thank the patients and their families for their participation. With the support of COVID-19 funding from the Departament de Salut de la Generalitat de Catalunya. We thank CERCA Programme/Generalitat de Catalunya for institutional support, and the unstoppable campaign of the Josep Carreras Leukaemia Foundation and the Cellex Foundation. We also thank the Radboud Genomics Technology Center for their technical support.

Publisher Copyright:
© Copyright © 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.

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