AUTHOR=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 , Capellá Gabriel , van de Veerdonk Frank L. , van der Hoven Ben , Corbella Xavier , Hoischen Alexander , Lázaro Conxi TITLE=Genetic Screening for TLR7 Variants in Young and Previously Healthy Men With Severe COVID-19 JOURNAL=Frontiers in Immunology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.719115 DOI=10.3389/fimmu.2021.719115 ISSN=1664-3224 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.