Frontiers in Immunology (Jul 2021)

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

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

DOI
https://doi.org/10.3389/fimmu.2021.719115
Journal volume & issue
Vol. 12

Abstract

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IntroductionLoss-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.MethodsWe 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.ResultsTLR7 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.ConclusionsThis 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.

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