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

<jats:sec><jats:title>Introduction</jats:title><jats:p>Loss-of-function <jats:italic>TLR7</jats:italic> 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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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 <jats:italic>TLR7</jats:italic> was sequenced to assess the presence of potentially deleterious variants.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p><jats:italic>TLR7</jats:italic> 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 <jats:italic>in silico</jats:italic> predictors. In a 30-year-old patient a maternally inherited variant [c.644A&gt;G; p.(Asn215Ser)] was identified, co-segregating in his 27-year-old brother who also contracted severe COVID-19. A second variant [c.2797T&gt;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.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>This study supports a rationale for the genetic screening for <jats:italic>TLR7</jats:italic> 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.</jats:p></jats:sec>