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.
【저자키워드】 COVID-19, SARS-CoV-2, host genetics, TLR7, immunodeficiency, genetic screening, 【초록키워드】 Treatment, Risk factors, severe COVID-19, Genetic, variant, Comorbidities, TLR7, genetic screening, interferon, Diagnosis, High-flow nasal oxygen, Comorbidity, oxygen, Blood cells, predictors, in silico, database, variants, pre-symptomatic, male, Patient, Mild, age, interferon response, imiquimod, Stimulation, Deleterious, blood cell, Support, deficiency, type I, median age, rationale, coding region, therapeutic interventions, treat, loss-of-function, predisposition, missense variant, men, Result, predicted, sequenced, reported, the patient, required, determine, absence, underlie, rare variant, IQR, prospectively studied, the median, 【제목키워드】 genetic screening, Screening,