Genetic Screening for TLR7 Variants in Young and Previously Healthy Men With Severe COVID-19
| Autor: | 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 |
|---|---|
| Přispěvatelé: | Intensive Care |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Functional testing lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] Imiquimod COVID-19 (Malaltia) Cribado genético COVID-19 severe Cancer development and immune defence Radboud Institute for Health Sciences [Radboudumc 2] 0302 clinical medicine Immunology and Allergy Missense mutation Immunodeficiency TLR7 medicine.diagnostic_test Cribratge genètic genetic screening COVID-19 severo Cribatge genètic Factores de riesgo medicine.drug Agonist medicine.medical_specialty 616.9 Factors de risc medicine.drug_class Immunology 03 medical and health sciences All institutes and research themes of the Radboud University Medical Center Tractament del pacient Internal medicine Severity of illness Genetic screening medicine Tratamiento del paciente COVID-19 sever Genetic testing Immunodeficiència Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] business.industry SARS-CoV-2 Patient treatment COVID-19 RC581-607 medicine.disease 030104 developmental biology Risk factors host genetics Immunologic diseases. Allergy business immunodeficiency 030217 neurology & neurosurgery |
| Zdroj: | Frontiers in Immunology, 12:719115. Frontiers Media S.A. Frontiers in Immunology, Vol 12 (2021) Frontiers in Immunology, 12 Dipòsit Digital de la UB Universidad de Barcelona |
| ISSN: | 1664-3224 |
| Popis: | Contract grant sponsor: the Carlos III National Health Institute funded by FEDER funds - a way to build Europe - [PI19/00553 and CIBERONC]; the Government of Catalonia [2017SGR1282 and 2017SGR496]. AH is supported by the Solve-RD project. The Solve-RD project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 779257. FV was supported by a ZonMW (The Netherlands Organization for Health Research and Development) Vidi grant (No. 91718351). This research was part of the Netherlands X-omics Initiative and partially funded by NWO (The Netherlands Organization for Scientific Research; project 184.034.019). 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 |
| Databáze: | OpenAIRE |
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