TY - JOUR
T1 - Presence of Genetic Variants Among Young Men With Severe COVID-19
AU - van der Made, Caspar I.
AU - Simons, Annet
AU - Schuurs-Hoeijmakers, Janneke
AU - van den Heuvel, Guus
AU - Mantere, Tuomo
AU - Kersten, Simone
AU - van Deuren, Rosanne C.
AU - Steehouwer, Marloes
AU - van Reijmersdal, Simon V.
AU - Jaeger, Martin
AU - Hofste, Tom
AU - Astuti, Galuh
AU - Corominas Galbany, Jordi
AU - van der Schoot, Vyne
AU - van der Hoeven, Hans
AU - Hagmolen Of ten Have, Wanda
AU - Klijn, Eva
AU - van den Meer, Catrien
AU - Fiddelaers, Jeroen
AU - de Mast, Quirijn
AU - Bleeker-Rovers, Chantal P.
AU - Joosten, Leo A. B.
AU - Yntema, Helger G.
AU - Gilissen, Christian
AU - Nelen, Marcel
AU - van der Meer, Jos W. M.
AU - Brunner, Han G.
AU - Netea, Mihai G.
AU - van de Veerdonk, Frank L.
AU - Hoischen, Alexander
N1 - Funding Information:
Drs Gillissen, Brunner, and Hoischen are 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. Dr Netea was supported by an European Research Council Advanced Grant (No. 833247) and a Spinoza Grant of the Netherlands Organization for Scientific Research. Dr van de Veerdonk was supported by a ZonMW (The Netherlands Organization for Health Research and Development) Vidi grant (No. 91718351). Dr Mantere was supported by the Sigrid Jusélius Foundation. 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) and Radboud Institute for Molecular Life Sciences PhD grants (to Drs Hoischen and Netea).
Publisher Copyright:
© 2020 American Medical Association. All rights reserved.
PY - 2020/8/18
Y1 - 2020/8/18
N2 - This case series describes rare putative X-chromosomal loss-of-function variants associated with impaired peripheral mononuclear blood cell interferon signaling in 4 young male patients hospitalized with severe coronavirus disease 2019 (COVID-19) in the Netherlands.Question Are genetic variants associated with severe coronavirus disease 2019 (COVID-19) in young male patients? Findings In a case series that included 4 young male patients with severe COVID-19 from 2 families, rare loss-of-function variants of the X-chromosomal TLR7 were identified, with immunological defects in type I and II interferon production. Meaning These findings provide insights into the pathogenesis of COVID-19.Importance Severe coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objective To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19. Design, Setting, and Participants Case series of pairs of brothers without medical history meeting the selection criteria of young (age T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7, IFNB1, and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-gamma, a type II IFN, was decreased in patients in response to stimulation with imiquimod. Conclusions and Relevance In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.
AB - This case series describes rare putative X-chromosomal loss-of-function variants associated with impaired peripheral mononuclear blood cell interferon signaling in 4 young male patients hospitalized with severe coronavirus disease 2019 (COVID-19) in the Netherlands.Question Are genetic variants associated with severe coronavirus disease 2019 (COVID-19) in young male patients? Findings In a case series that included 4 young male patients with severe COVID-19 from 2 families, rare loss-of-function variants of the X-chromosomal TLR7 were identified, with immunological defects in type I and II interferon production. Meaning These findings provide insights into the pathogenesis of COVID-19.Importance Severe coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objective To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19. Design, Setting, and Participants Case series of pairs of brothers without medical history meeting the selection criteria of young (age T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7, IFNB1, and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-gamma, a type II IFN, was decreased in patients in response to stimulation with imiquimod. Conclusions and Relevance In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.
KW - SARS-COV-2
KW - INSIGHTS
KW - SARS
U2 - 10.1001/jama.2020.13719
DO - 10.1001/jama.2020.13719
M3 - Article
C2 - 32706371
SN - 0098-7484
VL - 324
SP - 663
EP - 673
JO - JAMA-Journal of the American Medical Association
JF - JAMA-Journal of the American Medical Association
IS - 7
ER -