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Presence of Genetic Variants Among Young Men With Severe COVID-19

Educational Objective
To understand the identifying genetic variants among young men with severe COVID-19 may provide additional insight into the pandemic

1 Credit CME

JAMA

Published Online: July 24, 2020

Preliminary Communication

Article Information and Disclosures

Caspar I. van der Made, MD^1,2,3,4;

Annet Simons, PhD¹;

Janneke Schuurs-Hoeijmakers, MD, PhD¹;

et al

Guus van den Heuvel, MD⁵;

Tuomo Mantere, PhD¹;

Simone Kersten, MSc^1,2,3;

Rosanne C. van Deuren, MSc^1,2,3;

Marloes Steehouwer, BSc¹;

Simon V. van Reijmersdal, BSc¹;

Martin Jaeger, PhD^2,3;

Tom Hofste, BSc¹;

Galuh Astuti, PhD¹;

Jordi Corominas Galbany, PhD¹;

Vyne van der Schoot, MD, PhD⁶;

Hans van der Hoeven, MD, PhD⁷;

Wanda Hagmolen of ten Have, MD, PhD⁵;

Eva Klijn, MD, PhD⁸;

Catrien van den Meer, MD⁹;

Jeroen Fiddelaers, MD¹⁰;

Quirijn de Mast, MD, PhD^2,3,4;

Chantal P. Bleeker-Rovers, MD, PhD^2,4,11;

Leo A. B. Joosten, PhD^2,3,4;

Helger G. Yntema, PhD^1,12;

Christian Gilissen, PhD^1,3;

Marcel Nelen, PhD¹;

Jos W. M. van der Meer, MD, PhD^2,3,4;

Han G. Brunner, MD, PhD^1,6,12,13;

Mihai G. Netea, MD, PhD^2,3,4,14;

Frank L. van de Veerdonk, MD, PhD^2,3,4;

Alexander Hoischen, PhD^1,2,3,4

Author Affiliations

¹Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
²Radboud University Medical Center Center for Infectious Diseases (RCI), Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
³Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
⁴Radboud Expertise Center for Immunodeficiency and Autoinflammation and Radboud Center for Infectious Disease (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
⁵Pulmonology Department, Radboud University Medical Center, Nijmegen, the Netherlands
⁶Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands
⁷Department of Intensive Care, Radboud University Medical Center Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands
⁸Department of Intensive Care, Erasmus Medical Center, Rotterdam, the Netherlands
⁹Department of Intensive Care, Ziekenhuis Rivierenland, Tiel, the Netherlands
¹⁰Department of Pulmonology, Admiraal de Ruyter Ziekenhuis, Goes, the Netherlands
¹¹Radboud Institute Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
¹²Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
¹³GROW School of Oncology and developmental biology, and MHeNs School of Mental Health and Neuroscience, Maastricht University, the Netherlands
¹⁴Immunology and Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany

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Key Points

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.

Abstract

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 <35 years) brother pairs admitted to the intensive care unit (ICU) due to severe COVID-19. Four men from 2 unrelated families were admitted to the ICUs of 4 hospitals in the Netherlands between March 23 and April 12, 2020. The final date of follow-up was May 16, 2020. Available family members were included for genetic variant segregation analysis and as controls for functional experiments.

Exposure Severe COVID-19.

Main Outcome and Measures Results of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Subsequently, basic genetic and immunological tests were performed in primary immune cells isolated from the patients and family members to characterize any immune defects.

Results The 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomal TLR7. In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c.2383G>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-γ, 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.

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Article Information

Corresponding Author: Alexander Hoischen, PhD, Department of Human Genetics and Department of Internal Medicine, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, the Netherlands (Alexander.Hoischen@radboudumc.nl).

Accepted for Publication: July 10, 2020.

Published Online: July 24, 2020. doi:10.1001/jama.2020.13719

Author Contributions: Dr Hoischen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs van de Veerdonk and Hoischen contributed equally.

Concept and design: van der Made, Simons, Schuurs-Hoeijmakers, van der Schoot, J. van der Meer, Brunner, Netea, van de Veerdonk, Hoischen.

Acquisition, analysis, or interpretation of data: van der Made, Simons, Schuurs-Hoeijmakers, van den Heuvel, Mantere, Kersten, van Deuren, Steehouwer, van Reijmersdal, Jaeger, Hofste, Astuti, Corominas Galbany, van der Hoeven, Hagmolen of ten Have, Klijn, C. van der Meer, Fiddelaers, de Mast, Bleeker-Rovers, Joosten, Yntema, J. van der Meer, Gilissen, Nelen, Brunner, van de Veerdonk, Hoischen.

Drafting of the manuscript: van der Made, Simons, Schuurs-Hoeijmakers, van Deuren, Steehouwer, van Reijmersdal, Hofste, Astuti, Corominas Galbany, van der Schoot, van der Hoeven, Hagmolen of ten Have, Klijn, C. van der Meer, Fiddelaers, Bleeker-Rovers, Yntema, Nelen, Brunner, van de Veerdonk, Hoischen.

Critical revision of the manuscript for important intellectual content: van der Made, Simons, Schuurs-Hoeijmakers, van den Heuvel, Mantere, Kersten, Jaeger, van der Hoeven, C. van der Meer, de Mast, Joosten, J. van der Meer, Gilissen, Brunner, Netea, van de Veerdonk, Hoischen.

Statistical analysis: van der Made, van Deuren, Gilissen.

Obtained funding: Hoischen.

Administrative, technical, or material support: Simons, Schuurs-Hoeijmakers, van den Heuvel, Kersten, Steehouwer, van Reijmersdal, Jaeger, Hofste, Astuti, Corominas Galbany, van der Schoot, Hagmolen of ten Have, Klijn, C. van der Meer, Fiddelaers, J. van der Meer, Nelen.

Supervision: Schuurs-Hoeijmakers, de Mast, Yntema, J. van der Meer, Netea, van de Veerdonk, Hoischen.

Conflict of Interest Disclosures: Dr Joosten reported being a scientific founder of Trained Therapeutic Discovery and a scientific advisory board member of Olatec Therapeutics. Dr Netea reported being a scientific founder of Trained Therapeutic Discovery and receiving grants from ViiV HealthCare outside the submitted work. No other disclosures were reported.

Funding/Support: Ms Steehouwer and 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).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank the patients and their families for their participation. We thank Radboud University Medical Center (RUMC) personnel: W. Melchers, PhD; S. D. van der Velde-Visser; M. M. H. M. Jacobs-Camps, M. van de Vorst, BSc; G. Khazeeva, MSc; all colleagues of the multidisciplinary immuno-exome sign-out meeting (MDO); all colleagues of the diagnostic primary immunodeficiency–exome interpretation group, in particular: J. H. S. Diepstra, BSc, E. P. D. Hoenselaar, BSc, and M. Weiss, PhD; the COVID-19 clinical team, in particular: W. Hoefsloot, MD, PhD, J. Hoogerwerf, MD, PhD, M. Reijers, MD, PhD; the Radboud University Medical Center Center for Infectious Diseases (RCI) COVID-19 team; and all colleagues at the Laboratory for Experimental Internal Medicine, in particular H. Lemmers, BSc, F. Weren, MSc, H. Dijkstra, BSc, L. van Emst, BSc, and L. Fransman, BSc. We also thank R. A. Willemze, MD, PhD, Viroscience, Erasmus MC, Rotterdam, the Netherlands. None of the persons indicated above received compensation for their role in the study.

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