2. Academic Validation
  3. Presence of Genetic Variants Among Young Men With Severe COVID-19

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

  • JAMA. 2020 Aug 18;324(7):663-673. doi: 10.1001/jama.2020.13719.
Caspar I van der Made 1 2 3 4,  Annet Simons 1,  Janneke Schuurs-Hoeijmakers 1,  Guus van den Heuvel 5,  Tuomo Mantere 1,  Simone Kersten 1 2 3,  Rosanne C van Deuren 1 2 3,  Marloes Steehouwer 1,  Simon V van Reijmersdal 1,  Martin Jaeger 2 3,  Tom Hofste 1,  Galuh Astuti 1,  Jordi Corominas Galbany 1,  Vyne van der Schoot 6,  Hans van der Hoeven 7,  Wanda Hagmolen Of Ten Have 5,  Eva Klijn 8,  Catrien van den Meer 9,  Jeroen Fiddelaers 10,  Quirijn de Mast 2 3 4,  Chantal P Bleeker-Rovers 2 4 11,  Leo A B Joosten 2 3 4,  Helger G Yntema 1 12,  Christian Gilissen 1 3,  Marcel Nelen 1,  Jos W M van der Meer 2 3 4,  Han G Brunner 1 6 12 13,  Mihai G Netea 2 3 4 14,  Frank L van de Veerdonk 2 3 4,  Alexander Hoischen 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 2 Radboud University Medical Center Center for Infectious Diseases (RCI), Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 3 Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 4 Radboud Expertise Center for Immunodeficiency and Autoinflammation and Radboud Center for Infectious Disease (RCI), Radboud University Medical Center, Nijmegen, the Netherlands.
  • 5 Pulmonology Department, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 6 Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands.
  • 7 Department of Intensive Care, Radboud University Medical Center Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands.
  • 8 Department of Intensive Care, Erasmus Medical Center, Rotterdam, the Netherlands.
  • 9 Department of Intensive Care, Ziekenhuis Rivierenland, Tiel, the Netherlands.
  • 10 Department of Pulmonology, Admiraal de Ruyter Ziekenhuis, Goes, the Netherlands.
  • 11 Radboud Institute Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 12 Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 13 GROW School of Oncology and developmental biology, and MHeNs School of Mental Health and Neuroscience, Maastricht University, the Netherlands.
  • 14 Immunology and Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany.
PMID: 32706371 DOI: 10.1001/jama.2020.13719
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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