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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
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.

References
1.
Klompas  M , Baker  MA , Rhee  C .  Airborne transmission of SARS-CoV-2: theoretical considerations and available evidence.   JAMA. 2020. doi:10.1001/jama.2020.12458PubMedGoogle Scholar
2.
Richardson  S , Hirsch  JS , Narasimhan  M ,  et al; and the Northwell COVID-19 Research Consortium.  Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.   JAMA. 2020;323(20):2052-2059. doi:10.1001/jama.2020.6775PubMedGoogle ScholarCrossref
3.
Grasselli  G , Zangrillo  A , Zanella  A ,  et al; COVID-19 Lombardy ICU Network.  Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy.   JAMA. 2020;323(16):1574-1581. doi:10.1001/jama.2020.5394PubMedGoogle ScholarCrossref
4.
Guan  WJ , Ni  ZY , Hu  Y ,  et al; China Medical Treatment Expert Group for Covid-19.  Clinical characteristics of coronavirus disease 2019 in China.   N Engl J Med. 2020;382(18):1708-1720. doi:10.1056/NEJMoa2002032 PubMedGoogle ScholarCrossref
5.
Tay  MZ , Poh  CM , Rénia  L , MacAry  PA , Ng  LFP .  The trinity of COVID-19: immunity, inflammation and intervention.   Nat Rev Immunol. 2020;20(6):363-374. doi:10.1038/s41577-020-0311-8 PubMedGoogle ScholarCrossref
6.
Rijksinstituut voor Volksgezondheid en Milieu. Epidemiologische situatie COVID-19 in Nederland. Published May 14, 2020. Accessed May 15, 2020. https://www.rivm.nl/documenten/epidemiologische-situatie-covid-19-in-nederland-14-mei-2020
7.
Scully  EP , Haverfield  J , Ursin  RL , Tannenbaum  C , Klein  SL .  Considering how biological sex impacts immune responses and COVID-19 outcomes.   Nat Rev Immunol. 2020;20(7):442-447. doi:10.1038/s41577-020-0348-8 PubMedGoogle ScholarCrossref
8.
Marina  S , Piemonti  L . Gender and age effects on the rates of infection and deaths in individuals with confirmed SARS-CoV-2 infection in six European countries. SSRN. Preprint posted April 28, 2020.
9.
Green  MS , Swartz  N , Nitzan  D , Peer  V . The male excess in case-fatality rates for COVID-19: a meta-analytic study of the age-related differences and consistency over six countries. medRxiv. Preprint posted June 17, 2020. doi:10.1101/2020.06.11.20128439
10.
Deden  C , Neveling  K , Zafeiropopoulou  D ,  et al.  Rapid whole exome sequencing in pregnancies to identify the underlying genetic cause in fetuses with congenital anomalies detected by ultrasound imaging.   Prenat Diagn. 2020. doi:10.1002/pd.5717 PubMedGoogle Scholar
11.
Lelieveld  SH , Reijnders  MRF , Pfundt  R ,  et al.  Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.   Nat Neurosci. 2016;19(9):1194-1196. doi:10.1038/nn.4352 PubMedGoogle ScholarCrossref
12.
Arts  P , Simons  A , AlZahrani  MS ,  et al.  Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies.   Genome Med. 2019;11(1):38. doi:10.1186/s13073-019-0649-3 PubMedGoogle ScholarCrossref
13.
Bousfiha  A , Jeddane  L , Picard  C ,  et al.  Human inborn errors of immunity: 2019 update of the IUIS Phenotypical Classification.   J Clin Immunol. 2020;40(1):66-81. doi:10.1007/s10875-020-00758-x PubMedGoogle ScholarCrossref
14.
Hoischen  A , van Bon  BWM , Gilissen  C ,  et al.  De novo mutations of SETBP1 cause Schinzel-Giedion syndrome.   Nat Genet. 2010;42(6):483-485. doi:10.1038/ng.581 PubMedGoogle ScholarCrossref
15.
Oosting  M , Kerstholt  M , Ter Horst  R ,  et al.  Functional and genomic architecture of Borrelia burgdorferi-induced cytokine responses in humans.   Cell Host Microbe. 2016;20(6):822-833. doi:10.1016/j.chom.2016.10.006 PubMedGoogle ScholarCrossref
16.
Li  ZJ , Sohn  KC , Choi  DK ,  et al.  Roles of TLR7 in activation of NF-κB signaling of keratinocytes by imiquimod.   PLoS One. 2013;8(10):e77159. doi:10.1371/journal.pone.0077159 PubMedGoogle Scholar
17.
To  EE , Erlich  J , Liong  F ,  et al.  Intranasal and epicutaneous administration of toll-like receptor 7 (TLR7) agonists provides protection against influenza A virus-induced morbidity in mice.   Sci Rep. 2019;9(1):2366. doi:10.1038/s41598-019-38864-5 PubMedGoogle ScholarCrossref
18.
Kaplanis  J , Samocha  KE , Wiel  L ,  et al. Integrating healthcare and research genetic data empowers the discovery of 28 novel developmental disorders. bioRxiv. Preprint posted April 1, 2020. doi:10.1101/797787
19.
Cervantes-Barragan  L , Züst  R , Weber  F ,  et al.  Control of coronavirus infection through plasmacytoid dendritic-cell-derived type I interferon.   Blood. 2007;109(3):1131-1137. doi:10.1182/blood-2006-05-023770 PubMedGoogle ScholarCrossref
20.
Moreno-Eutimio  MA , López-Macías  C , Pastelin-Palacios  R .  Bioinformatic analysis and identification of single-stranded RNA sequences recognized by TLR7/8 in the SARS-CoV-2, SARS-CoV, and MERS-CoV genomes.   Microbes Infect. 2020;22(4-5):226-229. doi:10.1016/j.micinf.2020.04.009 PubMedGoogle ScholarCrossref
21.
Channappanavar  R , Fehr  AR , Zheng  J ,  et al.  IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes.   J Clin Invest. 2019;129(9):3625-3639. doi:10.1172/JCI126363 PubMedGoogle ScholarCrossref
22.
Lek  M , Karczewski  KJ , Minikel  EV ,  et al; Exome Aggregation Consortium.  Analysis of protein-coding genetic variation in 60,706 humans.   Nature. 2016;536(7616):285-291. doi:10.1038/nature19057 PubMedGoogle ScholarCrossref
23.
Karczewski  KJ , Francioli  LC , Tiao  G ,  et al; Genome Aggregation Database Consortium.  The mutational constraint spectrum quantified from variation in 141,456 humans.   Nature. 2020;581(7809):434-443. doi:10.1038/s41586-020-2308-7 PubMedGoogle ScholarCrossref
24.
Casanova  J-L , Abel  L .  Human genetics of infectious diseases: unique insights into immunological redundancy.   Semin Immunol. 2018;36:1-12. doi:10.1016/j.smim.2017.12.008 PubMedGoogle ScholarCrossref
25.
Casanova  J-L , Abel  L , Quintana-Murci  L .  Human TLRs and IL-1Rs in host defense: natural insights from evolutionary, epidemiological, and clinical genetics.   Annu Rev Immunol. 2011;29(1):447-491. doi:10.1146/annurev-immunol-030409-101335 PubMedGoogle ScholarCrossref
26.
Quach  H , Wilson  D , Laval  G ,  et al.  Different selective pressures shape the evolution of toll-like receptors in human and African great ape populations.   Hum Mol Genet. 2013;22(23):4829-4840. doi:10.1093/hmg/ddt335 PubMedGoogle ScholarCrossref
27.
Zhang  S-Y , Jouanguy  E , Ugolini  S ,  et al.  TLR3 deficiency in patients with herpes simplex encephalitis.   Science. 2007;317(5844):1522-1527. doi:10.1126/science.1139522 PubMedGoogle ScholarCrossref
28.
Casrouge  A , Zhang  S-Y , Eidenschenk  C ,  et al.  Herpes simplex virus encephalitis in human UNC-93B deficiency.   Science. 2006;314(5797):308-312. doi:10.1126/science.1128346 PubMedGoogle ScholarCrossref
29.
de Wit  E , van Doremalen  N , Falzarano  D , Munster  VJ .  SARS and MERS: recent insights into emerging coronaviruses.   Nat Rev Microbiol. 2016;14(8):523-534. doi:10.1038/nrmicro.2016.81 PubMedGoogle ScholarCrossref
30.
Blanco-Melo  D , Nilsson-Payant  BE , Liu  WC ,  et al.  Imbalanced host response to SARS-CoV-2 drives development of COVID-19.   Cell. 2020;181(5):1036-1045.e9. doi:10.1016/j.cell.2020.04.026 PubMedGoogle ScholarCrossref
31.
Hadjadj  J , Yatim  N , Barnabei  L ,  et al.  Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients.   Science. Published online July 13, 2020. doi:10.1126/science.abc6027 PubMedGoogle Scholar
32.
Acharya  D , Liu  G , Gack  MU .  Dysregulation of type I interferon responses in COVID-19.   Nat Rev Immunol. 2020;20(7):397-398. doi:10.1038/s41577-020-0346-x PubMedGoogle ScholarCrossref
33.
Ellinghaus  D , Degenhardt  F , Bujanda  L ,  et al; Severe Covid-19 GWAS Group.  Genomewide association study of severe Covid-19 with respiratory failure.   N Engl J Med. 2020. doi:10.1056/NEJMoa2020283 PubMedGoogle Scholar
34.
Meier  A , Chang  JJ , Chan  ES ,  et al.  Sex differences in the toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1.   Nat Med. 2009;15(8):955-959. doi:10.1038/nm.2004 PubMedGoogle ScholarCrossref
35.
Oh  DY , Baumann  K , Hamouda  O ,  et al.  A frequent functional toll-like receptor 7 polymorphism is associated with accelerated HIV-1 disease progression.   AIDS. 2009;23(3):297-307. doi:10.1097/QAD.0b013e32831fb540 PubMedGoogle ScholarCrossref
36.
Buschow  SI , Biesta  PJ , Groothuismink  ZMA ,  et al.  TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands.   Antiviral Res. 2018;157:27-37. doi:10.1016/j.antiviral.2018.06.015 PubMedGoogle ScholarCrossref
37.
Henmyr  V , Carlberg  D , Manderstedt  E ,  et al.  Genetic variation of the toll-like receptors in a Swedish allergic rhinitis case population.   BMC Med Genet. 2017;18(1):18. doi:10.1186/s12881-017-0379-6 PubMedGoogle ScholarCrossref
38.
Souyris  M , Cenac  C , Azar  P ,  et al.  TLR7 escapes X chromosome inactivation in immune cells.   Sci Immunol. 2018;3(19):eaap8855. doi:10.1126/sciimmunol.aap8855 PubMedGoogle Scholar
39.
Souyris  M , Mejía  JE , Chaumeil  J , Guéry  J-C .  Female predisposition to TLR7-driven autoimmunity: gene dosage and the escape from X chromosome inactivation.   Semin Immunopathol. 2019;41(2):153-164. doi:10.1007/s00281-018-0712-y PubMedGoogle ScholarCrossref
40.
Azar  P , Mejía  JE , Cenac  C ,  et al.  TLR7 dosage polymorphism shapes interferogenesis and HIV-1 acute viremia in women.   JCI Insight. 2020;5(12):136047. doi:10.1172/jci.insight.136047 PubMedGoogle Scholar
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