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    2 Comments for this article
    Great Analysis
    Khalid Alawfi, Cardiologist | AFH, Muscat, Oman
    I think this is great work. I wish that larger number of patients were included. I would suggest in a next study that patients who have no comorbidities and who succumb to an unexpectedly severe form of COVID-19 are included, with study of all possible & common genetic variants that might help us predict the clinical course of such patients. In our hospital for example we had one family where affected non-comorbid patients succumbed to a severe illness and died. So it is extremely important that we study certain families for these variants. Excellent job.
    Errors in labelling of eFigure 6.
    David Curtis, MD PhD | UCL Genetics Institute, University College London
    I'm afraid I can't make sense at all of the labelling of the subjects in eFigure 6. The legend refers to a single patient and a number of "negative controls" but the columns seem to be labelled with what look like two cases and two parents and a control. It's just impossible to work out.

    Incidentally, it would be very nice if they could find male relatives who had these variants so they could look at imiquimod response in them.

    There is a mistake in the statistics. The probability of having a qualifying variant is given as (about)
    1.0e-3. The probability of two unrelated both males having a qualifying variant would be the square of this, 1.0e-6. In fact, it's hard to predict the effect of missense variants but they might be better off quoting the probability for a male subject to have a loss-of-function variant. These are quite rare in this gene - from gnomAD about 2e-5. Whether the missense one is doing anything is hard to tell without functional studies. Which is what eFigure 6 is supposed to show but at the moment it's uninterpretable.
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    Preliminary Communication
    July 24, 2020

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

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


    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.