COVID-19: Rare variants increase the risk of severe COVID-19

Evidence is mounting that rare loss-of-function variants in the TLR7 gene predispose men with no medical history to severe forms of COVID-19.
  1. Frank L van de Veerdonk  Is a corresponding author
  2. Mihai G Netea
  1. Department of Internal Medicine, Radboudumc Center for Infectious Diseases, Netherlands
  2. Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Germany

COVID-19 is a disease that does not strike equally: while most individuals will experience no or only mild respiratory symptoms, a minority – including young patients in their 20s or 30s – will develop severe pneumonia and acute respiratory distress syndrome, sometimes resulting in death. Identifying the underlying factors that predispose to severe COVID-19, especially in young individuals, is crucial to initiate preventive measures and design treatment strategies for at-risk patients.

Accumulating evidence suggests that rare loss-of-function mutations in a single gene known as TLR7 could predispose men under 50 without known risk factors to severe COVID-19. TLR7 codes for a Toll-like receptor that can recognise single-strand RNA present in viruses such as SARS-CoV-2, the agent responsible for COVID-19. Once activated, the receptor helps to switch on the immune response, triggering the production of pro-inflammatory molecules and the release of type I and II interferon proteins that regulate the activity of the immune system.

Now, in eLife, Alessandra Renieri and colleagues at the University of Siena and a number of other institutes in Italy – including Chiara Fallerini, Sergio Daga, and Stefania Mantovani as joint first authors – report five cases of men (three under 50, and two in their mid-60s) with severe COVID-19 who carry rare TLR7 variants (Fallerini et al., 2021). These data validate and extend two other studies we have been involved in: one highlights two sets of two young brothers (median age of 26) carrying a rare TLR7 variant who suffered from severe COVID-19 (van der Made et al., 2020); the other identified TLR7 variants in a selected group of COVID-19 patients (Solanich et al., submitted to medRxiv). In total, these three reports describe eight rare TLR7 variants in 12 male patients with no medical history who still developed severe COVID-19. We are therefore more confident with suggesting that variants of this single gene are responsible for an important proportion of risk factor for severe COVID-19 in men under 50.

Functional studies have started to shed light on the mechanism by which TLR7 variants can lead to severe COVID-19. This work shows that the variants disrupt the production of type I and type II interferon after stimulation of the TLR7 receptor, which suggests that the mutations lead to a loss-of-function in the antiviral response to SARS-CoV-2 (van der Made et al., 2020). However, Fallerini et al. show that some of the rare TLR7 variants only have a marginal effect on the release of type I interferon, indicating that additional pathways influence the body's defence against SARS-CoV-2.

Given these studies, it is somewhat surprising that a global initiative using exome or genome sequencing in 657 patients with severe COVID-19 did not report TLR7 variants, focusing instead on the pathways that allow the recognition of viral infections such as influenza. This initiative identified defects in the TLR3 and IRF7 pathway that could be responsible for up to 3.5% of patients with severe COVID-19 (Zhang et al., 2020). The field is now anxiously waiting for potential TLR7 variants to be identified in this large dataset as well. Indeed, Fallerini et al. suggest that at least 2% of severely ill Italian COVID-19 patients have loss of function TLR7 variants, but this percentage could be even higher in other populations.

Since the first report on TLR7 variants in severe COVID-19, diagnostic pipelines have been developed to discover such mutations. Being aware that this monogenetic factor predisposes young men to severe outcomes has several consequences. First, families of patients with TLR7 variants could be screened, and individuals fast-tracked for vaccination if identified as carriers. Second, unvaccinated carriers of rare TLR7 variants that predispose to severe COVID-19 could benefit from prophylactic interferon gamma treatment, similar to that given to patients with chronic granulomatous disease to prevent severe infection (The International Chronic Granulomatous Disease Cooperative Study Group, 1991; Marciano et al., 2004). Third, patients with these variants should be admitted to hospital earlier, be monitored more closely for complications, and be treated more aggressively once they become critically ill. Indeed, there is an argument for screening all men under 50 who have been admitted to intensive care (and their families) for the TLR7 variants. Together, these measures might have a dramatic impact on clinical outcome.

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Article and author information

Author details

  1. Frank L van de Veerdonk

    Frank L van de Veerdonk is in the Department of Internal Medicine, Radboudumc Center for Infectious Diseases, Nijmegen, The Netherlands

    For correspondence
    frank.vandeveerdonk@radboudumc.nl
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1121-4894
  2. Mihai G Netea

    Mihai G Netea is in the Department of Internal Medicine, Radboudumc Center for Infectious Diseases, Nijmegen, The Netherlands and the Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany

Publication history

  1. Version of Record published: March 23, 2021 (version 1)

Copyright

© 2021, van de Veerdonk and Netea

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

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  1. Frank L van de Veerdonk
  2. Mihai G Netea
(2021)
COVID-19: Rare variants increase the risk of severe COVID-19
eLife 10:e67860.
https://doi.org/10.7554/eLife.67860

Further reading

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    2. Genetics and Genomics
    Vahid Akbari et al.
    Research Article

    Imprinting is a critical part of normal embryonic development in mammals, controlled by defined parent-of-origin (PofO) differentially methylated regions (DMRs) known as imprinting control regions. Direct nanopore sequencing of DNA provides a means to detect allelic methylation and to overcome the drawbacks of methylation array and short-read technologies. Here, we used publicly available nanopore sequencing data for 12 standard B-lymphocyte cell lines to acquire the genome-wide mapping of imprinted intervals in humans. Using the sequencing data, we were able to phase 95% of the human methylome and detect 94% of the previously well-characterized, imprinted DMRs. In addition, we found 42 novel imprinted DMRs (16 germline and 26 somatic), which were confirmed using whole-genome bisulfite sequencing (WGBS) data. Analysis of WGBS data in mouse (Mus musculus), rhesus monkey (Macaca mulatta), and chimpanzee (Pan troglodytes) suggested that 17 of these imprinted DMRs are conserved. Some of the novel imprinted intervals are within or close to imprinted genes without a known DMR. We also detected subtle parental methylation bias, spanning several kilobases at seven known imprinted clusters. At these blocks, hypermethylation occurs at the gene body of expressed allele(s) with mutually exclusive H3K36me3 and H3K27me3 allelic histone marks. These results expand upon our current knowledge of imprinting and the potential of nanopore sequencing to identify imprinting regions using only parent-offspring trios, as opposed to the large multi-generational pedigrees that have previously been required.

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    2. Medicine
    Martin W Breuss et al.
    Short Report

    Background:

    De novo mutations underlie individually rare but collectively common pediatric congenital disorders. Some of these mutations can also be detected in tissues and from cells in a parent, where their abundance and tissue distribution can be measured. We previously reported that a subset of these mutations is detectable in sperm from the father, predicted to impact the health of offspring.

    Methods:

    As a cohort study, in three independent couples undergoing in vitro fertilization, we first identified male gonadal mosaicism through deep whole genome sequencing. We then confirmed variants and assessed their transmission to preimplantation blastocysts (32 total) through targeted ultra-deep genotyping.

    Results:

    Across 55 gonadal mosaic variants, 15 were transmitted to blastocysts for a total of 19 transmission events. This represented an overall predictable but slight undertransmission based upon the measured mutational abundance in sperm. We replicated this conclusion in an independent, previously published family-based cohort.

    Conclusions:

    Unbiased preimplantation genetic testing for gonadal mosaicism may represent a feasible approach to reduce the transmission of potentially harmful de novo mutations. This—in turn—could help to reduce their impact on miscarriages and pediatric disease.

    Funding:

    No external funding was received for this work.