corona virus-Covid19

Genetic Change Detected in Brothers Helps Explain Why COVID-19 More Severe in Men Interview with:

Caspar van der Made, MD
Resident in Internal Medicine, PhD-student
Alexander Hoischen, PhD
Geneticist, Assistant professor,
Departments of Human Genetics and Internal Medicine

Radboud University Medical enter
Nijmegen, The Netherlands 

First author Caspar van der Made is a resident in Internal Medicine and PhD-student on the topic of immunogenomics.
Alexander Hoischen is geneticist with a special focus on the application of genomic technologies in primary immunodeficiencies and last author of this study. What is the background for this study?  

Response: This study was initiated to investigate the presence of monogenic factors that predispose young individuals to develop a severe form of COVID-19. It has become clear that several general risk factors such as obesity, hypertension and diabetes mellitus increase the risk of developing severe coronavirus disease. However, even though differences in interindividual genetic make-up are thought to influence the immune response to SARS-CoV-2, such specific genetic risk factors had not yet been identified.

We therefore chose to study young brother pairs (sharing half of their genomes) without any general risk factors that nevertheless contracted severe COVID-19.

We hypothesized these highly selected case series may offer the most optimal chance of identifying a (possible X-linked) primary immunodeficiency specific to COVID-19. What are the main findings?

Response: In this case series, two young brother pairs – of which all four individuals with a mean age of 26 years required mechanical ventilation at the ICU – were enrolled and studied. We performed rapid clinical whole-exome sequencing of the patients and segregation in available family members to identify loss-of-function variants of the X-chromosomal TLR7. This gene encodes the toll-like receptor 7 protein that plays a critical role in the innate immune response against coronaviruses, predominantly by mediating the production of type I interferons. Especially in SARS-CoV-2 infections this response is crucial, as the virus has evasive mechanisms to disrupt a proper type I interferon response. In primary peripheral blood mononuclear cells extracted from the patients, we have shown that the transcription of type I-interferon genes was lower in patients upon stimulation with the TLR7 agonist imiquimod, as compared to controls. Furthermore, the production of the type II interferon IFNg was also decreased in patients. What should readers take away from your report?

Response: To our knowledge this is the first report that proposes a specific monogenic factor to develop severe COVID-19. We aim to highlight the important contribution of genetics in the susceptibility to develop COVID-19 and hope to create awareness among physicians to consider genetic evaluation of young patients with unexplained severe COVID-19.

The finding of TLR7 deficiency in these patients furthermore underlines the importance of an intact type I and II interferon response to fight off SARS-CoV-2 and provides insight in the timing of possible treatment options. What recommendations do you have for future research as a result of this work?

Response: While the TLR7 deficiency is most likely a rare phenomenon, with an estimate of 1:10,000 TLR7 mutation carriers in the general population; our findings shall be replicated and expanded by others. Similar to other rare disease genetic studies, this shall allow additional insides into disease pathogenesis in general. Further research should focus on the elucidation of the exact role of TLR7-signaling in the pathogenesis of SARS-CoV-2 and ultimately the exploration of rational treatment options.

Also, these findings may provide part of the explanation for the male sex bias observed in COVID-19, which should be addressed more in-depth. More generally, we encourage further studies towards the identification of other genetic risk factors and applaud the efforts already undertaken by other large consortia. Is there anything else you would like to add?

Response: We are very grateful to the families that participated in this study, and would like to acknowledge our interdisciplinary team of collaborators. 

Any disclosures?

No relevant conflict of interest for any of the authors. 


van der Made CI, Simons A, Schuurs-Hoeijmakers J, et al. Presence of Genetic Variants Among Young Men With Severe COVID-19. JAMA. Published online July 24, 2020. doi:10.1001/jama.2020.13719 

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Aug 11, 2020 @ 8:17 pm

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