A study has found that rare genetic alterations in the TLR7 gene may have predisposed two sets of brothers who fell severely ill with COVID-19.
COVID-19, the disease associated with viral infection by SARS-CoV-2, has been causing concern due to the variety of symptoms it has been associated with. COVID-19 can cause anything from mild symptoms such as loss of taste or smell to severe respiratory disease and even death. While age, sex and pre-existing conditions have been associated with more severe disease, there is growing evidence that host genetics can influence disease severity as well.
In a new case series appearing in the Journal of the American Medical Association, Dutch researchers examined the exomes of two pairs of healthy brothers under the age of 32 who became severely ill with COVID-19 and required ventilation, with one of them sadly dying.
Severe COVID-19 symptoms are less common in younger patients. Alexander Hoischen from Radboud University Medical Center said “In such a case, you immediately wonder whether genetic factors could play a role. Getting sick from an infection is always an interplay between – in this case – the virus and the human immune system. It may be a mere coincidence that two brothers from the same family became more severely ill. But it is also possible that an inborn error of the immune system has played an important role”.
Hoischen and his colleagues analysed whole-exome sequencing data from the two sets of brothers, and they found that all four had variants affecting the TLR7 gene, which is involved in pathogen recognition and immune system activation. They also analysed whether there were any alterations found on the X-chromosome, which could explain why men have generally fared less well during the pandemic.
The researchers found two different rare variants in the TLR7 gene, located on the X chromosome. TLR7 encodes the toll-like receptor 7, which has a role in the activation of interferons and triggers an immune response. One of the sets of brothers had a four-nucleotide deleted in TLR7, while the other had a missense variant. Both alterations are predicted to be deleterious and appear to impair host viral response. The researchers also noted decreased expression of the type I IFN gene IRF7, IFNB1 and ISG15, compared to unaffected family members and controls.
First author Cas Van der Made said in a statement that “these tests make it clear that [SARS-CoV-2] appears to have free rein in people without properly functioning TLR7 because it is not recognised by the immune system”. It also suggests that TLR7 is required for protection against SARS-CoV-2 and it could be a potential treatment approach.
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