USA, New Jersey, Portrait of man with down syndrome

To learn more about the association between genetic factors and outcomes from COVID-19 infection in Down syndrome, a pair of researchers at the Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain revealed a number of genetic influences—both positive and negative.

To understand the potential differential impact of COVID-19 in individuals with Down syndrome compared to the general population, the team mapped the transcriptomic changes induced by the chromosome 21 trisomy onto the pathways and proteins known to be affected by SARS-CoV-2, the virus causing COVID-19.

After studying public transcriptomic datasets, the team discovered several genes impacting molecular pathways which revealed a Down syndrome/COVID-19 network. These gene factors influence disease susceptibility in Down syndrome at the infection stage and in disease progression leading to serious respiratory distress and lung fibrosis.

At the infection stage, individuals with Down syndrome may be more susceptible to infection due to having three copies of TMPRSS2, a gene found on chromosome 21. The TMPRSS2 gene activates the viral spike (S) protein thereby aiding in the ability of the virus to enter host cells. Mechanistically, the TMPRSS2 gene encodes for a serine protease that proteolytically activates the S protein for its interaction with the angiotensin-converting enzyme 2 (ACE2) as the entry receptor, allowing the entrance of the SARS-CoV-2 virus in the host cell.

Those with Down syndrome, who have an extra chromosome 21 copy, have 60 percent higher TMPRSS2 expression levels than people without Down syndrome.

After infection, the prognosis for some individuals with Down syndrome might be negatively affected due to upregulation of inflammatory genes increasing the chances of the COVID-19 cytokine storm, a process where the body’s immune system overcompensates from infection and attacks its own tissues. In their research, the team found higher expression levels for CXCL10 in Down syndrome, a gene known to trigger a cytokine storm.

Post-infection, individuals with Down syndrome appear to have a heightened susceptibility to bacterial infections. The team discovered that the trisomic cells in Down syndrome display a large downregulation of the NLRP3 gene, an essential gene known for homeostasis maintenance against pathogenic infections. This lowered expression of the NLRP3 gene may partly explain why some Down syndrome patients with COVID-19 experience bacterial infection complications.

Balancing these negative influences, the team discovery that anti-viral interferon I signaling is also upregulated in Down syndrome, theoretically overactivating the body’s initial anti-viral response, inhibiting viral genome release, viral replication, and viral assembly. Two of the genes linked to an interferon response—Interferon Alpha and Beta Receptor Subunits 1 and 2 (IFNAR1 and IFNAR2) that together form a heterodimeric interferon receptor—are tripled in Down syndrome due to their location on chromosome 21.

One of the limitations of the study is that the datasets studied cannot be used to assess the risk of COVID-19 across different ages. This information would be interesting since a recent survey from the Trisomy 21 Research Survey showed heightened risk of death from COVID-19 in individuals with Down syndrome from age 40 (compared with age 60 in those without Down syndrome).

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