Genome Mapping Reveals Key Structural Variants Impacting COVID-19 Disease Severity

One of the greatest mysteries of COVID-19 infection is the varying nature of disease severity; COVID-19 causes mortality in some yet no symptoms in others.

One study, published in iScience, found rare structural gene variants in the sickest COVID-19 patients that allowed the SARS-CoV-2 virus to attach to cells, enter cells, multiply, and cause inflammation.

“Millions of people get infected, and fortunately only a very small percentage become symptomatic, and a very small percentage of the symptomatic individuals require oxygen and a small percentage of those individuals are hospitalized and die,” said Dr. Ravindra Kolhe, a corresponding author of the study and the director of the Georgia Esoteric and Molecular Laboratory at the Medical College of Georgia at Augusta University. “But even a small percentage amounts to millions of people and that is too many.”

The first-of-its-kind study used optical genome mapping to identify structural variations that could be predisposition factors associated with severe COVID-19 disease.

The investigators included 52 severely ill COVID-19 patients to identify rare structural variants. Their 3-dimensional assessment of the genome revealed rare structural variants in 9 of the sickest patients, affecting a total of 31 genes that mediated the pathways between host and virus.

The 9 sickest patients shared common comorbidities, while 32 required mechanical ventilation and 13 of the 52 died while in the intensive care unit.

The investigators identified 7 structural variants involving genes implicated in innate immunity and inflammatory response, and viral replication and spread, both key host-viral interaction pathways. The results may explain the clinical variability in response to COVID-19 among different individuals.

The investigators noted that the large structural variants they identified were not caused by COVID-19, but rather the virus used the variants to its advantage. The identified structural variants may not increase susceptibility to conditions other than SARS-CoV-2.

This research points to a need for an assay to test for genetic variants that, once identified, would allow for early vaccination and other protective measures among individuals more susceptible to severe COVID-19 infection and disease.