Solving the genomics of unsolved rare life-threatening COVID-19 using genome sequencing

COVID-19, caused by the SARS-CoV-2 virus, has been declared a pandemic and is one of the most urgent global health crises. The phenotypes of COVID-19 are highly heterogeneous, and a major challenge is the early recognition of severe COVID-19 to support early clinical intervention and targeted therapy. Certain individuals may have a higher risk of severe disease, for example, people with pre-existing respiratory, cardiac, or immune disorders. However, in some rare cases, severe disease occurs in young individuals without any risk factors and is unexplained. We hypothesize that severe illness with COVID-19 in people who do not otherwise have pre-existing risk factors is attributable to monogenic causes in some cases. We have an opportunity to study this in participants recruited to the Alberta Host Genetic Susceptibility project (led by Pfeffer lab) within Hostseq, which focused on younger patients who required hospitalization and did not have pre-existing comorbidities. We will apply cutting-edge genome sequencing (GS) analytical approaches developed by Tarailo-Graovac lab with correlation to comprehensive clinical data. We have successfully applied GS methods to unravel the complex genetic mechanisms underlying rare undiagnosed diseases by identification of previously missed variants of interest. I will work with genomes of the rare severe patients with COVID-19 using the "three stages" and "two levels" strategy to identify causative genes and complex genetic scenarios in independent cohorts. We will apply the background variant information from the Hostseq database to help narrow down the candidates. As such, this work has the potential to build a diagnostic workflow for rare, life-threatening COVID-19 patients and provide clues for identifying individuals predisposed to severe COVID-19 outcomes.