Contribution of Predicted High-Impact Genetic Variants in Multi-system Inflammatory Syndrome in Children & Adolescents (MIS-C)

Approximately four to six weeks after infection by SARS-CoV-2, some children (316 per 1000000) presented a multisystem inflammatory syndrome with features of Kawasaki disease. While the condition can be considered rare, it is very severe in clinical impact, including fever, which is variably accompanied by a rash, conjunctival injection, gastrointestinal symptoms, shock, myocardial dysfunction and coronary arterial dilation. This condition has been named Multisystem inflammatory syndrome in children (MIS-C), and while the incidence of COVID-19 is lower in children, the infection can still trigger worrying consequences. The genetic risk factors that may contribute to MIS-C presentation are still unresolved. We plan to use data from the HostSeq initiative, which includes the whole genome sequence of thousands of Canadians infected by SARS-CoV-2 who have been severely impacted. This Hostseq databank, which includes detailed clinical information and corresponding whole genome sequences will enable testing for the correlation of specific genetic variants with clinical outcomes. Building from my own expertise in statistical genetics, and from our team's role in developing the HostSeq resource, I will implement the quality control, and population structure components, and examine for rare (<1% population frequency) "damaging" genetic variants that are exclusive in the MIS-C positive patients. The rare variants will be identified as potential pathogenicity according to the American College of Medical Genetics and American College of Pathologist (ACMG/AMP) guidelines. In this way, I expect to identify rare damaging variants that were shared by affected subjects possibly similar biological pathways. Having such data may contribute to revealing the genetic susceptibilities that predispose patients to MIS-C, which not only could improve the care and outcomes of this emerging condition, but also increase the understanding of the underlying disorders of immune dysregulation.