Single gene inborn errors of immunity underlying SARS-CoV2-related multisystem inflammatory syndrome in children. – GenMIS-C

Since April 2020, a rare and life-threatening SARS-CoV2-related Kawasaki-like disease, designated by the CDC as Multisystem Inflammatory Syndrome in Children (MIS-C), emerged in communities with high rates of COVID-19, in particular in children. Available epidemiological data provided compelling evidence for SARS-CoV2 being the trigger of MIS-C. We have previously identified a number of monogenic inborn errors of immunity (IEIs) underlying a variety of severe viral diseases including critical COVID-19 pneumonia. We now aim to dissect the immunopathogenesis of MIS-C by testing a monogenic hypothesis. We have recruited >500 previously healthy MIS-C patients, and are performing whole exome sequencing (WES) and whole genome sequencing (WGS) sequentially for them. We will search for rare single gene IEIs underlying MIS-C via an unbiased genome-wide approach, by analyzing the WES and WGS data at the cohort population and individual patient levels, testing models of genetic and immunological homogeneity and heterogeneity. For all candidate MIS-C-causing genes, we will perform in-depth characterization at the molecular and cellular levels, to connect the candidate genotype to molecular mechanism(s) and cellular phenotype(s) relevant to the MIS-C pathogenesis. This project will enable us to better understand the immunopathogenesis of MIS-C. The results of this project will also permit genetic diagnosis and counseling, while facilitating the development of novel preventive and therapeutic strategies in both genetic and non-genetic cases.