Genetic Risk Factors for Multi-system Inflammatory Syndrome in Children and Pediatric Post COVID Condition

Overview

We will perform Whole Exome Sequencing on DNA from saliva. We will include: Children with a history of MIS-C; children with post-COVID condition; and controls in order to identify rare, high impact genetic variants in immunological genes and pathways in children with a history of MIS-C or pediatric post-COVID condition.

Rationale: Following infection with SARS-CoV-2, some children develop the potentially life-threatening disease Multi-System Inflammatory Syndrome in Children (MIS-C) and some children develop post-COVID condition (formerly 'long COVID'). It is unknown why some children develop severe or prolonged symptoms after SARS-CoV-2 infection, while most children have asymptomatic or mild disease. We hypothesize that rare variants in genes associated with the immune system predispose children to develop MIS-C or post-COVID condition after infection with SARS-CoV-2. Objective: Primary objective: To identify rare, high impact genetic variants in immunological genes and pathways in children with a history of MIS-C or pediatric post-COVID condition. Secondary objectives: To analyze the clinical characteristics and long-term effects of pediatric COVID-19 and MIS-C. To characterize the functional and clinical impact of genetic variants in MIS-C and post-COVID condition and identify targets for therapy. Study design: We will do an observational study. We will perform Whole Exome Sequencing (WES) using Next Generation Sequencing (NGS) on DNA from blood or saliva. We will include: (1) MIS-C cases: Children with a history of MIS-C; (2) post-COVID condition cases: Children with post-COVID condition; and (3) Controls: SARS-CoV-2 exposed age-matched control group: children who were infected with SARS-CoV-2 but did not develop moderate to severe COVID-19, MIS-C or post-COVID condition. Study population: Children 0-19 years old with a history of MIS-C (n=100), post-COVID condition (n=100), or uncomplicated SARS-CoV-2 infection (n=200). Main study parameters/endpoints: 1. To evaluate if some children with MIS-C or post-COVID condition have an inborn error of immunity by determining the presence of pathogenic or likely pathogenic variants in immunological genes 2. To evaluate if a larger proportion of cases with MIS-C or post-COVID condition have rare and presumably deleterious variants in immunological genes than children with an asymptomatic or mild infection