Genomic and phenotypic characterization of Multisystem Inflammatory Syndrome in Children (MIS-C): a prospective multicenter study from the Middle East

Importance: Clinical, genetic and laboratory characteristics of patients with multisystem inflammatory syndrome in children (MISC) in the Middle East have not yet been documented. Objective: To uncover rare genetic variants contributing to MISC in patients of primarily Arab and Asian origin. Design, Setting, and Participants: A prospective multicenter cohort study was conducted between September 2020 and August 2021 in the United Arab Emirates and Jordan. Forty-five patients meeting the case definition of MISC, and a matched control group of twenty-five healthy children with a confirmed severe acute respiratory syndrome coronavirus 2 (SARSCoV2) infection status, were recruited. Whole Exome Sequencing (WES) in all 70 participants was performed to identify rare likely deleterious variants in patients with MISC and to correlate genetic findings with the clinical course of illness. Exposures: SARSCoV2. Main Outcomes and Measures: Fever, organ system complications, laboratory biomarkers, WES findings, treatments, and clinical outcomes. Mann Whitney U test was used to assess the association between genetic variations and MISC attributes. Fishers exact test was used to compute the genetic burden in MISC relative to controls. Results: In 45 MISC patients (23 boys [51.1%]; average age, 7 years [range, 2-14 years]), key inflammatory markers were significantly dysregulated in all patients. Mucocutaneous and gastrointestinal manifestations were reported in 80% (95% CI 66% to 89%) while cardiac and neurological findings were reported in 49% (95% CI 35% to 63%) and 31% (95% CI 19.5% to 45.6%) of patients, respectively. Rare, likely deleterious heterozygous variants in immune related genes including TLR3, TLR6, IFNAR2, IL22RA2, IFNB1, and IFNA6, were identified in 19 patients (42.2%, 95% CI 29% to 56.7%), of whom seven had more than one variant. There was significant enrichment of genetic variants in patients relative to the control group (29 versus 3, P<.0001). Those variants were significantly associated with earlier onset of disease (31.5%, 95% CI 15.4% to 54% of patients with versus 7.7%, 95% CI 2% to 24% without genetic findings were < 3 years) and resistance to treatment (42%, 95% CI 23% to 64% of patients with versus 11.5%, 95% CI 4% to 29% of patients without genetic findings received two doses of IVIG). Conclusions and Relevance: Rare, likely deleterious genetic variants contribute to MISC onset and management.