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 (MIS-C) in the Middle East have not yet been documented.

Objective

To uncover rare genetic variants contributing to MIS-C 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 MIS-C, and a matched control group of twenty-five healthy children with a confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection status, were recruited. Whole Exome Sequencing (WES) in all 70 participants was performed to identify rare likely deleterious variants in patients with MIS-C and to correlate genetic findings with the clinical course of illness.

Exposures

SARS-CoV-2

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 MIS-C attributes. Fisher’s exact test was used to compute the genetic burden in MIS-C relative to controls.

Results

In 45 MIS-C 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 MIS-C onset and management.

Key Points