Genomic and phenotypic characterization of Multisystem Inflammatory Syndrome in Children (MIS-C): a prospective multicenter study from the Middle East
Authors: Abuhammour Walid , Yavuz Lemis , Jain Ruchi , Hammour Khawla Abu , Al-Hammouri Ghalia F. , Naofal Maha El , Halabi Nour , Yaslam Sawsan , Ramaswamy Sathishkumar , Taylor Alan , Wafadari Deena , Alsarhan Ali , Khansaheb Hamda , Deesi Zulfa Omar , Varghese Rupa Murthy , Uddin Mohammed , Suwaidi Hanan Al , Alkhaja Abdulmajeed , AlDabal Laila Mohamed , Loney Tom , Nowotny Norbert , Khayat Abdulla Al , Alsheikh-Ali Alawi , Tayoun Ahmad Abou 
Published: December 2021

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

Question

What are the clinical, genetic, and laboratory characteristics of multisystem inflammatory syndrome in children (MIS-C) of the Middle East?

Findings

In this prospective study of 45 MIS-C patients of primarily Arab and Asian origins, we show that the clinical course was consistent with that of previously characterized patients from other backgrounds. However, we find an enrichment of rare, likely deleterious immune-related genetic variants, in MIS-C patients, and an association of genetic status with MIS-C onset and resistance to treatment.

Meaning

Comprehensive genetic profiling of MIS-C patients of diverse ancestries is essential to characterize the genetic contribution to this disease.