Genetic and Clinical Characteristics of Patients in the Middle East With Multisystem Inflammatory Syndrome in Children

Abstract

Importance: Clinical, genetic, and laboratory characteristics of Middle Eastern patients with multisystem inflammatory syndrome in children (MIS-C) have not yet been documented.

Objective: To assess the genetic and clinical characteristics of patients with MIS-C of primarily Arab and Asian origin.

Design, setting, and participants: A prospective, multicenter cohort study was conducted from September 1, 2020, to August 31, 2021, in the United Arab Emirates and Jordan. Forty-five patients with MIS-C and a matched control group of 25 healthy children with a confirmed SARS-CoV-2 infection status were recruited. Whole exome sequencing 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, whole exome sequencing findings, treatments, and clinical outcomes were measured. The Mann-Whitney U test was used to assess the association between genetic variants and MIS-C attributes. The Fisher exact test was used to compute the genetic burden in MIS-C relative to controls.

Results: A total of 45 patients with MIS-C (23 [51.1%] male; 30 [66.7%] of Middle Eastern origin; mean [SD] age, 6.7 [3.6] years) and 25 controls (17 [68.0%] male; 24 [96.0%] of Middle Eastern origin; mean [SD] age 7.4 [4.0] years) participated in the study. Key inflammatory markers were significantly dysregulated in all patients with MIS-C. Mucocutaneous and gastrointestinal manifestations were each reported in 36 patients (80.0%; 95% CI, 66.1%-89.1%), cardiac findings were reported in 22 (48.9%; 95% CI, 35.0%-63.0%), and neurologic findings were reported in 14 (31.1%; 95% CI, 19.5%-45.6%). Rare, likely deleterious heterozygous variants in immune-related genes, including TLR3, TLR6, IL22RA2, IFNB1, and IFNA6, were identified in 19 patients (42.2%; 95% CI, 29.0%-56.7%), of whom 7 had multiple variants. There was higher enrichment of genetic variants in patients relative to controls (29 vs 3, P < .001). Patients with those variants tended to have earlier disease onset (7 patients [36.8%; 95% CI, 19.1%-58.9%] with genetic findings vs 2 [7.7%; 95% CI, 2.1%-24.1%] without genetic findings were younger than 3 years at onset) and resistance to treatment (8 patients [42.1%; 95% CI, 23.1%-63.7%] with genetic findings vs 3 patients [11.5%; 95% CI, 4.0%-29.0%] without genetic findings received 2 doses of intravenous immunoglobulin).

Conclusions and relevance: The results of this cohort study suggest that rare, likely deleterious genetic variants may contribute to MIS-C disease. This finding paves the way for additional studies with larger, diverse populations to fully characterize the genetic contribution to this new disease entity.

Figure 1.. Graphical Representation of Study Design, Participants, Sequencing Protocol, Bioinformatic Analysis, and Genomic and Clinical Characterization of Patients With Multisystem Inflammatory Syndrome in Children (MIS-C)

ACE-2 indicates angiotensin-converting enzyme 2; LoF, loss of function; gnomAD, Genome Aggregation Database; MEV, Middle East Variome database; IVIG, intravenous immunoglobulin; and PICU, pediatric intensive care unit.

Figure 2.. Age, Sex, and Country of Origin of Patients With Multisystem Inflammatory Syndrome in Children

^aPatients self-identified as being from the US (no other information is available).

Figure 3.. Burden of Immune-Related Loss of Function (LoF) and Missense Variants in Patients With Multisystem Inflammatory Syndrome in Children (MIS-C)

gnomAD indicates Genome Aggregation Database; MEV, Middle East Variome database.

Figure 4.. Genetic Findings and Associations With Age and Response to Treatment

Among 19 patients with multisystem inflammatory syndrome in children with positive genetic findings, 7 (36.8%) were younger than 3 years, whereas 12 (63.2%) were older than 3 years. Of 26 patients with no genetic variants, 2 (7.7%) were younger than 3 years, whereas 24 (92.3%) were older. Although most patients received 1 dose of intravenous immunoglobulin (IVIG), a significantly higher proportion of patients with genetic findings (8 of 19 [42.1%]) received a second dose compared with those without genetic variants (3 of 26 [11.5%]).