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Multisystem Inflammatory Syndrome in Children Linked to Rare, Immune-Related Variants

NEW YORK – With genetic and clinical data for dozens of children in Dubai and Jordan, a United Arab Emirates-led team has started defining genetic factors that may contribute to multisystem inflammatory syndrome in children (MIS-C) after infection with SARS-CoV-2.

"Our cohort included patients who were mostly from the Middle East (66.7 percent), including 26 from Arab countries and nine from Asian countries," senior author Ahmad Abou Tayoun, a clinical molecular geneticist affiliated with the Al Jalila Children's Specialty Hospital and Mohammed Bin Rashid University of Medicine and Health Sciences, and his colleagues wrote. "Patients of such backgrounds have long been underrepresented in genetic studies, emphasizing the importance of our study in characterizing the genetic landscape of MIS-C disease in this cohort."

Based on findings from their prospective, multicenter study, published in JAMA Network Open on Tuesday, he and his colleagues suggested that "comprehensive genetic profiling of patients with MIS-C of diverse ethnicities is essential to characterize the genetic contribution to this disease."

The researchers analyzed exome sequences for 45 children with MIS-C and 25 without it, searching for genetic features distinguishing cases and controls, along with variants linked to the clinical characteristics for individuals with MIS-C, including treatment histories, clinical outcomes, fever patterns, documented biomarker data, and documented organ symptoms.

"In this cohort study, we characterize the genomic landscape, phenotypic features, inflammatory and cellular markers, and clinical management and outcomes of the largest prospective cohort to date of patients with MIS-C from the Middle East," Abou Tayoun noted in an email, quoting his team's paper, adding that "[t]o our knowledge, this study is also the largest MIS-C cohort involving whole exome sequencing data."

The MIS-C cases mainly involved children with Middle Eastern ancestry treated at hospitals in the United Arab Emirates or Jordan from the fall of 2020 to August 2021, the team noted. All the cases involved children with two or more MIS-C-affected organs, who had confirmed or suspected SARS-CoV-2 infections or a recent exposure to someone with COVID-19.

MIS-C "is a critical and potentially life-threatening complication of COVID-19 in pediatric settings," the authors explained. While the condition shares some clinical features with Kawasaki disease, they added, studies so far suggest that the immune features linked to Kawasaki disease differ from those that occur in MIS-C.

Along with features linked to MIS-C in past studies of children from other populations, the new study highlighted an overrepresentation of rare variants in genes involved in immune responses and other processes in affected children.

In particular, the investigators flagged rare, likely deleterious variants affecting at least one copy of interferon-mediated immune signaling and Toll-like receptor signaling pathway immune genes such as IFNB1, IFNA6, TLR3, and TLR6, along with genes from NOD-like receptor signaling and retinoic acid–inducible gene I–like receptor pathways.

"Those pathways, which overlap with the currently characterized immunologic profile in patients with MIS-C, might represent new therapeutic targets for those patients," Abou Tayoun wrote, noting that "patients with rare genetic variants tended to have earlier disease onset and resistance to treatment suggesting those patients can be managed differently."

Even so, the investigators emphasized that larger studies will be needed in the future to confirm and expand on results from the current analysis.

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

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