Abstract
Background: Multisystem inflammatory syndrome in children (MIS-C) is a pediatric complication of severe acute respiratory syndrome coronavirus 2 infection that is characterized by multiorgan inflammation and frequently by cardiovascular dysfunction. It occurs predominantly in otherwise healthy children. We previously reported haploinsufficiency of suppressor of cytokine signaling 1 (SOCS1), a negative regulator of type I and II interferons, as a genetic risk factor for MIS-C.
Objectives: We aimed to identify additional genetic mechanisms underlying susceptibility to severe acute respiratory syndrome coronavirus 2-associated MIS-C.
Methods: In a single-center, prospective cohort study, whole exome sequencing was performed on patients with MIS-C. The impact of candidate variants was tested by using patients’ PBMCs obtained at least 7 months after recovery.
Results: We enrolled 18 patients with MIS-C (median age = 8 years; interquartile range = 5-12.25 years), of whom 89% had no conditions other than obesity. In 2 boys with no significant infection history, we identified and validated hemizygous deleterious defects in XIAP, encoding X-linked inhibitor of apoptosis, and CYBB, encoding cytochrome b-245, beta subunit. Including the previously reported SOCS1 haploinsufficiency, a genetic diagnosis was identified in 3 of 18 patients (17%). In contrast to patients with mild COVID-19, patients with defects in SOCS1, XIAP, or CYBB exhibit an inflammatory immune cell transcriptome with enrichment of differentially expressed genes in pathways downstream of IL-18, oncostatin M, and nuclear factor κB, even after recovery.
Conclusions: Although inflammatory disorders are rare in the general population, our cohort of patients with MIS-C was enriched for monogenic susceptibility to inflammation. Our results support the use of next-generation sequencing in previously healthy children who develop MIS-C.
Keywords: COVID-19; MIS-C; Multisystem inflammatory syndrome in children; SARS-CoV-2; whole exome sequencing.
【저자키워드】 COVID-19, SARS-CoV-2, multisystem inflammatory syndrome in children, MIS-C, whole exome sequencing., 【초록키워드】 Transcriptome, Apoptosis, Inflammation, coronavirus, pediatric, children, susceptibility, obesity, Sequencing, Genetic, variant, Infection, interferons, Diagnosis, cytokine, prospective cohort study, severe acute respiratory syndrome Coronavirus, MIS-C, Next-generation sequencing, Patient, pathway, Mild, PBMC, Beta, General population, respiratory, inhibitor, Differentially expressed genes, cytokine signaling, differentially expressed gene, Multiorgan, Inflammatory, PBMCs, Immune cell, Pathways, Deleterious, inflammatory disorders, Support, interquartile range, acute respiratory syndrome, inflammatory disorder, Exome, subunit, acute respiratory syndrome coronavirus, enrichment, type I, median age, syndrome, single-center, healthy children, cardiovascular dysfunction, haploinsufficiency, suppressor, IL-18, downstream, nuclear, XIAP, SOCS1, CYBB, genetic risk factor, X-linked, enrolled, identify, develop, reported, was performed, characterized, condition, occur, had no, cohort of patient, genetic mechanism, Including, was tested, 【제목키워드】 children, genetic susceptibility, Inflammatory, syndrome,