Mechanisms underlying genetic susceptibility to Multisystem Inflammatory Syndrome in Children (MIS-C)

Chou, Janet; Platt, Craig D.; Habiballah, Saddiq; Nguyen, Alan A.; Elkins, Megan; Weeks, Sabrina; Peters, Zachary; Day-Lewis, Megan; Novak, Tanya; Armant, Myriam; Williams, Lucinda; Rockowitz, Shira; Sliz, Piotr; Williams, David A.; Randolph, Adrienne G.; Geha, Raif S.; Almutairi, Abduarahman; Jaber, Faris; Banzon, Tina; Roberts, Jordan; Halyabar, Olha; Lo, Mindy; Kahn, Stacy; Henderson, Lauren A.; Lee, Pui Y.; Son, Mary Beth; Cheng, Leah

Background Multisystem Inflammatory Syndrome in Children (MIS-C) is a pediatric complication of SARS-CoV-2 infection characterized by multiorgan inflammation and frequently, 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 SARS-CoV-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 using patients’ peripheral blood mononuclear cells obtained at least seven months after recovery. Results We enrolled 18 patients with MIS-C (median age: 8 years, IQR 5 – 12.25 years), of whom 89% had no conditions other than obesity. In two 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. Including the previously reported SOCS1 haploinsufficiency, a genetic diagnosis was identified in three (17%) of 18 patients. Even after recovery, 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 NF-κB, compared to those with mild COVID-19. 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.