Mechanisms underlying genetic susceptibility to multisystem inflammatory syndrome in children (MIS-C)
Janet Chou, Craig D Platt, Saddiq Habiballah, Alan A Nguyen, Megan Elkins, Sabrina Weeks, Zachary Peters, Megan Day-Lewis, Tanya Novak, Myriam Armant, Lucinda Williams, Shira Rockowitz, Piotr Sliz, David A Williams, Adrienne G Randolph, Raif S Geha, Taking on COVID-19 Together Study Investigators, Abduarahman Almutairi, Faris Jaber, Tina Banzon, Jordan Roberts, Olha Halyabar, Mindy Lo, Stacy Kahn, Lauren A Henderson, Pui Y Lee, Mary Beth Son, Leah Cheng, Janet Chou, Craig D Platt, Saddiq Habiballah, Alan A Nguyen, Megan Elkins, Sabrina Weeks, Zachary Peters, Megan Day-Lewis, Tanya Novak, Myriam Armant, Lucinda Williams, Shira Rockowitz, Piotr Sliz, David A Williams, Adrienne G Randolph, Raif S Geha, Taking on COVID-19 Together Study Investigators, Abduarahman Almutairi, Faris Jaber, Tina Banzon, Jordan Roberts, Olha Halyabar, Mindy Lo, Stacy Kahn, Lauren A Henderson, Pui Y Lee, Mary Beth Son, Leah Cheng
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.
Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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Source: PubMed