1. Mechanisms underlying genetic susceptibility to Multisystem Inflammatory Syndrome in Children (MIS-C)
- Author
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David A. Williams, Leah Cheng, Janet Chou, Sabrina Weeks, Saddiq Habiballah, Megan Elkins, Faris Jaber, Mary Beth F. Son, Alan A. Nguyen, Lucinda Williams, Megan Day-Lewis, Tina Banzon, Zachary Peters, Stacy A. Kahn, Raif S. Geha, Pui Y. Lee, Lauren A. Henderson, Craig D. Platt, Mindy S. Lo, Tanya Novak, Jordan E Roberts, Abduarahman Almutairi, Adrienne G. Randolph, Olha Halyabar, Piotr Sliz, Myriam Armant, and Shira Rockowitz
- Subjects
CRP, C reactive protein ,Male ,RT-PCR, reverse transcriptase-polymerase chain reaction ,whole exome sequencing ,NOD2 ,Immunology and Allergy ,Medicine ,Prospective cohort study ,Child ,Exome sequencing ,COVID-19, coronavirus disease 2019 ,education.field_of_study ,Systemic Inflammatory Response Syndrome ,Child, Preschool ,Host-Pathogen Interactions ,XIAP, X-linked inhibitor of apoptosis ,Cytokines ,Female ,Disease Susceptibility ,Haploinsufficiency ,WES, whole exome sequencing ,NOD, nucleotide-binding oligomerization domain-containing ,Immunology ,Population ,HLH, hemophagocytic lymphohistiocytosis ,MIS-C ,SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 ,Article ,Multisystem Inflammatory Syndrome in Children ,CYBB, Cytochrome b(-245) ,EBV, Epstein Barr virus ,Genetic predisposition ,Humans ,IFN, interferon ,Genetic Predisposition to Disease ,CYBB ,education ,Hemophagocytic lymphohistiocytosis ,business.industry ,SARS-CoV-2 ,COVID-19 ,CGD, chronic granulomatous disease ,medicine.disease ,IVIG, intravenous immunoglobulin ,NGS, next-generation sequencing ,SOCS1, Suppressor of cytokine signaling 1 ,MIS-C, multisystem inflammatory syndrome in children ,business ,Biomarkers - Abstract
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., Graphical abstract, Capsule Summary: Hypomorphic inborn errors of immunity may predispose children to SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Children (MIS-C).
- Published
- 2021