Mechanisms underlying genetic susceptibility to multisystem inflammatory syndrome in children (MIS-C)

J Allergy Clin Immunol. 2021 Sep;148(3):732-738.e1. doi: 10.1016/j.jaci.2021.06.024. Epub 2021 Jul 2.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Biomarkers
  • COVID-19 / complications
  • COVID-19 / diagnosis
  • COVID-19 / etiology*
  • COVID-19 / metabolism*
  • COVID-19 / virology
  • Child
  • Child, Preschool
  • Cytokines / metabolism
  • Disease Susceptibility*
  • Female
  • Genetic Predisposition to Disease*
  • Host-Pathogen Interactions / immunology
  • Humans
  • Male
  • SARS-CoV-2
  • Systemic Inflammatory Response Syndrome / diagnosis
  • Systemic Inflammatory Response Syndrome / etiology*
  • Systemic Inflammatory Response Syndrome / metabolism*


  • Biomarkers
  • Cytokines

Supplementary concepts

  • pediatric multisystem inflammatory disease, COVID-19 related