Mechanisms underlying genetic susceptibility to multisystem inflammatory syndrome in children (MIS-C).
J Allergy Clin Immunol
; 148(3): 732-738.e1, 2021 09.
Article
in English
| MEDLINE | ID: covidwho-1293879
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
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Systemic Inflammatory Response Syndrome
/
Genetic Predisposition to Disease
/
Disease Susceptibility
/
COVID-19
Type of study:
Cohort study
/
Diagnostic study
/
Observational study
/
Prognostic study
Topics:
Long Covid
/
Variants
Limits:
Child
/
Child, preschool
/
Female
/
Humans
/
Male
Language:
English
Journal:
J Allergy Clin Immunol
Year:
2021
Document Type:
Article
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