Screening of autoinflammatory genes in patients with SARS-CoV-2-associated MIS-C

Multisystem inflammatory syndrome in children (MIS-C) is a rare but severe complication of SARS-CoV-2 infection, characterized by systemic hyperinflammation. Evidence indicates innate immunity defects may predispose children to MIS-C. Host genetics may influence MIS-C susceptibility and severity, but underlying mechanisms remain incompletely understood. The aim of this study was to identify rare genetic variants in autoinflammatory genes that may contribute to MIS-C.

Whole-exome sequencing was performed in 21 unvaccinated Brazilian children with MIS-C, stratified as non-critical or critical. Variant prioritization focused on single nucleotide variants with minor allele frequency < 0.001 in autoinflammatory genes. Functional impact was inferred using variant pathogenicity metrics, gene constraint scores, and in silico molecular docking. Four heterozygous missense variants were prioritized in three genes (SH3BP2, CARD14, and ADAM17), all in critical patients. ADAM17 was the most constrained gene, with variants in protein maturation (P18L) and substrate recognition (T663N) domains. Docking analyses showed both substitutions could affected ADAM17 interactions. ADAM17-NOTCH1 binding was predicted to be impaired by in silico analysis.

Rare deleterious variants in autoinflammatory genes, especially ADAM17, may influence immune regulation and MIS-C severity. Our results highlight genetic pathways underlying MIS-C and provide a framework for mechanistic studies. Understanding how ADAM17 variants affect immune regulation may improve risk stratification and guide targeted therapies.