Introduction: MIS-C is a post–SARS-CoV-2 syndrome with frequent cardiac and vascular involvement. The clinical overlap between MISC and Kawasaki disease suggests convergent pathways and supports the hypothesis that KD may represent a final common inflammatory outcome of diverse infectious triggers in genetically predisposed children [1].
Rationale: Rare monogenic inborn errors of immunity have been reported in MIS-C [2–4]. TNFAIP3 encodes A20, a negative regulator of NF-κB signaling, and A20 haploinsufficiency is expected to lower the threshold for infection-triggered inflammation. We identified a pathogenic variant in TNFAIP3 in a child with recurrent inflammatory episodes who presented with severe MIS-C, leading to diagnosis of HA20. We screened a large MIS-C exome dataset (n=558) for rare TNFAIP3 variants. In parallel, within the French network for inflammatory diseases, patients with molecularly confirmed HA20 were reviewed for MISC or KD. We analyzed the functional impact of prioritized variants and investigated clinical overlap with KD in HA20.
Results: The index patient had recurrent fevers before MIS-C and developed shock-like hyperinflammation with TCR Vβ21.3+ T-cell expansion and a positive type I IFN signature. Exome sequencing identified rare nonsynonymous TNFAIP3 variants in MIS-C (n=14) and KD (n=4) cases (MAF <0.01), which were prioritized for functional testing. In parallel, two molecularly confirmed HA20 patients with a KD phenotype and one MIS-C–like case carrying a TNFAIP3 VUS were identified. Overall, 13 variants, including the index case, selected exome-derived variants (n=9), HA20/KD variants (n=2), and the MIS-C VUS, were functionally tested. In an NF-κB luciferase reporter assay, 3/13 variants (R271* as positive control) showed loss of function due to reduced protein expression. SARS-CoV-2 infection assays and PBMC single-cell RNA sequencing are ongoing to further dissect SARS-CoV-2 responses in HA20 patients.
Conclusion: These findings support a role for IEIs in a subset of MIS-C and identify TNFAIP3 as a shared monogenic contributor to MIS-C and KD, supporting a common genetic architecture. NF-κB dysregulation may underlie their phenotypic overlap and intersect with interferon responses. Clinically, recurrent or atypical KD and severe MIS-C should prompt consideration of monogenic IEIs, including TNFAIP3.