Multi-omics characterization of Yao syndrome identifies three pathophysiological axes and disease-specific divergence from Blau syndrome.

Yao syndrome (YAOS, OMIM #617321) is a NOD2-associated systemic autoinflammatory disease whose molecular pathophysiology remains uncharacterized, with no patient-level omics data reported. We performed the first integrated multi-omics characterization of YAOS. Peripheral blood mononuclear cell (PBMC) transcriptomics (RNA-seq; DESeq2), quantitative plasma proteomics (7352 proteins; DIA-MS/DIA-NN), and untargeted metabolomics (1051 MS2-annotated metabolites) were performed on six YAOS patients carrying NOD2 variants across all four functional domains (CARD, NBD, NBD-LRR junction, LRR) and healthy controls (HC). Analyses included transcription factor (TF) activity inference, CIBERSORTx immune deconvolution, co-expression network analysis, drug target mapping, and parallel transcriptomic comparison with Blau syndrome (n = 3). Despite >100-fold C-reactive protein (CRP) variation (0.31-36.34 mg/L) and regimens ranging from no treatment to quadruple immunosuppression, 600 differentially expressed genes (DEGs) were identified (|log₂FC|> 1, false discovery rate [FDR] < 0.05). NF-κB was the dominant transcriptional program (TF activity P= 0.008). Cross-platform integration identified three convergent pathophysiological axes: NF-κB/pyroptosis-driven innate immune activation (7/7 effectors directionally concordant between transcriptome and proteome), metabolic reprogramming linked to acylcarnitine accumulation (log₂FC = +0.75 to +1.42, nominal P<0.05), and gut-immune axis disruption. This inflammatory architecture persisted across all regimens examined. Drug target mapping indicated that none of the six currently targeted gene products reached transcriptomic significance, whereas three untargeted nodes-RELA, gasdermin D (GSDMD), and tyrosine kinase 2 (TYK2)-were among the most significantly upregulated (all FDR < 0.001). Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) emerged as the top co-expression hub. Parallel comparison with Blau syndrome (BS, OMIM #186580) revealed qualitatively distinct effector programs-pyroptosis execution with M1 polarization in YAOS versus inflammasome activation without pyroptosis in BS. This first patient-level multi-omics characterization of a NOD2-associated autoinflammatory disease identifies a convergent, YAOS-specific inflammatory architecture and a treatment-target mismatch, generating mechanistic and therapeutic hypotheses that require validation in adequately powered cohorts.