Pathway-level transcriptional convergence between Gaucher disease and common variable immunodeficiency reveals concordant interferon and antigen-processing signatures.

BACKGROUND: Gaucher disease (GD), an inborn error of metabolism, and common variable immunodeficiency (CVID), an inborn error of immunity, have distinct etiologies but may exhibit convergent downstream transcriptional responses. We investigated transcriptional robustness and pathway-level convergence using a robustness-oriented transcriptomic framework.

METHODS: Public datasets were analyzed independently for GD and CVID. Patient-level GD fibroblast profiles (GSE124283) underwent differential-expression analysis, leave-one-patient-out (LOPO) testing, expression-scale sensitivity analysis, and Reactome gene-set enrichment analysis (GSEA), with validation in GSE21899 and GSE303993. CVID whole-blood profiles (GSE51404) were analyzed using group-only and age/sex-adjusted models. Cross-disease convergence was assessed among robust Reactome pathways.

RESULTS: 18 Reactome pathways remained robust across GD patient-exclusion and expression-scale analyses. The validation demonstrated context-dependent replication, including concordant enrichment of 11/18 pathways in the neuronopathic GD organoid model. In CVID, only 2 genes were differentially expressed between inflammatory and non-inflammatory CVID at FDR < 0.05, whereas 143 pathways remained robust to demographic adjustment. 11 robust GD pathways overlapped with this CVID comparison, all with concordant enrichment direction, prominently involving interferon and antigen-processing programs; mitochondrial pathways showed context-dependent patterns.

CONCLUSION: GD and CVID exhibit selective pathway-level transcriptional convergence rather than a shared causal mechanism, supporting robustness-aware pathway analysis across heterogeneous disorders.