Dissecting the molecular heterogeneity of common variable immunodeficiency using an integrative multi-omics approach

Common variable immunodeficiency (CVID), the most common clinically significant inborn error of immunity (IEI), is characterized by hypogammaglobulinemia and impaired antibody responses to infections and vaccination. Although monogenic defects have been identified in a subset of patients, the molecular basis of CVID remains unresolved in most cases, reflecting substantial clinical and biological heterogeneity and contributions from polygenic, epigenetic, and environmental factors. In this narrative review, we summarize recent advances in genomics, epigenomics, transcriptomics, proteomics, microbiomics, metabolomics, and multi-omic integration based on published literature identified through searches of major biomedical databases. These approaches have uncovered dysregulated immune signaling pathways, impaired B-cell differentiation programs, inflammatory molecular endotypes, altered immune tolerance mechanisms, and host–microbiome–metabolite interactions contributing to disease heterogeneity. Emerging multi-omic studies further demonstrate mechanistic links among microbial translocation, metabolic re-programming, inflammatory signaling, and immune dysfunction in CVID. Integrative multi-omic approaches enable improved disease stratification, refined molecular classification of CVID phenotypes, enhanced diagnostic resolution, and identification of biomarkers and therapeutic targets, particularly in genetically unresolved patients. Emerging evidence also supports precision medicine strategies by linking molecular endotypes with pathway-directed therapeutic interventions. Continued advances in integrated multi-omic approaches are expected to improve molecular diagnosis and facilitate more personalized management of CVID.