Common variable immunodeficiency, same name but different etiologies: unraveling heterogeneity through functional and genetic profiling

Introduction Common variable immunodeficiency (CVID) represents a challenge for medical genomics, as it does not fully conform to a classical Mendelian inheritance model. Beyond the monogenic model, diverse molecular mechanisms, including polygenic contributions, somatic mutations, epigenetic modifications, and skewed X-chromosome inactivation, may play relevant roles in disease development, driving a broad clinical spectrum from classical antibody deficiency to complex immune dysregulation. Integrating clinical, immunological, functional, and genetic data is therefore essential to unravel this complexity and advance toward personalized precision medicine. Methods We conducted an in-depth clinical, immunological, functional, and genetic characterization of four distinct selected cases (P1–P4) from a cohort of adult patients with CVID. Targeted next-generation sequencing (NGS), cytokine profiling, and specific in vitro functional assays were performed to validate B-cell maturation defects, intracellular signaling, and variant pathogenicity. Results We identified novel and rare pathogenic variants in key B-cell pathways that converged on a common B-cell maturation defect but diverged into distinct phenotypes. Patient 1 (P1) presented a novel IKZF1 variant that disrupted early B-cell ontogeny, whereas Patient 2 (P2) exhibited a rare compound heterozygous defect in TNFRSF13B (TACI) that affected peripheral B-cell activation, both manifesting a predominantly infectious phenotype. In contrast, Patients 3 and 4 presented with severe immune dysregulation. Patient 3 (P3) harbored a novel splice-site deficiency in LRBA , while Patient 4 (P4) exhibited concurrent heterozygous variants in BLK and EBF1 , supporting a novel oligogenic "double-hit" hypothesis. Functional assays validated the deleterious impact of these variants across all cases. Discussion Our findings not only expand the known phenotypic spectrum but also underscore the value of functional assays in validating novel genotypes. Ultimately, this comprehensive profiling provides essential insights to refine prognosis and advance toward tailored precision medicine in CVID.