Novel mutation and expanding phenotype in IRF2BP2 deficiency.

This article focuses on the identification and characterization of a novel pathogenic variant in the IFN regulatory factor-2 binding protein 2 (IRF2BP2) gene associated with common variable immunodeficiency (CVID) and immune dysregulation. The study reports a 33-year-old male patient with recurrent infections, colitis, and seronegative rheumatoid arthritis (RA), harboring a de novo nonsense IRF2BP2 variant leading to a truncated protein that impairs B cell maturation, plasmablast formation, and intracellular calcium signaling upon B cell receptor stimulation. Additionally, the patient exhibited impaired T cell cytokine production, reduced CTLA4 expression on regulatory T cells, and an elevated type I interferon signature. These findings expand the phenotypic spectrum of IRF2BP2 deficiency, linking it to both humoral immunodeficiency and autoimmune manifestations, and underscore the importance of genetic and functional diagnostics in tailoring therapeutic approaches for inborn errors of immunity.