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Novel mutation and expanding phenotype in IRF2BP2 deficiency.

OBJECTIVES
Inborn errors of immunity (IEI) manifest with susceptibility to infection but may also present with immune dysregulation only. According to the European Society for Immunodeficiencies (ESID) Registry about 50% of IEI are classified as common variable immunodeficiencies (CVID). In only few CVID patients monogenic causes are identified. IRF2BP2 is one of 20 known genes associated with CVID phenotypes and has only been reported in two families so far. We report another IRF2BP2 deficient patient with novel pathogenic variant and phenotype and characterize impaired B-cell function and immune dysregulation.


METHODS
We performed trio whole exome sequencing (WES), determined B-cell subpopulations and intracellular calcium mobilization upon B-cell receptor (BCR) crosslinking in B cells. T-cell subpopulations, T-cell proliferation and a type 1 interferon-signature were measured. Colonoscopy and gastroduodenoscopy including histopathology were performed.


RESULTS
The 33-year-old male presented with recurrent respiratory infections since childhood, colitis, and rheumatoid arthritis (RA) beginning at age 25. We identified a novel de novo nonsense IRF2BP2 variant c.1618C>T; p.(Q540*). IgG deficiency was detected as consequence of a severe B-cell differentiation defect. This was confirmed by impaired plasmablast formation upon stimulation with CpG. No serum autoantibodies were detected. Intracellular cytokine production in CD4+ T cells and CTLA4 expression on FOXP3+ Tregs were impaired. Type 1 interferon-signature was elevated.


CONCLUSION
The identified loss-of-function variant in IRF2BP2 severely impairs B-cell development, T-cell homeostasis and may be associated with colitis and RA. Our results provide further evidence for association of IRF2BP2 with CVID and contribute to understanding the underlying pathomechanisms.