%0 Case Reports
%T Novel mutation and expanding phenotype in IRF2BP2 deficiency.
%A Körholz J
%A Gabrielyan A
%A Sczakiel HL
%A Schulze L
%A Rejzek M
%A Laass MW
%A Leuchten N
%A Tiebel O
%A Aust D
%A Conrad K
%A Röber N
%A Jacobsen EM
%A Ehmke N
%A Berner R
%A Lucas N
%A Lee-Kirsch MA
%A Wiedemuth R
%A Roesler J
%A Roers A
%A Amendt T
%A Schuetz C
%J Rheumatology (Oxford)
%V 62
%N 4
%D 04 2023 3
%M 36193988
%F 7.046
%R 10.1093/rheumatology/keac575
%X Inborn errors of immunity manifest with susceptibility to infection but may also present with immune dysregulation only. According to the European Society for Immunodeficiencies Registry about 50% of inborn errors of immunity are classified as common variable immunodeficiencies (CVID). In only few CVID patients are monogenic causes identified. IFN regulatory factor-2 binding protein 2 (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 a novel pathogenic variant and phenotype and characterize impaired B cell function and immune dysregulation.<BR>We performed trio whole-exome sequencing, determined B cell subpopulations and intracellular calcium mobilization upon B cell receptor crosslinking in B cells. T cell subpopulations, T cell proliferation and a type I IFN signature were measured. Colonoscopy and gastroduodenoscopy including histopathology were performed.<BR>The 33-year-old male presented with recurrent respiratory infections since childhood, colitis and RA beginning at age 25 years. 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 I IFN signature was elevated.<BR>The identified loss-of-function variant in IRF2BP2 severely impairs B cell development and 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 the understanding of the underlying pathomechanisms.