{Reference Type}: Case Reports
{Title}: Novel mutation and expanding phenotype in IRF2BP2 deficiency.
{Author}: Körholz J;Gabrielyan A;Sczakiel HL;Schulze L;Rejzek M;Laass MW;Leuchten N;Tiebel O;Aust D;Conrad K;Röber N;Jacobsen EM;Ehmke N;Berner R;Lucas N;Lee-Kirsch MA;Wiedemuth R;Roesler J;Roers A;Amendt T;Schuetz C;
{Journal}: Rheumatology (Oxford)
{Volume}: 62
{Issue}: 4
{Year}: 04 2023 3
{Factor}: 7.046
{DOI}: 10.1093/rheumatology/keac575
{Abstract}: 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.