Yaygın değişken immün yetmezliği olan multipleks bir ailede yeni bir heterozigot NFkB2 varyantının karakterizasyonu

Common variable immune deficiency (CVID) is a complex primary immunodeficiency characterized by low levels of serum immunoglobulins (IgG, and IgA and/or IgM) and higher vulnerability to recurrent infections, autoimmunity, and malignancies. Despite extensive clinical characterization, the underlying genetic causes of CVID remain elusive in many cases, complicating both diagnosis and treatment. In our study, we conducted a detailed genetic investigation of a multiplex family, in which both father and his two sons were affected by CVID. To identify inborn monogenic defects underlying CVID in this family, we performed whole exome sequencing (WES) on two affected members. We discovered a novel missense heterozygous variant (NM_001322934.2:c.2602T>A:p.Y868N) in NFKB2, encoding NF-κB2 protein, present in all patients but absent in the healthy mother, consistent with an autosomal dominant mode of inheritance with complete penetrance. To characterize the impact of this variant on the expression and function NF-κB2, we conducted various biochemical and functional studies using overexpression systems and patients' cells. We showed that the p.Y868N variant impairs the generation of active p52 from p100, thereby culminating in p100 accumulation. This accumulation leads to a gain-of-function (GOF) in inhibitory activity of IκBδ and a loss-of-function (LOF) in transcriptional activity of p52. These results suggested a causative link between the NFKB2 mutation and CVID in the patients. Our findings further expand the genetic spectrum of CVID and emphasize the importance of incorporating next generation sequencing technologies, such as WES, in the diagnostic evaluation of patients with CVID. Genetic dissection of CVID not only enhances our current understanding of its pathogenesis in humans, but also provides genetic testing and counselling in affected families and supports the development of more personalized therapeutic approaches, ultimately improving disease outcomes.