Novel heterozygous NFKB1 mutation—variable penetrance in a family cohort

Background: Common variable immunodeficiency (CVID) is a term used to define a heterogeneous group of patients who commonly have hypogammaglobulinemia and variable degrees of modest T cell dysfunction. Recent advances made in next generation sequencing technologies have accelerated the identification of CVID disease-causing genes, including NFKB1, a component of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Objective: We sought to identify the genetic defect in a 3-generation family of patients with CVID who presented with cytopenias, eczema, and recurrent sinopulmonary infections. Methods: Whole exome sequencing and Sanger confirmation was performed, and a combination of molecular and cellular techniques used to assess the variant impact on B and T cell function. Results: A novel heterozygous frameshift mutation in NFKB1, encoding the transcriptional regulator protein p50/p105, was identified. This resulted in c.1584dupG (p.M528fs). We demonstrate that c.1584dupG is a loss-of-function variant, responsible for reduced p105/p50 protein expression in affected individuals as well as variable increased CD21low B cell numbers. Conclusion: This novel mutation affecting NFKB1 causes a CVID phenotype with variable clinical manifestations. Given the wide spectrum of age in this kindred, this may reflect diversity of phenotype expression, or more probably, age-related expression of typical features. Statement of novelty: We report here a novel loss-of-function frameshift mutation in NFKB1.