Loss of function NFKB1 variants are the most common monogenic cause of CVID in Europeans

Publication date: Available online 2 March 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Paul Tuijnenburg, Hana Lango Allen, Siobhan O. Burns, Daniel Greene, Machiel H. Jansen, Emily Staples, Jonathan Stephens, Keren J. Carss, Daniele Biasci, Helen Baxendale, Moira Thomas, Anita Chandra, Sorena Kiani-Alikhan, Hilary J. Longhurst, Suranjith L. Seneviratne, Eric Oksenhendler, Ilenia Simeoni, Godelieve J. de Bree, Anton T.J. Tool, Ester M.M. van Leeuwen, Eduard H.T.M. Ebberink, Alexander B. Meijer, Salih Tuna, Deborah Whitehorn, Matthew Brown, Ernest Turro, Adrian J. Thrasher, Kenneth G.C. Smith, James E. Thaventhiran, Taco W. Kuijpers
BackgroundThe genetic etiology of primary immunodeficiency disease (PID) carries prognostic information.ObjectiveWe conducted a whole-genome sequencing study assessing a large proportion of the NIHR-BioResource – Rare Disease cohort.MethodsIn the predominantly European study population of principally sporadic unrelated PID cases (n=846), a novel Bayesian method identified NFKB1 as one most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n=390) in the cohort. Amino-acid substitutions predicted to be pathogenic were assessed by analysis of structural protein data. Immunophenotyping, immunoblotting and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype co-segregation analyses.ResultsBoth sporadic and familial cases demonstrated evidence of the non-infective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%) and autoimmune disease (48%), features prior studies correlate with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B lymphocyte differentiation. Detailed assessment of B lymphocyte numbers, phenotype and function identifies the presence of a raised CD21^low B cell population: combined with identification of the disease-causing variant, this distinguishes between healthy individuals, asymptomatic carriers and clinically affected cases.ConclusionWe show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID that results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.

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