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

Tuijnenburg, P; Lango Allen, H; Burns, SO; Greene, D; Jansen, MH; Staples, E; Stephens, J; ... NIHR-BioResource – Rare Diseases Consortium, .; + view all (2018) Loss of function NFKB1 variants are the most common monogenic cause of CVID in Europeans. Journal of Allergy and Clinical Immunology , 142 (4) pp. 1285-1296. 10.1016/j.jaci.2018.01.039. Green open access

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Abstract

BACKGROUND: The genetic etiology of primary immunodeficiency disease (PID) carries prognostic information. OBJECTIVE: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR-BioResource - Rare Disease cohort. METHODS: In 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. RESULTS: Both 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 CD21lowB cell population: combined with identification of the disease-causing variant, this distinguishes between healthy individuals, asymptomatic carriers and clinically affected cases. CONCLUSION: We 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.

Type: Article
Title: Loss of function NFKB1 variants are the most common monogenic cause of CVID in Europeans
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jaci.2018.01.039
Publisher version: https://doi.org/10.1016/j.jaci.2018.01.039
Language: English
Additional information: The is the author accepted manuscript version made available under a Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (http://creativecommons.org/licenses/by/4.0/).
Keywords: B cells; Common Variable Immunodeficiency; NF-κB1
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10044633
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