Tuijnenburg, P., Lango Allen, H., Burns, S.O. et al. (85 more authors) (2018) Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans. Journal of Allergy and Clinical Immunology, 142 (4). pp. 1285-1296. ISSN 0091-6749
Abstract
Background: The genetic cause 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 Diseases cohort. Methods: In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes 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 means of 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 cosegregation analyses. Results: Both sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated 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 an increased CD21lowB-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, 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, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 The Authors. Published by Elsevier Inc. on behalf of the American Academy ofAllergy, Asthma & Immunology. This is an open access article under the CC BY li-cense (http://creativecommons.org/licenses/by/4.0/). |
Keywords: | B cells; common variable immunodeficiency; nuclear factor κB1 |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 06 Aug 2018 11:40 |
Last Modified: | 07 Aug 2020 12:14 |
Status: | Published |
Publisher: | Elsevier |
Refereed: | Yes |
Identification Number: | 10.1016/j.jaci.2018.01.039 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:132993 |