Pathogenic NFKB2 variant in the ankyrin repeat domain (R635X) causes a variable antibody deficiency.

Clinical immunology (Orlando, Fla.) 2019 Jun

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Genetic studies are identifying an increasing number of monogenic causes of Common Variable Immunodeficiency (CVID). Pathogenic variants in the C-terminus of NFKB2 have been identified in the subset of CVID patients whose immunodeficiency is associated with ectodermal dysplasia and central adrenal insufficiency. We describe 2 unrelated CVID pedigrees with 4 cases of pathogenic stop gain variants (c.1903C > T) in the ankyrin repeat domain (ARD) of NF-κB2, leading to a premature truncation of the protein at p.Arg635Term (R635X). By immunophenotyping and functional ex vivo B- and T-cell experiments we characterized the variant by reduced class-switched memory B-cell counts and immature plasmablasts, unable to produce IgG and IgA. Features of a poor proliferative T-cell response and reduced expansion of CD4+CXCR5+ T cells was only observed in the two clinically affected index cases without any clear clinical correlate. In conclusion, pathogenic stop variants in the ARD of NFKB2 can cause 'infection-only' CVID with an abnormal B-cell phenotype and a variable clinical penetrance. Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Paul Tuijnenburg, Hana Lango Allen, Godelieve J de Bree, Sinisa Savic, Machiel H Jansen, Claire Stockdale, Ilenia Simeoni, Ineke J M Ten Berge, Ester M M van Leeuwen, NIHR BioResource, James E Thaventhiran, Taco W Kuijpers. Pathogenic NFKB2 variant in the ankyrin repeat domain (R635X) causes a variable antibody deficiency. Clinical immunology (Orlando, Fla.). 2019 Jun;203:23-27