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

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, James E. Thaventhiran, Taco W. Kuijpers, NIHR BioResource

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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.
Original languageEnglish
Pages (from-to)23-27
JournalClinical Immunology
Publication statusPublished - 1 Jun 2019

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