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

Clin Immunol. 2019 Jun:203:23-27. doi: 10.1016/j.clim.2019.03.010. Epub 2019 Apr 3.


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.

Keywords: B cells; Common variable immunodeficiency; NFKB2; T cells.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Insufficiency / congenital
  • Ankyrin Repeat / genetics
  • B-Lymphocytes / immunology*
  • Cells, Cultured
  • Common Variable Immunodeficiency / genetics
  • Common Variable Immunodeficiency / immunology*
  • Ectodermal Dysplasia
  • Female
  • Humans
  • Immunoglobulin Class Switching / genetics
  • Immunologic Memory
  • Immunophenotyping
  • Lymphocyte Activation
  • Male
  • Mutation / genetics*
  • NF-kappa B p52 Subunit / genetics*
  • Pedigree
  • Receptors, CXCR5 / metabolism
  • T-Lymphocytes / immunology*


  • CXCR5 protein, human
  • NF-kappa B p52 Subunit
  • NFKB2 protein, human
  • Receptors, CXCR5

Supplementary concepts

  • Adrenal Insufficiency, Congenital