TY - JOUR
T1 - Pathogenic NFKB2 variant in the ankyrin repeat domain (R635X) causes a variable antibody deficiency
AU - NIHR BioResource
AU - Tuijnenburg, Paul
AU - Lango Allen, Hana
AU - de Bree, Godelieve J.
AU - Savic, Sinisa
AU - Jansen, Machiel H.
AU - Stockdale, Claire
AU - Simeoni, Ilenia
AU - ten Berge, Ineke J. M.
AU - van Leeuwen, Ester M. M.
AU - Thaventhiran, James E.
AU - Kuijpers, Taco W.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85064199923&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30953794
U2 - https://doi.org/10.1016/j.clim.2019.03.010
DO - https://doi.org/10.1016/j.clim.2019.03.010
M3 - Article
C2 - 30953794
SN - 1521-6616
VL - 203
SP - 23
EP - 27
JO - Clinical Immunology
JF - Clinical Immunology
ER -