TY - JOUR
T1 - Loss of function NFKB1 variants are the most common monogenic cause of CVID in Europeans
AU - Tuijnenburg, Paul
AU - Lango Allen, Hana
AU - Burns, Siobhan O.
AU - Greene, Daniel
AU - Jansen, Machiel H.
AU - Staples, Emily
AU - Stephens, Jonathan
AU - Carss, Keren J.
AU - Biasci, Daniele
AU - Baxendale, Helen
AU - Thomas, Moira
AU - Chandra, Anita
AU - Kiani-Alikhan, Sorena
AU - Longhurst, Hilary J.
AU - Seneviratne, Suranjith L.
AU - Oksenhendler, Eric
AU - Simeoni, Ilenia
AU - de Bree, Godelieve J.
AU - Tool, Anton T. J.
AU - van Leeuwen, Ester M. M.
AU - Ebberink, Eduard H. T. M.
AU - Meijer, Alexander B.
AU - Tuna, Salih
AU - Whitehorn, Deborah
AU - Brown, Matthew
AU - Turro, Ernest
AU - Thrasher, Adrian J.
AU - Smith, Kenneth G. C.
AU - Thaventhiran, James E.
AU - Kuijpers, Taco W.
PY - 2018
Y1 - 2018
N2 - The genetic etiology of primary immunodeficiency disease (PID) carries prognostic information. We conducted a whole-genome sequencing study assessing a large proportion of the NIHR-BioResource - Rare Disease cohort. In the predominantly European study population of principally sporadic unrelated PID cases (n=846), a novel Bayesian method identified NFKB1 as one 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 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 co-segregation analyses. lowB cell population: combined with identification of the disease-causing variant, this distinguishes between healthy individuals, asymptomatic carriers and clinically affected cases. We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID that results in a temporally progressive defect in the formation of immunoglobulin-producing B cells
AB - The genetic etiology of primary immunodeficiency disease (PID) carries prognostic information. We conducted a whole-genome sequencing study assessing a large proportion of the NIHR-BioResource - Rare Disease cohort. In the predominantly European study population of principally sporadic unrelated PID cases (n=846), a novel Bayesian method identified NFKB1 as one 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 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 co-segregation analyses. lowB cell population: combined with identification of the disease-causing variant, this distinguishes between healthy individuals, asymptomatic carriers and clinically affected cases. We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID that results in a temporally progressive defect in the formation of immunoglobulin-producing B cells
U2 - https://doi.org/10.1016/j.jaci.2018.01.039
DO - https://doi.org/10.1016/j.jaci.2018.01.039
M3 - Article
C2 - 29477724
SN - 0091-6749
VL - 142
SP - 1285
EP - 1296
JO - Journal of allergy and clinical immunology
JF - Journal of allergy and clinical immunology
IS - 4
ER -