Whole Genome Sequencing identifies loss of function variants in NFKB1 as the most common monogenic cause of Common Variable Immunodeficiency in Europeans

ObjectiveWe conducted a whole-genome sequencing study assessing a large proportion of the NIHR-BioResource–Rare Disease cohort.MethodsIn 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.ResultsBoth sporadic and familial …