Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans

Abstract

BackgroundThe genetic cause of primary immunodeficiency disease (PID) carries prognostic information.ObjectiveWe conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource–Rare Diseases cohort.MethodsIn the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes 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 means of 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 cosegregation analyses.ResultsBoth sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21low B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases.ConclusionWe show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.

Common variable immune deficiency: Dissection of the variable

“…114,154 These also lead to a quite variable form of autosomal dominant antibody deficiency, with respiratory infections, unusual infections, autoimmunity and lymphoproliferative disease. 115,154,155 First reported in a large Dutch family with six subjects with CVID in three generations, the family was re-investigated and additional members were found to have moderate to severe hypogammaglobulinemia or IgA deficiency. 156,157 Subsequently in this and two other families, different heterozygous mutations in the NFKB1 gene were identified.…”

Functions of Tfh Cells in Common Variable Immunodeficiency

“…Nevertheless, a genetic cause has been identified in about 25% of CVID patients using next-generation sequencing. As examples, mutations in several genes encoding for B cell receptor complex associated proteins, B cell activating factor receptor (BAFF-R), inducible co-stimulator (ICOS), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), phosphatidylinositol 3-kinase (PI3K), and in lipopolysaccharide-responsive beige-like anchor (LRBA) protein or more recently the NFκB family have been described (5)(6)(7). Mutations in the TNFRSF13B gene encoding the transmembrane activator and CAML interactor (TACI) are found in 8-10% of patients (8) but relatives to CVID patients with mutations in TACI display normal levels of Ig.…”

Whole-genome sequencing of rare disease patients in a national healthcare system

“…Our recent genetic discoveries have informed treatment decisions: 27 patients with early-onset dystonia due to variants in KMT2B can be treated by deep brain stimulation 9 ; cases with DIAPH1related macrothrombocytopenia and deafness 10 can have their platelet count restored to a safe level in a preoperative setting with Eltrombopag 11 ; and a case of severe thrombocytopenia accompanied by myelofibrosis and bleeding caused by a gain-of-function variant in SRC 12 was cured by an allogeneic haematopoietic stem cell transplant. In addition, our diagnoses have helped stratify patient care: patients with Primary Immune Disorders (PID) due to variants in NFKB1, which we have shown are the commonest monogenic cause of combined variable immunodeficiency (CVID) 13 , have unexplained splenomegaly and an increased risk of cancer; 27 cases from the Bleeding, Thrombotic and Platelet Disorders (BPD) domain with isolated thrombocytopenia caused by variants in ANKRD26, ETV6 or RUNX1 have an increased risk of malignancy 14,15,16 compared to 19 cases with benign thrombocytopenia due to variants in ACTN1, CYCS or TUBB1 17 ; and the prognosis for patients with Pulmonary Arterial Hypertension (PAH) caused by mutations in ATP13A3, AQP1, GDF2 and SOX17, genes which we have recently reported as aetiological 18 , is better than the prognosis for patients with mutations in BMPR2 19 or EIF2AK4 20 .…”

“…We inferred strong evidence for association between 29 phenotypic tags, spanning nine domains, and 99 genes. These included 62 established DGGs, 18 DGGs discovered since 2015 18,22,23,24,25,26,13,27,28,29,8,17,30,31,25,32,9,33,10 and 19 candidates requiring further investigation ( Fig. 3).…”