NFKB1

Inheritance Pattern: AD

Disease ID:MONDO:0014697

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014697

Submitter: ClinGen

*NFKB1* was first reported in relation to autosomal dominant common variable immunodeficiency in 2015 (Fliegauf M et al., PMID: 26279205). Common variable immunodeficiency associated with pathogenic NFKB1 variants has a heterogeneous presentation in patients, often including hypogammaglobulinemia with or without changes to the size of the overall B cell population and increased susceptibility to autoimmunity, infections, and malignancies (PMID: 29477724). Ten variants (e.g. missense, nonsense, frameshift, and splice site) that have been reported in ten probands in two publications (PMIDs: 29477724, 26279205) are included in this curation. In addition, segregation of an NFKB1 variant in a family with common variable immunodeficiency was included as evidence (PMID: 26279205). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease association is also supported by animal models and in vitro functional assays (PMIDs: 7834752, 25225457, 27022143, 28115215). Specifically, mouse models with abrogated NFKB1 expression presented with features of human disease, including increased susceptibility to certain infections, decreased levels of certain antibody subtypes, and increased incidence of autoimmunity (PMIDs: 7834752, 27022143). Defects in T-cell-dependent antigen-specific antibody production by B cells with decreased p50 expression in mice were found to be overcome by genetically increased expression of p50 (PMID: 25225457). In addition, human cell lines expressing missense *NFKB1* variants were found to have functional defects, including reduced nuclear translocation of NFKB1 and stability (PMID: 28115215). Notably, *NFKB1*-associated common variable immunodeficiency has a reduced penetrance that is estimated to be 60-80% based on family studies and intra- and inter-familial differences in expressivity, age of onset, and clinical features have been reported. (PMIDs: 28115215, 29477724). While *NFKB1* is clearly associated with common variable immunodeficiency, patients with alternative phenotypes have been reported, including one family with postoperative necrotizing cellulitis and neutrophilia in the absence of hypogammaglobulinemia and increased susceptibility to infections and another family with Behcet’s disease along with hypogammaglobulinemia and recurrent infections (PMID: 28115215). Therefore, the clinical signs and symptoms associated with *NFKB1* may still be emerging and *NFKB1* defects should be considered in patients with immunodeficiency and associated evidence of autoinflammation. In summary, *NFKB1* is definitively associated with autosomal dominant common variable immunodeficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. **Data provided by the ClinGen Monogenic Diabetes GCEP on February 19, 2025:** Currently, there is limited evidence that loss-of-function variants in *NFKB1* are implicated in diabetes. The first report of the gene in an individual with diabetes occurred in 2019 in an individual harboring the c.904dup, p.(Ser302PhefsTer7) variant, who was reported to have type 2 diabetes mellitus in addition to hypogammaglobulinemia, recurrent bronchitis, sinusitis, CMV-colitis, splenomegaly, nodular lymphoid hyperplasia of the gastrointestinal tract, nodular regenerative hyperplasia of the liver, non-Hodgkin lymphoma, and Addison’s disease (PMID: 31803180). Two of their younger family members were also found to harbor the variant, but neither of them had a history of diabetes. Additionally, another study reported that 1.8% of 106 participants harboring a pathogenic *NKFB1* variant had type I diabetes (T1D) (PMID: 32278790); the specific variant associated with T1D was not reported. Another loss-of-function variant was identified in an individual with a history of pyoderma gangrenosum with recurrent fevers and increased neutrophile and white blood cell counts in addition to diabetes. Most recently, a heterozygous splice site variant c.1753-1G>C was reported in an individual with a history of “atypical diabetes” (PMID: 37104866). While diabetes has in rare instances been observed in individuals with pathogenic *NFKB1* variants, there is insufficient evidence to prove or disprove a causal relationship at this time. Given the wide range of autoimmune manifestations associated with *NFKB1,* individuals found to have a pathogenic variant in the context of diabetes should also receive regular thyroid, blood, liver, renal, and pulmonary screening.

Inheritance Pattern: AD

Disease ID:MONDO:0014697

Submitter: Labcorp Genetics (formerly Invitae)