Submission Details

NFKBIA was first reported in relation to autosomal-dominant anhidrotic ectodermal dysplasia with immune deficiency (AD-EDA-ID) in 2003 (Courtois et al., PMID: 14523047). NFKBIA is an inhibitor of NF-κB and encodes the protein IκBα. When the IκB kinase (IKK) complex phosphorylates IκBα at specific serine residues thereby promoting its ubiquitnation and degradation by the proteasome, the NF-κB complex is released and allowed to translocate into the nucleus and activate target genes. AD-EDA-ID is a form of ectodermal dysplasia, a group of conditions defined by abnormal development of ectodermal tissues including skin, hair, and sweat glands. Additionally, patients with EDA-ID often have reduced immune functions, with a combined T and B cell immunodeficiency alongside impaired monocyte and neutrophil responses to TLR stimulation, leading to susceptibility to bacterial, fungal, viral, and other opportunistic infections. Symptoms are evident soon after birth, with variable severity. 14 variants (11 missense and 3 nonsense) that have been reported in 18 probands in 16 publications (PMIDs: 23864385, 14523047, 23708964, 17931563, 22078572, 18412279, 23870671, 29948576, 35005117, 28417298, 28629746, 31683054, 32222431, 36292785, 15337789, 26691317) are included in this curation. Case-Level evidence supports this gene-disease relationship, with the majority of variants being de novo and having functional evidence. The mechanism of pathogenicity is reported to be gain of function due to increased resistance to degradation. This gene-disease relationship is also supported by mouse models, in vitro functional assays, expression studies, and biochemical function (PMIDs: 23864385, 14523047, 23708964, 25601653). A mouse model was made to be heterozygous for S32I mutation in NFKBIA (PMID: 25601653). This mouse has many features that reflect the presentation of EDA-ID seen in patients with NFKBIA mutations, including teeth and hair abnormalities and impaired immune responses. The in vitro functional assays and expression studies further support the role of NFKBIA mutations in the disease by demonstrating a connection to altered NF-kB signaling. More evidence is available in the literature, but the maximum score for experimental evidence (6 pts.) has been reached. In summary, there is definitive evidence supporting the relationship between NFKBIA and AD-EDA-ID. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen SCID-CID GCEP on the meeting date January 16th, 2025 (SOP Version 11).