Heterozygous germline variants in IKBKB were first reported in relationship to anhidrotic ectodermodysplasia with immunodeficiency due to IKBKB GOF mutations in 2018 (PMID: 30337470). Subsequent reports have described affected individuals presenting with variable onset of recurrent infections, progressive combined T and B cell deficiency, and immune dysregulation manifesting as autoimmunity, autoinflammation, or ectodermal abnormalities (PMID: 40403933, 32554083, 36378426, 38758301). In total, there have been a reported four different heterozygous missense gain-of-function (GOF) variants across 19 probands.
IKKβ is the catalytic subunit of the IκB kinase (IKK) complex, responsible for phosphorylating IκB and triggering its degradation and activating the NF-κB pathway. GOF variants in IKBKB lead to constitutive and hyperresponsive activation of canonical NF-κB signaling, characterized by increased phosphorylation of IKKα/β and p65 with enhanced degradation of IκBα (PMID: 30337470). Functional studies using patient-derived cells demonstrate excessive NF-κB activity, impaired proliferative capacity, and abnormal B- and T-cell differentiation and function (PMID: 30337470, 40403933). Clinically affected individuals show phenotypic heterogeneity and age-related penetrance, with some patients becoming phenotypically apparent only after the age of 30 (PMID: 40403933). A mouse model harboring an IKBKB GOF mutation recapitulates key features observed reported probands (PMID: 30337470).
In summary, there is moderate evidence to support this gene-disease relationship. This association 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 Working Group on 10/23/2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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