Submission Details

IKBKG was first reported in relation to X-linked recessive immunodeficiency with or without ectodermal dysplasia in 2000 (Zonana J, et al., 2000, PMID: 11047757). The IKBKG gene is located on chromosome X at Xq28 and encodes the regulatory (γ) subunit of the inhibitor of kappaB kinase (IKK) complex (or NEMO protein), which activates NF-κB. Complete loss-of-function mutations in IKBKG are lethal in male fetuses and causative of dominant incontinentia pigmenti (IP) in females. Whereas variants that impair but do not abolish NF-κB signaling are associated with ectodermal dysplasias and immune-deficiency syndromes in hemizygous males, including immunodeficiency (ID), anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) and anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome (OL-EDA-ID) (PMID: 12351572). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism, inheritance pattern and phenotypic variability between IP and the ectodermal dysplasia/immunodeficiency syndromes, but little difference between ID, EDA-ID and OL-EDA-ID. Therefore, IP (OMIM:308300) has been split from ID, EDA-ID and OL-EDA-ID, and the disease entities, ID (OMIM:300636), EDA-ID (OMIM:300291), and OL-EDA-ID, have been lumped into one disease entity, IKBKG-related immunodeficiency with or without ectodermal dysplasia. Additionally, IKBKG mutations that lead to skipping of exon 5 cause a distinct clinical phenotype of systemic autoinflammatory disease (OMIM: 301081), which will be considered separately from the immunodeficiency with or without ectodermal dysplasia.

Curated evidence supporting the gene-disease relationship of IKBKG-related immunodeficiency with or without ectodermal dysplasia includes 24 probands plus 4 additional affected family members, with hemizygous variants (missense and truncating), reported in 9 publications (PMIDs:  11047757, 11242109, 15356572, 20499091, 15577852, 12045264, 18350553, 26117626, 33318999). Additional evidence is available in the literature, however the maximum score was achieved. This gene-disease relationship is also supported by experimental evidence, including its function in NF-κB activation (PMID: 9657155), which is altered in patient cells (PMID:  12045264, 11242109). No mouse models have been generated recapitulating this disease, however models of IP (PMIDs: 10911991, 10911992) and conditional knockouts (PMID:12235208) are consistent with roles of IKBKG in ectodermal and immunodeficiency phenotypes. In summary, IKBKG is definitively associated with X-linked recessive immunodeficiency with or without ectodermal dysplasia. 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 Working Group on the meeting date September 15, 2022 (SOP Version 9).