IKBKG

Inheritance Pattern: XL

Disease ID:MONDO:0010631

Submitter: PanelApp Australia

Inheritance Pattern: XL

Disease ID:MONDO:0010631

Submitter: ClinGen

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. The IKBKG gene was first reported in relation to X-linked incontinentia pigmenti (IP) in 2000 (Smahi et al., 2000 PMID 10839543​). The major diagnostic criteria of the disease, which primarily affects heterozygous females, include skin lesions. Minor criteria include teeth, hair, nail, eye and central nervous system defects. Variants in the gene are also 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) (Smahi et al., 2002). 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 in these between ID, EDA-ID and OL-EDA-ID. Therefore, IP (OMIM:308300) has been split from ID, ID-EDA-ID and OL-EDA-ID, and the following 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. Twenty-two variants (missense, nonsense, frameshift and large deletion) that have been reported in 23 IP probands in 3 publications (PMIDs: 10839543, 33085210 and 18350553) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by expression and functional alteration studies, as well as animal models (PMIDs: 10911991, 15229184, 28702714, 10911991, 10911992). The IKBKG gene encodes the regulatory subunit of the IKK complex, which activates cytokine-associated genes through the activation of the NF-κB pathway. Expression studies showed defective IKBKG protein expression in human IP patient cells (PMID 10911991) and functional alteration studies show little to no NF-κB activation in IKBKG-deficient cells (PMIDs: 15229184, 28702714). Two mouse models showed that skin lesions, dermatopathy and increased apoptosis leading to skewed X-chromosome inactivation, all disease characteristics of IP, were recapitulated in female mice heterozygous for loss-of-function Ikbkg variants (PMIDs: 10911991, 10911992). In summary, IKBKG is definitively associated with X-linked incontinentia pigmenti. 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 Syndromic Disorders Gene Curation Expert Panel on the meeting date 06.01.2022 (SOP Version 8).

Inheritance Pattern: XL

Disease ID:MONDO:0010631

Submitter: G2P

Inheritance Pattern: XL

Disease ID:MONDO:0010631

Submitter: Genomics England PanelApp

Inheritance Pattern: XL

Disease ID:MONDO:0010295

Submitter: Orphanet

Inheritance Pattern: XL

Disease ID:MONDO:0010631

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0010293

Submitter: Orphanet

Inheritance Pattern: XL

Disease ID:MONDO:0010631

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: XL

Disease ID:MONDO:0020740

Submitter: G2P

Inheritance Pattern: XL

Disease ID:MONDO:0100162

Submitter: PanelApp Australia

Inheritance Pattern: XL

Disease ID:MONDO:0800129

Submitter: PanelApp Australia

Inheritance Pattern: XL

Disease ID:MONDO:0100162

Submitter: ClinGen

*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).