ClinGen Dosage Sensitivity Curation Page

IKBKG

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
15229184 Fusco et al. (2004) assessed 122 subjects with Incontinentia Pigmenti (IP) using PCR-based assays and DHPLC analysis. A recurrent exon 4-10 deletion was identified in 73 of 122 patients (59.8%). Single nucleotide variants and indels were identified in an additional 10 of 122 patients (8.2%), and included three missense variants, three stopgain variants, one frameshift insertion, two frameshift deletions, and one in-frame deletion.
10839543 The International Incontinentia Pigmenta (IP) Consortium (2000) assessed 47 subjects with IP using restriction enzyme mapping and PCR-based assays. The recurrent exon 4-10 deletion was identified in 38 of 47 subjects (80.8%). An additional 6 of 47 subjects harboured small indels, missense and stopgain mutations.
22121116 Fusco et al. (2012) describe non-recurrent deletions identified in 7 of 20 IP who did not harbour the recurrent exon 4-10 deletion. Non-recurrent deletions ranged in size from approximately 4.8 kb to 115 kb, and overlapped partially or fully the exonic coding sequence of IKBKG and upstream G6PD.

Haploinsufficiency phenotype comments:

Intragenic deletions and other loss of function mutations in IKBKG cause Incontinentia Pigmenti which is typically lethal in males unless there is mosaicism or a 47,XXY karyotype; see Gene Reviews. Individuals with Incontinentia Pigmenti (IP) present with abnormal skin pigmentation, with variable expressivity of retinal detachment, anodontia, alopecia, nail dystrophy and nervous system defects (Fusco et al. 2004). A recurrent exon 4-10 deletion is identified in up to 80% of patients (see PMIDs 10839543 and 15229184). Additionally, sequence level changes that result in reduced activity have been reported in individuals with hypo/anhidrotic ectodermal dysplasia with immune deficiency and immunodeficiencies without ectodermal dysplasia (OMIM: 300291, 300301, 300584, 300640, 300636).

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity
Evidence for triplosensitivity phenotype
PubMed ID Description
24721901 van Asbeck et al. (2014) describe a 167 kb de novo duplication within the Xq28 region that was identified in a female patient by microarray analysis and confirmed by qPCR. The patient presented with immune deficiency, skin abnormalities, macrocephaly, gastroparesis, peripheral small-fiber neuropathy, and benign tumors. The duplication encompasses the entire IKBKG gene, in addition to FAM3A, G6PD, GAB3, CTAG1A, CTAG1B, and CTAG2. The duplication does not include GDI1 or MECP2. The authors suggest that the Xq28 duplication identified in their patient represents a novel contiguous gene syndrome, with triplosensitivity of IKBKG being associated with skin abnormalities and immune deficiency specifically.

Triplosensitivity phenotype comment:

As whole gene duplications involving only IKBKG have not been described, the triplosensitivity score is 0.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.