Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: IKBKE

I don't know

Comment on list classification: There are two unrelated cases identified with monoallelic IKBKE variants and functional evidence is also available for these variants. However, different phenotypes were reported in these two patients (HSV-2 meningitis vs autoinflammatory disease). Hence, this gene can only be rated amber with the current evidence.

Created: 6 Aug 2026, 2:05 p.m. | Last Modified: 6 Aug 2026, 2:05 p.m.

Panel Version: 9.70

PMID:37937644 (2023) reported the identification of a heterozygous variant in the IKBKE gene (c.312delC/ p.Phe105fs*19) in a female patient that experienced multiple episodes of HSV-2 meningitis. Extensive functional and cellular rescue experiments supported causality for impaired antiviral defense, though the mother of this patient carries the same variant without any HSV-2 disease history.

PMID:39524436 (2024) reported a female patient that had a remittent fever, arthritis, and oral ulcers for 20 years. She was identified with a novel heterozygous c.1877G>A (pCys626Tyr) variant in IKBKE. Functional analysis identified the variant activating T cells, while also diminishing NFκB and type I IFN signaling. The patient exhibited a notably diminished proportion of Naive CD4 T cells. RNA sequencing (RNA-seq) of immune cell subsets from peripheral blood revealed diverse immune cell gene expression changes, especially in T cells. This evidence suggests the possibility of a novel autoinflammatory disorder due to impaired function of IKBKE and T cell activation.

This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 06 August 2026).

Created: 6 Aug 2026, 1:56 p.m. | Last Modified: 6 Aug 2026, 1:56 p.m.

Panel Version: 9.66

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Herpes Simplex Virus type 2 (HSV-2) meningitis; autoinflammatory syndrome, MONDO:0019751

Publications

• 37937644
• 39524436

Red List (low evidence)

IKBKE encodes IKKε (Inhibitor of nuclear factor kappa-B kinase subunit epsilon), a noncanonical IκB kinase that plays a nonredundant role in mediating the innate immune response to viral infections.

Reyahi et al. identified a monoallelic truncating variant in IKBKE (c.312delC) as the cause of highly disabling, recurrent Herpes Simplex Virus type 2 (HSV-2) meningitis. Functional analyses demonstrate that this mutated allele encodes a truncated protein lacking kinase activity, which exerts a dominant-negative effect over the wild-type protein. This results in a functional deficiency within the cGAS/STING pathway, impaired STING phosphorylation, and a failure of patient cells (including stem cell-derived microglia) to mount an adequate IFN-β antiviral response against HSV-2 and double-stranded DNA.
Sources: Literature

Created: 17 Jun 2026, 3:40 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Herpes Simplex Virus type 2 (HSV-2) meningitis; Mollaret meningitis

Publications

• 37937644