Autoinflammatory disorders

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 and only one of them have autoinflammatory disease (other with HSV-2 meningitis). 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, 2:25 p.m.

Panel Version: 3.15

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