autoinflammatory disease, X-linked

Summary

autoinflammatory disease, X-linked (MONDO:0800129) is a disease caused by IKBKG (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: IKBKG (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autoinflammatory disease, X-linked
Mondo ID	MONDO:0800129
OMIM	301081
Orphanet	699605
UMLS	C5676885
MedGen	1811268
GARD	0026447
Is cancer (heuristic)	no

Also known as: autoinflammatory syndrome, X-linked · NEMO deleted exon 5 syndrome

Data availability: 9 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › autoinflammatory syndrome › autoinflammatory disease, X-linked

Related subtypes (36): cherubism, chronic recurrent multifocal osteomyelitis, Pelger-Huet-like anomaly and episodic fever with abdominal pain, pyogenic arthritis-pyoderma gangrenosum-acne syndrome, psoriasis 14, pustular, autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation, periodic fever syndrome, infantile onset panniculitis with uveitis and systemic granulomatosis, idiopathic recurrent pericarditis, pyoderma gangrenosum-acne-suppurative hidradenitis syndrome, neonatal inflammatory skin and bowel disease, magic syndrome, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, Schnitzler syndrome, PFAPA syndrome, pyoderma gangrenosum, SAPHO syndrome, sarcoidosis, adult-onset Still disease, systemic-onset juvenile idiopathic arthritis, VEXAS syndrome, autoinflammatory syndrome, familial, Behcet-like, CEBPE-associated autoinflammation-immunodeficiency-neutrophil dysfunction syndrome, type 1 interferonopathy, autoinflammatory syndrome with immunodeficiency, early-onset pulmonary and cutaneous vasculitis, autoinflammatory syndrome due to TBK1 deficiency, F12-associated cold autoinflammatory syndrome, neonatal-onset severe multisystemic autoinflammatory disease with increased IL18, SAMD9L-associated autoinflammatory syndrome, autoinflammatory syndrome of childhood, autoinflammatory disease, systemic, with vasculitis, granulomatous autoinflammatory syndrome of childhood, autoinflammatory disease, multisystem, with immune dysregulation, X-linked, PAPASH syndrome, Sharpin-related autoinflammatory syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

9 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 3 pathogenic, 1 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1687109	NM_001099857.5(IKBKG):c.519-2A>G	IKBKG	Pathogenic	no assertion criteria provided
1687111	NM_001099857.5(IKBKG):c.671+2T>G	IKBKG	Pathogenic	criteria provided, single submitter
1687112	NM_001099857.5(IKBKG):c.671+5G>A	IKBKG	Pathogenic	no assertion criteria provided
625962	NM_001321396.3(IKBKG):c.-16+3G>A	G6PD	Uncertain significance	criteria provided, single submitter
1303538	NM_001099857.5(IKBKG):c.597G>A (p.Val199=)	IKBKG	Uncertain significance	criteria provided, single submitter
1527844	NM_001099857.5(IKBKG):c.760C>G (p.Arg254Gly)	IKBKG	Uncertain significance	criteria provided, multiple submitters, no conflicts
2431822	NM_001099857.5(IKBKG):c.51T>C (p.Ser17=)	IKBKG	Uncertain significance	criteria provided, single submitter
3891377	NM_001099857.5(IKBKG):c.151C>T (p.Leu51Phe)	IKBKG	Likely benign	criteria provided, single submitter
68234	NM_001099857.5(IKBKG):c.169G>A (p.Glu57Lys)	IKBKG	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
IKBKG	Strong	X-linked	autoinflammatory disease, X-linked	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IKBKG	Orphanet:464	Incontinentia pigmenti
IKBKG	Orphanet:69088	Hypohidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome
IKBKG	Orphanet:699605	NEMO deleted exon 5 autoinflammatory syndrome
IKBKG	Orphanet:98813	Hypohidrotic ectodermal dysplasia with immunodeficiency
G6PD	Orphanet:466026	Class I glucose-6-phosphate dehydrogenase deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IKBKG	HGNC:5961	ENSG00000269335	Q9Y6K9	NF-kappa-B essential modulator	gencc,clinvar
G6PD	HGNC:4057	ENSG00000160211	P11413	Glucose-6-phosphate 1-dehydrogenase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IKBKG	NF-kappa-B essential modulator	Regulatory subunit of the IKK core complex which phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor.
G6PD	Glucose-6-phosphate 1-dehydrogenase	Catalyzes the rate-limiting step of the oxidative pentose-phosphate pathway, which represents a route for the dissimilation of carbohydrates besides glycolysis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IKBKG	Other/Unknown	no		NEMO_N, CC2-LZ_dom, NEMO_ZF
G6PD	Enzyme (other)	yes	1.1.1.49	G6P_DH, G6P_DH_AS, G6P_DH_NAD-bd

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	2
blood	1
spleen	1
right testis	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IKBKG	134	ubiquitous	marker	granulocyte, blood, spleen
G6PD	218	ubiquitous	marker	stromal cell of endometrium, granulocyte, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IKBKG	4,981
G6PD	4,226

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
G6PD	P11413	25
IKBKG	Q9Y6K9	17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 91. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
IKBKB deficiency causes SCID	1	1903.3×	0.016	IKBKG
IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR)	1	1903.3×	0.016	IKBKG
SLC15A4:TASL-dependent IRF5 activation	1	951.7×	0.016	IKBKG
IkBA variant leads to EDA-ID	1	815.7×	0.016	IKBKG
NFE2L2 regulates pentose phosphate pathway genes	1	713.8×	0.016	G6PD
ZBP1(DAI) mediated induction of type I IFNs	1	519.1×	0.016	IKBKG
SUMOylation of immune response proteins	1	475.8×	0.016	IKBKG
Pentose phosphate pathway	1	475.8×	0.016	G6PD
Diseases of Immune System	1	439.2×	0.016	IKBKG
Diseases associated with the TLR signaling cascade	1	439.2×	0.016	IKBKG
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	1	439.2×	0.016	IKBKG
Downstream signaling events of B Cell Receptor (BCR)	1	407.9×	0.016	IKBKG
IRAK1 recruits IKK complex	1	407.9×	0.016	IKBKG
IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation	1	407.9×	0.016	IKBKG
MAP3K8 (TPL2)-dependent MAPK1/3 activation	1	356.9×	0.016	IKBKG
RIP-mediated NFkB activation via ZBP1	1	335.9×	0.016	IKBKG
Regulation of NF-kappa B signaling	1	317.2×	0.016	IKBKG
TICAM1, RIP1-mediated IKK complex recruitment	1	300.5×	0.016	IKBKG
Modulation of host responses by IFN-stimulated genes	1	300.5×	0.016	IKBKG
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1	1	259.6×	0.016	IKBKG
TCR signaling	1	248.3×	0.016	IKBKG
activated TAK1 mediates p38 MAPK activation	1	248.3×	0.016	IKBKG
IKK complex recruitment mediated by RIP1	1	248.3×	0.016	IKBKG
TRAF6 mediated NF-kB activation	1	228.4×	0.017	IKBKG
TNF signaling	1	211.5×	0.017	IKBKG
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1	178.4×	0.017	IKBKG
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	178.4×	0.017	IKBKG
Signaling by the B Cell Receptor (BCR)	1	173.0×	0.017	IKBKG
TNFR1-induced NF-kappa-B signaling pathway	1	167.9×	0.017	IKBKG
Antigen processing-Cross presentation	1	158.6×	0.017	IKBKG

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ribose phosphate biosynthetic process	1	8426.0×	0.002	G6PD
response to iron(III) ion	1	4213.0×	0.002	G6PD
pentose biosynthetic process	1	4213.0×	0.002	G6PD
positive regulation of calcium ion transmembrane transport via high voltage-gated calcium channel	1	4213.0×	0.002	G6PD
pentose-phosphate shunt, oxidative branch	1	2106.5×	0.004	G6PD
establishment of vesicle localization	1	1203.7×	0.006	IKBKG
pentose-phosphate shunt	1	766.0×	0.006	G6PD
NADP+ metabolic process	1	766.0×	0.006	G6PD
negative regulation of cell growth involved in cardiac muscle cell development	1	702.2×	0.006	G6PD
anoikis	1	648.1×	0.006	IKBKG
glucose 6-phosphate metabolic process	1	648.1×	0.006	G6PD
negative regulation of reactive oxygen species metabolic process	1	468.1×	0.007	G6PD
erythrocyte maturation	1	421.3×	0.007	G6PD
negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1	421.3×	0.007	IKBKG
positive regulation of T cell receptor signaling pathway	1	383.0×	0.007	IKBKG
regulation of neuron apoptotic process	1	351.1×	0.007	G6PD
B cell homeostasis	1	280.9×	0.008	IKBKG
positive regulation of ubiquitin-dependent protein catabolic process	1	280.9×	0.008	IKBKG
positive regulation of macroautophagy	1	263.3×	0.008	IKBKG
response to food	1	247.8×	0.008	G6PD
cholesterol biosynthetic process	1	210.7×	0.009	G6PD
canonical NF-kappaB signal transduction	1	183.2×	0.010	IKBKG
substantia nigra development	1	183.2×	0.010	G6PD
glutathione metabolic process	1	175.5×	0.010	G6PD
glucose metabolic process	1	127.7×	0.013	G6PD
obsolete positive regulation of NF-kappaB transcription factor activity	1	102.8×	0.016	IKBKG
negative regulation of canonical NF-kappaB signal transduction	1	86.0×	0.018	IKBKG
cellular response to oxidative stress	1	77.3×	0.019	G6PD
T cell receptor signaling pathway	1	75.9×	0.019	IKBKG
response to ethanol	1	73.3×	0.019	G6PD

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
G6PD	BREXANOLONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
G6PD	8	4
IKBKG	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BREXANOLONE	4	G6PD
APOMORPHINE HYDROCHLORIDE	4	G6PD
PRASTERONE	4	G6PD
EBSELEN	3	G6PD
PICEID	2	G6PD
SEPRANOLONE	2	G6PD
PREGNENOLONE	1	G6PD
16.ALPHA.-BROMOEPIANDROSTERONE	1	G6PD

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
G6PD	49	Binding:46, ADMET:2, Functional:1
IKBKG	38	Binding:30, Functional:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
G6PD	1.1.1.49	glucose-6-phosphate dehydrogenase (NADP+)

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
G6PD	1

Chemical tractability of cohort targets

8 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
BREXANOLONE	4	G6PD
APOMORPHINE HYDROCHLORIDE	4	G6PD
PRASTERONE	4	G6PD
EBSELEN	3	G6PD
PICEID	2	G6PD
SEPRANOLONE	2	G6PD
PREGNENOLONE	1	G6PD
16.ALPHA.-BROMOEPIANDROSTERONE	1	G6PD

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	G6PD
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	IKBKG

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
IKBKG	38	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.