Ectodermal dysplasia and immunodeficiency 1

Summary

Ectodermal dysplasia and immunodeficiency 1 (MONDO:0020740) is a disease caused by IKBKG (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: IKBKG (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 25

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ectodermal dysplasia and immunodeficiency 1
Mondo ID	MONDO:0020740
OMIM	300291
DOID	DOID:0081078
NCIT	C176592
UMLS	C1846008
MedGen	375787
GARD	0025232
Is cancer (heuristic)	no

Also known as: ectodermal dysplasia and immunodeficiency 1, X-linked recessive · EDA-Id · EDAID1 · HED-Id

Data availability: 25 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › ectodermal dysplasia and immune deficiency › ectodermal dysplasia and immunodeficiency 1

Related subtypes (1): ectodermal dysplasia and immunodeficiency 2

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

25 retrieved; paginated sample, class counts are floors:

10 pathogenic, 5 likely pathogenic, 4 uncertain significance, 2 likely benign, 2 conflicting classifications of pathogenicity, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1684654	Single allele	ATP6AP1	Pathogenic	criteria provided, single submitter
11453	NM_001099857.5(IKBKG):c.1171G>T (p.Glu391Ter)	IKBKG	Pathogenic	criteria provided, single submitter
11454	NM_001099857.5(IKBKG):c.1249T>C (p.Cys417Arg)	IKBKG	Pathogenic	no assertion criteria provided
11456	NM_001099857.5(IKBKG):c.1250G>T (p.Cys417Phe)	IKBKG	Pathogenic	no assertion criteria provided
11459	NG_009896.1:g.19984_24446dup	IKBKG	Pathogenic	no assertion criteria provided
11460	NM_001099857.5(IKBKG):c.458T>G (p.Leu153Arg)	IKBKG	Pathogenic	no assertion criteria provided
11461	NM_001099857.5(IKBKG):c.1207C>T (p.Gln403Ter)	IKBKG	Pathogenic	no assertion criteria provided
11463	NM_001099857.5(IKBKG):c.1049dup (p.Ala351fs)	IKBKG	Pathogenic	no assertion criteria provided
11466	NM_001099857.5(IKBKG):c.863C>G (p.Ala288Gly)	IKBKG	Pathogenic	no assertion criteria provided
372387	NM_001099857.5(IKBKG):c.1167dup (p.Glu390fs)	IKBKG	Pathogenic	criteria provided, multiple submitters, no conflicts
11457	NM_001099857.5(IKBKG):c.1217A>T (p.Asp406Val)	IKBKG	Likely pathogenic	criteria provided, single submitter
11462	NM_001099857.5(IKBKG):c.768+5G>A	IKBKG	Likely pathogenic	criteria provided, single submitter
36380	NM_001099857.5(IKBKG):c.262GAG[1] (p.Glu89del)	IKBKG	Likely pathogenic	criteria provided, single submitter
36382	NM_001099857.5(IKBKG):c.470A>C (p.Gln157Pro)	IKBKG	Likely pathogenic	criteria provided, single submitter
68239	NM_001099857.5(IKBKG):c.931G>A (p.Asp311Asn)	IKBKG	Likely pathogenic	criteria provided, single submitter
36379	NM_001099857.5(IKBKG):c.1056-6=	IKBKG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
430903	NM_001099857.5(IKBKG):c.185G>A (p.Arg62Gln)	IKBKG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
625962	NM_001321396.3(IKBKG):c.-16+3G>A	G6PD	Uncertain significance	criteria provided, single submitter
1342446	NM_001099857.5(IKBKG):c.399+6C>T	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
3393245	NM_001099857.5(IKBKG):c.1056-6C>T	IKBKG	Uncertain significance	criteria provided, single submitter
1699101	NM_001099856.6(IKBKG):c.148C>T (p.Arg50Cys)	G6PD	Likely benign	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
68235	NM_001099857.5(IKBKG):c.337G>A (p.Asp113Asn)	IKBKG	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 6 · 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	Definitive	X-linked	ectodermal dysplasia and immunodeficiency 1	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
ATP6AP1	Orphanet:692790	ATP6AP1-CDG

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

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
ATP6AP1	HGNC:868	ENSG00000071553	Q15904	V-type proton ATPase subunit S1	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.
ATP6AP1	V-type proton ATPase subunit S1	Accessory subunit of the proton-transporting vacuolar (V)-ATPase protein pump, which is required for luminal acidification of secretory vesicles.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	4.0×	0.460
Other/Unknown	2	1.2×	0.587

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
ATP6AP1	Other/Unknown	no		Ac45_acc_su, VAS1_LD, VAS1/VOA1_TM

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	2
blood	1
spleen	1
right testis	1
stromal cell of endometrium	1
Brodmann (1909) area 10	1
endometrium epithelium	1
paraflocculus	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
ATP6AP1	291	ubiquitous	marker	endometrium epithelium, Brodmann (1909) area 10, paraflocculus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IKBKG	4,981
G6PD	4,226
ATP6AP1	1,759

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
G6PD	P11413	25
IKBKG	Q9Y6K9	17
ATP6AP1	Q15904	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 95. Enrichment computed across 3 evidence-associated genes (3 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 3 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	1268.9×	0.025	IKBKG
IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR)	1	1268.9×	0.025	IKBKG
SLC15A4:TASL-dependent IRF5 activation	1	634.4×	0.025	IKBKG
IkBA variant leads to EDA-ID	1	543.8×	0.025	IKBKG
NFE2L2 regulates pentose phosphate pathway genes	1	475.8×	0.025	G6PD
ZBP1(DAI) mediated induction of type I IFNs	1	346.1×	0.025	IKBKG
SUMOylation of immune response proteins	1	317.2×	0.025	IKBKG
Pentose phosphate pathway	1	317.2×	0.025	G6PD
Diseases of Immune System	1	292.8×	0.025	IKBKG
Diseases associated with the TLR signaling cascade	1	292.8×	0.025	IKBKG
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	1	292.8×	0.025	IKBKG
Downstream signaling events of B Cell Receptor (BCR)	1	271.9×	0.025	IKBKG
IRAK1 recruits IKK complex	1	271.9×	0.025	IKBKG
IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation	1	271.9×	0.025	IKBKG
MAP3K8 (TPL2)-dependent MAPK1/3 activation	1	237.9×	0.025	IKBKG
RIP-mediated NFkB activation via ZBP1	1	223.9×	0.025	IKBKG
Regulation of NF-kappa B signaling	1	211.5×	0.025	IKBKG
TICAM1, RIP1-mediated IKK complex recruitment	1	200.3×	0.025	IKBKG
Modulation of host responses by IFN-stimulated genes	1	200.3×	0.025	IKBKG
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1	1	173.0×	0.025	IKBKG
TCR signaling	1	165.5×	0.025	IKBKG
activated TAK1 mediates p38 MAPK activation	1	165.5×	0.025	IKBKG
IKK complex recruitment mediated by RIP1	1	165.5×	0.025	IKBKG
TRAF6 mediated NF-kB activation	1	152.3×	0.026	IKBKG
TNF signaling	1	141.0×	0.026	IKBKG
Insulin receptor recycling	1	126.9×	0.026	ATP6AP1
Transferrin endocytosis and recycling	1	122.8×	0.026	ATP6AP1
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1	119.0×	0.026	IKBKG
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	119.0×	0.026	IKBKG
Signaling by the B Cell Receptor (BCR)	1	115.3×	0.026	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 3 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	5617.3×	0.005	G6PD
response to iron(III) ion	1	2808.7×	0.005	G6PD
pentose biosynthetic process	1	2808.7×	0.005	G6PD
positive regulation of calcium ion transmembrane transport via high voltage-gated calcium channel	1	2808.7×	0.005	G6PD
pentose-phosphate shunt, oxidative branch	1	1404.3×	0.007	G6PD
obsolete regulation of cellular pH	1	1123.5×	0.007	ATP6AP1
endosome to plasma membrane protein transport	1	1123.5×	0.007	ATP6AP1
establishment of vesicle localization	1	802.5×	0.007	IKBKG
osteoclast development	1	702.2×	0.007	ATP6AP1
cellular response to increased oxygen levels	1	702.2×	0.007	ATP6AP1
Golgi lumen acidification	1	561.7×	0.007	ATP6AP1
pentose-phosphate shunt	1	510.7×	0.007	G6PD
NADP+ metabolic process	1	510.7×	0.007	G6PD
negative regulation of cell growth involved in cardiac muscle cell development	1	468.1×	0.007	G6PD
anoikis	1	432.1×	0.007	IKBKG
glucose 6-phosphate metabolic process	1	432.1×	0.007	G6PD
endosomal lumen acidification	1	401.2×	0.007	ATP6AP1
intracellular pH reduction	1	401.2×	0.007	ATP6AP1
synaptic vesicle lumen acidification	1	312.1×	0.009	ATP6AP1
negative regulation of reactive oxygen species metabolic process	1	312.1×	0.009	G6PD
erythrocyte maturation	1	280.9×	0.009	G6PD
negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1	280.9×	0.009	IKBKG
positive regulation of T cell receptor signaling pathway	1	255.3×	0.009	IKBKG
vacuolar acidification	1	244.2×	0.009	ATP6AP1
regulation of neuron apoptotic process	1	234.1×	0.009	G6PD
lysosomal lumen acidification	1	224.7×	0.009	ATP6AP1
B cell homeostasis	1	187.2×	0.010	IKBKG
positive regulation of ubiquitin-dependent protein catabolic process	1	187.2×	0.010	IKBKG
positive regulation of macroautophagy	1	175.5×	0.011	IKBKG
response to food	1	165.2×	0.011	G6PD

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 3 of 3 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
ATP6AP1	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
ATP6AP1	7	Binding:7

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: 3; 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	2	IKBKG, ATP6AP1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
IKBKG	38	—
ATP6AP1	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.