Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome

Summary

Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome (MONDO:0013599) is a disease caused by STAT1 (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: STAT1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 625
• Phenotypes (HPO): 47

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Europe	Validated

Signs & symptoms

Clinical features (HPO)

47 HPO clinical features (Orphanet curated; top 47 by frequency):

HPO ID	Term	Frequency
HP:0000009	Functional abnormality of the bladder	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0002242	Abnormal intestine morphology	Very frequent (80-99%)
HP:0002728	Chronic mucocutaneous candidiasis	Very frequent (80-99%)
HP:0002750	Delayed skeletal maturation	Very frequent (80-99%)
HP:0002788	Recurrent upper respiratory tract infections	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0000818	Abnormality of the endocrine system	Frequent (30-79%)
HP:0000823	Delayed puberty	Frequent (30-79%)
HP:0000832	Primary hypothyroidism	Frequent (30-79%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0000964	Eczematoid dermatitis	Frequent (30-79%)
HP:0001433	Hepatosplenomegaly	Frequent (30-79%)
HP:0001888	Lymphopenia	Frequent (30-79%)
HP:0001890	Autoimmune hemolytic anemia	Frequent (30-79%)
HP:0001920	Renal artery stenosis	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002110	Bronchiectasis	Frequent (30-79%)
HP:0002719	Recurrent infections	Frequent (30-79%)
HP:0002721	Immunodeficiency	Frequent (30-79%)
HP:0002958	Immune dysregulation	Frequent (30-79%)
HP:0004387	Enterocolitis	Frequent (30-79%)
HP:0004944	Dilatation of the cerebral artery	Frequent (30-79%)
HP:0005353	Recurrent herpes	Frequent (30-79%)
HP:0010976	Decreased total B cell count	Frequent (30-79%)
HP:0011123	Inflammatory abnormality of the skin	Frequent (30-79%)
HP:0011473	Villous atrophy	Frequent (30-79%)
HP:0012163	Carotid artery dilatation	Frequent (30-79%)
HP:0040160	Generalized osteoporosis	Frequent (30-79%)
HP:0100646	Thyroiditis	Frequent (30-79%)
HP:0100651	Type I diabetes mellitus	Frequent (30-79%)
HP:0100817	Renovascular hypertension	Frequent (30-79%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0001655	Patent foramen ovale	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Occasional (5-29%)
HP:0001904	Neutropenia in presence of anti-neutropil antibodies	Occasional (5-29%)
HP:0001973	Autoimmune thrombocytopenia	Occasional (5-29%)
HP:0002092	Pulmonary arterial hypertension	Occasional (5-29%)
HP:0002383	Infectious encephalitis	Occasional (5-29%)
HP:0002724	Recurrent Aspergillus infections	Occasional (5-29%)
HP:0003613	Antiphospholipid antibody positivity	Occasional (5-29%)
HP:0004966	Medial calcification of large arteries	Occasional (5-29%)
HP:0011459	Esophageal carcinoma	Occasional (5-29%)
HP:0012115	Hepatitis	Occasional (5-29%)
HP:0012182	Oropharyngeal squamous cell carcinoma	Occasional (5-29%)
HP:0030355	Abnormal serum interferon-gamma level	Occasional (5-29%)
HP:0005403	Decreased total T cell count	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome
Mondo ID	MONDO:0013599
OMIM	614162
Orphanet	391487
DOID	DOID:0111946
UMLS	C3279990
MedGen	481620
GARD	0012314
Is cancer (heuristic)	no

Also known as: CANDF7 · candidiasis familial chronic mucocutaneous, autosomal dominant · candidiasis familial, 7 · familial chronic mucocutaneous, autosomal dominant · IMD31C · immunodeficiency 31C · immunodeficiency 31C, chronic mucocutaneous candidiasis, autosomal dominant · immunodeficiency type 31C

Data availability: 625 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › autoimmune disorder of endocrine system › autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome

Related subtypes (12): type 1 diabetes mellitus, autoimmune thyroid disease, immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome, autoimmune pancreatitis, autoimmune hepatitis, autoimmune polyendocrinopathy, autoimmune hypoparathyroidism, insulin autoimmune syndrome, IgG4-related sclerosing cholangitis, lymphocytic hypophysitis, autoimmune oophoritis, autoimmune primary ovarian failure

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

600 retrieved; paginated sample, class counts are floors:

294 likely benign, 199 uncertain significance, 42 pathogenic, 20 likely pathogenic, 16 benign, 14 conflicting classifications of pathogenicity, 14 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1074337	NM_007315.4(STAT1):c.1398C>A (p.Ser466Arg)	STAT1	Pathogenic	criteria provided, single submitter
1354984	NM_007315.4(STAT1):c.1999_2000del (p.Leu667fs)	STAT1	Pathogenic	criteria provided, single submitter
1403340	NM_007315.4(STAT1):c.1231_1232del (p.Glu411fs)	STAT1	Pathogenic	criteria provided, single submitter
1420518	NM_007315.4(STAT1):c.802G>T (p.Glu268Ter)	STAT1	Pathogenic	criteria provided, single submitter
144004	NM_007315.4(STAT1):c.537C>A (p.Asn179Lys)	STAT1	Pathogenic	no assertion criteria provided
144005	NM_007315.4(STAT1):c.854A>G (p.Gln285Arg)	STAT1	Pathogenic	criteria provided, single submitter
144006	NM_007315.4(STAT1):c.1154C>T (p.Thr385Met)	STAT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1457465	NM_007315.4(STAT1):c.71_74dup (p.Ser25fs)	STAT1	Pathogenic	criteria provided, single submitter
1524110	NM_007315.4(STAT1):c.2102A>G (p.Tyr701Cys)	STAT1	Pathogenic	criteria provided, single submitter
160354	NM_007315.4(STAT1):c.820C>G (p.Arg274Gly)	STAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1704320	NM_007315.4(STAT1):c.1398C>G (p.Ser466Arg)	STAT1	Pathogenic	no assertion criteria provided
208141	NM_007315.4(STAT1):c.832A>G (p.Lys278Glu)	STAT1	Pathogenic	no assertion criteria provided
2097602	NM_007315.4(STAT1):c.200A>C (p.Gln67Pro)	STAT1	Pathogenic	criteria provided, single submitter
2203238	NM_007315.4(STAT1):c.1162A>G (p.Lys388Glu)	STAT1	Pathogenic	criteria provided, single submitter
2203239	NM_007315.4(STAT1):c.1159A>G (p.Thr387Ala)	STAT1	Pathogenic	criteria provided, single submitter
2424633	NC_000002.11:g.(?191835429)(192012929_?)del	STAT1	Pathogenic	criteria provided, single submitter
2500092	NM_007315.4(STAT1):c.25C>T (p.Gln9Ter)	STAT1	Pathogenic	criteria provided, single submitter
2925337	NM_007315.4(STAT1):c.961A>G (p.Arg321Gly)	STAT1	Pathogenic	criteria provided, single submitter
2936500	NM_007315.4(STAT1):c.1688A>T (p.Glu563Val)	STAT1	Pathogenic	criteria provided, single submitter
2942064	NM_007315.4(STAT1):c.861C>G (p.Tyr287Ter)	STAT1	Pathogenic	criteria provided, single submitter
2948670	NM_007315.4(STAT1):c.1127+1G>A	STAT1	Pathogenic	criteria provided, single submitter
2952404	NM_007315.4(STAT1):c.1286_1287del (p.Glu429fs)	STAT1	Pathogenic	criteria provided, single submitter
30083	NM_007315.4(STAT1):c.820C>T (p.Arg274Trp)	STAT1	Pathogenic	criteria provided, multiple submitters, no conflicts
30084	NM_007315.4(STAT1):c.800C>T (p.Ala267Val)	STAT1	Pathogenic	criteria provided, multiple submitters, no conflicts
30085	NM_007315.4(STAT1):c.821G>A (p.Arg274Gln)	STAT1	Pathogenic	criteria provided, multiple submitters, no conflicts
30086	NM_007315.4(STAT1):c.857A>T (p.Lys286Ile)	STAT1	Pathogenic	no assertion criteria provided
30087	NM_007315.4(STAT1):c.604A>G (p.Met202Val)	STAT1	Pathogenic	criteria provided, single submitter
30089	NM_007315.4(STAT1):c.494A>G (p.Asp165Gly)	STAT1	Pathogenic	no assertion criteria provided
30090	NM_007315.4(STAT1):c.862A>G (p.Thr288Ala)	STAT1	Pathogenic	criteria provided, single submitter
30091	NM_007315.4(STAT1):c.508T>A (p.Tyr170Asn)	STAT1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 4 · 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
STAT1	Definitive	Autosomal dominant	autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STAT1	Orphanet:319595	Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency
STAT1	Orphanet:391311	Susceptibility to viral and mycobacterial infections due to STAT1 deficiency
STAT1	Orphanet:391487	STAT1-related autoimmune enteropathy and endocrinopathy-susceptibility to chronic infections syndrome
IL21R	Orphanet:357329	Combined immunodeficiency due to IL21R deficiency

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STAT1	HGNC:11362	ENSG00000115415	P42224	Signal transducer and activator of transcription 1-alpha/beta	gencc,clinvar
TNR	HGNC:11953	ENSG00000116147	Q92752	Tenascin-R	clinvar
ANKAR	HGNC:26350	ENSG00000151687	Q7Z5J8	Ankyrin and armadillo repeat-containing protein	clinvar
IL21R	HGNC:6006	ENSG00000103522	Q9HBE5	Interleukin-21 receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STAT1	Signal transducer and activator of transcription 1-alpha/beta	Signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and other growth factors.
TNR	Tenascin-R	Neural extracellular matrix (ECM) protein involved in interactions with different cells and matrix components.
IL21R	Interleukin-21 receptor	This is a receptor for interleukin-21.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 0 · 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
Antibody/Immunoglobulin	2	14.6×	0.020
Scaffold/PPI	1	4.3×	0.318
Transcription factor	1	2.1×	0.403

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STAT1	Transcription factor	no		SH2, STAT, p53-like_TF_DNA-bd_sf
TNR	Antibody/Immunoglobulin	yes		EGF, Fibrinogen_a/b/g_C_dom, FN3_dom
ANKAR	Scaffold/PPI	no		Armadillo, Ankyrin_rpt, ARM-like
IL21R	Antibody/Immunoglobulin	yes		Hempt_rcpt_S_F1_CS, FN3_dom, Ig-like_fold

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
epithelium of nasopharynx	1
mononuclear cell	1
vermiform appendix	1
CA1 field of hippocampus	1
entorhinal cortex	1
inferior vagus X ganglion	1
calcaneal tendon	1
left ovary	1
male germ line stem cell (sensu Vertebrata) in testis	1
blood	1
granulocyte	1
lymph node	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STAT1	294	ubiquitous	marker	epithelium of nasopharynx, vermiform appendix, mononuclear cell
TNR	109	tissue_specific	marker	CA1 field of hippocampus, entorhinal cortex, inferior vagus X ganglion
ANKAR	163	ubiquitous	yes	calcaneal tendon, male germ line stem cell (sensu Vertebrata) in testis, left ovary
IL21R	178	broad	marker	granulocyte, lymph node, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STAT1	6,459
IL21R	1,596
TNR	1,405
ANKAR	573

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STAT1	P42224	10
IL21R	Q9HBE5	6
TNR	Q92752	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANKAR	Q7Z5J8	84.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 66. Enrichment computed across 4 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
Interleukin-21 signaling	2	761.3×	1e-04	STAT1, IL21R
Signaling by PDGFR in disease	1	543.8×	0.019	STAT1
Interleukin-6 family signaling	1	475.8×	0.019	STAT1
Interleukin-9 signaling	1	423.0×	0.019	STAT1
FGFR1 mutant receptor activation	1	380.7×	0.019	STAT1
Signaling by KIT in disease	1	380.7×	0.019	STAT1
Interleukin-27 signaling	1	346.1×	0.019	STAT1
Interleukin-6 signaling	1	317.2×	0.019	STAT1
Interleukin-35 Signalling	1	317.2×	0.019	STAT1
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	292.8×	0.019	STAT1
Signaling by PDGFRA extracellular domain mutants	1	292.8×	0.019	STAT1
Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)	1	292.8×	0.019	STAT1
Regulation of IFNG signaling	1	271.9×	0.019	STAT1
Signaling by cytosolic FGFR1 fusion mutants	1	211.5×	0.019	STAT1
Interleukin-2 family signaling	1	211.5×	0.019	STAT1
Signaling by CSF3 (G-CSF)	1	190.3×	0.019	STAT1
Signaling by NOTCH3	1	173.0×	0.019	STAT1
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	1	173.0×	0.019	STAT1
Interleukin-12 family signaling	1	158.6×	0.019	STAT1
Growth hormone receptor signaling	1	158.6×	0.019	STAT1
NOTCH3 Intracellular Domain Regulates Transcription	1	146.4×	0.019	STAT1
Regulation of IFNA/IFNB signaling	1	146.4×	0.019	STAT1
Inactivation of CSF3 (G-CSF) signaling	1	146.4×	0.019	STAT1
Signaling by FGFR in disease	1	141.0×	0.019	STAT1
Interleukin-20 family signaling	1	141.0×	0.019	STAT1
Downstream signal transduction	1	126.9×	0.020	STAT1
Downregulation of SMAD2/3:SMAD4 transcriptional activity	1	122.8×	0.020	STAT1
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	119.0×	0.020	STAT1
Signaling by CSF1 (M-CSF) in myeloid cells	1	115.3×	0.020	STAT1
Response of endothelial cells to shear stress	1	100.2×	0.022	STAT1

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
negative regulation of metanephric nephron tubule epithelial cell differentiation	1	5617.3×	0.005	STAT1
negative regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis	1	2808.7×	0.005	STAT1
negative regulation by virus of viral protein levels in host cell	1	2808.7×	0.005	STAT1
negative regulation of axon extension involved in regeneration	1	2808.7×	0.005	TNR
telencephalon cell migration	1	1872.4×	0.005	TNR
axon extension involved in regeneration	1	1872.4×	0.005	TNR
metanephric mesenchymal cell proliferation involved in metanephros development	1	1872.4×	0.005	STAT1
renal tubule development	1	1404.3×	0.006	STAT1
metanephric mesenchymal cell differentiation	1	1123.5×	0.006	STAT1
neuroblast migration	1	1123.5×	0.006	TNR
positive regulation of transmission of nerve impulse	1	802.5×	0.007	TNR
interleukin-27-mediated signaling pathway	1	802.5×	0.007	STAT1
interleukin-7-mediated signaling pathway	1	702.2×	0.007	STAT1
interleukin-9-mediated signaling pathway	1	702.2×	0.007	STAT1
negative regulation of synaptic transmission	1	561.7×	0.008	TNR
response to interferon-beta	1	510.7×	0.008	STAT1
type II interferon-mediated signaling pathway	1	401.2×	0.010	STAT1
neuron cell-cell adhesion	1	330.4×	0.010	TNR
negative regulation of cell-cell adhesion	1	330.4×	0.010	TNR
locomotory exploration behavior	1	330.4×	0.010	TNR
positive regulation of interferon-alpha production	1	216.1×	0.012	STAT1
positive regulation of synaptic transmission, glutamatergic	1	208.1×	0.012	TNR
positive regulation of mesenchymal cell proliferation	1	200.6×	0.012	STAT1
natural killer cell activation	1	193.7×	0.012	IL21R
cell surface receptor signaling pathway via STAT	1	187.2×	0.012	STAT1
negative regulation of endothelial cell proliferation	1	181.2×	0.012	STAT1
positive regulation of defense response to virus by host	1	175.5×	0.012	STAT1
response to type II interferon	1	175.5×	0.012	STAT1
cellular response to interferon-beta	1	175.5×	0.012	STAT1
blood circulation	1	170.2×	0.012	STAT1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) 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
STAT1	FILGOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
STAT1	5	4
TNR	0	0
ANKAR	0	0
IL21R	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FILGOTINIB	4	STAT1
DEUCRAVACITINIB	4	STAT1
EPIGALOCATECHIN GALLATE	3	STAT1
SURAMIN HEXASODIUM	3	STAT1
IPRIFLAVONE	2	STAT1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
STAT1	147	Binding:137, Functional:8, Unclassified:2

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
STAT1	147

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

5 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)
FILGOTINIB	4	STAT1
DEUCRAVACITINIB	4	STAT1
EPIGALOCATECHIN GALLATE	3	STAT1
SURAMIN HEXASODIUM	3	STAT1
IPRIFLAVONE	2	STAT1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	STAT1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	TNR, IL21R
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ANKAR

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TNR	0	—
ANKAR	0	—
IL21R	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.