STAT3-related early-onset multisystem autoimmune disease

Summary

STAT3-related early-onset multisystem autoimmune disease (MONDO:0014414) is a disease caused by STAT3 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: STAT3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 37

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		19	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	STAT3-related early-onset multisystem autoimmune disease
Mondo ID	MONDO:0014414
OMIM	615952
Orphanet	438159
DOID	DOID:0061160
NCIT	C157123
UMLS	C4014795
MedGen	863232
GARD	0017737
Is cancer (heuristic)	no

Also known as: ADMIO · ADMIO1 · autoimmune disease, multisystem, infantile-onset

Data availability: 37 ClinVar variants · 5 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autoimmune disease, multisystem, infantile-onset › STAT3-related early-onset multisystem autoimmune disease

Related subtypes (3): autoimmune disease, multisystem, infantile-onset, 2, autoimmune disease, multisystem, infantile-onset, 3, autoimmune disease, multisystem, infantile-onset, 5

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

37 retrieved; paginated sample, class counts are floors:

11 pathogenic, 10 uncertain significance, 7 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 3 likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
144030	NM_139276.3(STAT3):c.1175A>G (p.Lys392Arg)	STAT3	Pathogenic	no assertion criteria provided
144031	NM_139276.3(STAT3):c.1938C>G (p.Asn646Lys)	STAT3	Pathogenic	no assertion criteria provided
144032	NM_139276.3(STAT3):c.1974G>C (p.Lys658Asn)	STAT3	Pathogenic	no assertion criteria provided
18304	NM_139276.3(STAT3):c.1144C>T (p.Arg382Trp)	STAT3	Pathogenic	criteria provided, multiple submitters, no conflicts
18306	NM_139276.3(STAT3):c.1268G>A (p.Arg423Gln)	STAT3	Pathogenic	criteria provided, multiple submitters, no conflicts
224843	NM_139276.3(STAT3):c.1032G>C (p.Gln344His)	STAT3	Pathogenic	criteria provided, single submitter
224844	NM_139276.3(STAT3):c.1261G>A (p.Gly421Arg)	STAT3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224845	NM_139276.3(STAT3):c.1988C>T (p.Thr663Ile)	STAT3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224846	NM_139276.3(STAT3):c.454C>T (p.Arg152Trp)	STAT3	Pathogenic	criteria provided, multiple submitters, no conflicts
224847	NM_139276.3(STAT3):c.1057G>T (p.Val353Phe)	STAT3	Pathogenic	criteria provided, single submitter
224848	NM_139276.3(STAT3):c.2147C>T (p.Thr716Met)	STAT3	Pathogenic	criteria provided, multiple submitters, no conflicts
224849	NM_139276.3(STAT3):c.1260T>G (p.Asn420Lys)	STAT3	Pathogenic	criteria provided, single submitter
224850	NM_139276.3(STAT3):c.2107G>A (p.Ala703Thr)	STAT3	Pathogenic	criteria provided, single submitter
36784	NM_139276.3(STAT3):c.1243G>A (p.Glu415Lys)	STAT3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
421171	NM_139276.3(STAT3):c.2144C>T (p.Pro715Leu)	STAT3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
973671	NM_139276.3(STAT3):c.1973A>G (p.Lys658Arg)	STAT3	Likely pathogenic	no assertion criteria provided
976227	NM_139276.3(STAT3):c.1310A>T (p.His437Leu)	STAT3	Likely pathogenic	criteria provided, single submitter
977089	NM_139276.3(STAT3):c.1974G>T (p.Lys658Asn)	STAT3	Likely pathogenic	criteria provided, single submitter
1349527	NM_139276.3(STAT3):c.551-1G>C	STAT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2443043	NM_139276.3(STAT3):c.1004G>A (p.Arg335Gln)	STAT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
514074	NM_139276.3(STAT3):c.2228G>T (p.Gly743Val)	STAT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
546794	NM_139276.3(STAT3):c.373C>G (p.Gln125Glu)	STAT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
722798	NM_139276.3(STAT3):c.2049C>T (p.Phe683=)	STAT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
827744	NM_139276.3(STAT3):c.986T>G (p.Met329Arg)	STAT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
930424	NM_139276.3(STAT3):c.1233+19C>T	STAT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1027740	NM_139276.3(STAT3):c.1129G>A (p.Ala377Thr)	STAT3	Uncertain significance	criteria provided, single submitter
1192237	NM_139276.3(STAT3):c.1840A>C (p.Ser614Arg)	STAT3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1436769	NM_139276.3(STAT3):c.1887C>T (p.Ser629=)	STAT3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2431605	NM_139276.3(STAT3):c.2258-2A>G	STAT3	Uncertain significance	criteria provided, single submitter
2503129	NM_139276.3(STAT3):c.1339C>G (p.His447Asp)	STAT3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 7 · 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
STAT3	Strong	Autosomal dominant	STAT3-related early-onset multisystem autoimmune disease	9
ADIPOQ	Limited	Unknown	STAT3-related early-onset multisystem autoimmune disease

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STAT3	Orphanet:2314	Autosomal dominant hyper-IgE syndrome due to STAT3 deficiency
STAT3	Orphanet:438159	STAT3-related early-onset multisystem autoimmune disease
STAT3	Orphanet:512017	Chronic lymphoproliferative disorder of natural killer cells
STAT3	Orphanet:520	Acute promyelocytic leukemia
STAT3	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
STAT3	Orphanet:86872	T-cell large granular lymphocyte leukemia
STAT3	Orphanet:99885	Isolated permanent neonatal diabetes mellitus

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
STAT3	HGNC:11364	ENSG00000168610	P40763	Signal transducer and activator of transcription 3	gencc,clinvar
ADIPOQ	HGNC:13633	ENSG00000181092	Q15848	Adiponectin	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STAT3	Signal transducer and activator of transcription 3	Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors.
ADIPOQ	Adiponectin	Important adipokine involved in the control of fat metabolism and insulin sensitivity, with direct anti-diabetic, anti-atherogenic and anti-inflammatory activities.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STAT3	Transcription factor	no		SH2, STAT, p53-like_TF_DNA-bd_sf
ADIPOQ	Other/Unknown	no		C1q_dom, Collagen, Tumour_necrosis_fac-like_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
pericardium	2
lower lobe of lung	1
type B pancreatic cell	1
skin of hip	1
synovial joint	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STAT3	301	ubiquitous	marker	type B pancreatic cell, pericardium, lower lobe of lung
ADIPOQ	171	tissue_specific	yes	synovial joint, pericardium, skin of hip

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STAT3	10,108
ADIPOQ	3,816

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STAT3	P40763	6
ADIPOQ	Q15848	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 87. 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
Signalling to STAT3	1	1903.3×	0.010	STAT3
MET activates STAT3	1	1903.3×	0.010	STAT3
PTK6 Activates STAT3	1	1427.5×	0.010	STAT3
Signaling by PDGFR in disease	1	815.7×	0.010	STAT3
AMPK inhibits chREBP transcriptional activation activity	1	713.8×	0.010	ADIPOQ
Interleukin-6 family signaling	1	713.8×	0.010	STAT3
BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members	1	634.4×	0.010	STAT3
Interleukin-9 signaling	1	634.4×	0.010	STAT3
Interleukin-23 signaling	1	634.4×	0.010	STAT3
FGFR1 mutant receptor activation	1	571.0×	0.010	STAT3
Interleukin-21 signaling	1	571.0×	0.010	STAT3
Signaling by KIT in disease	1	571.0×	0.010	STAT3
Signaling by Leptin	1	519.1×	0.010	STAT3
Interleukin-27 signaling	1	519.1×	0.010	STAT3
STAT3 nuclear events downstream of ALK signaling	1	519.1×	0.010	STAT3
Interleukin-6 signaling	1	475.8×	0.010	STAT3
Interleukin-35 Signalling	1	475.8×	0.010	STAT3
POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation	1	439.2×	0.010	STAT3
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	439.2×	0.010	STAT3
Signaling by PDGFRA extracellular domain mutants	1	439.2×	0.010	STAT3
Interleukin-15 signaling	1	380.7×	0.011	STAT3
Signaling by cytosolic FGFR1 fusion mutants	1	317.2×	0.011	STAT3
Interleukin-2 family signaling	1	317.2×	0.011	STAT3
Signaling by ALK	1	285.5×	0.011	STAT3
Signaling by CSF3 (G-CSF)	1	285.5×	0.011	STAT3
Transcriptional regulation of pluripotent stem cells	1	271.9×	0.011	STAT3
Signaling by PTK6	1	271.9×	0.011	STAT3
Signaling by Non-Receptor Tyrosine Kinases	1	271.9×	0.011	STAT3
Interleukin-37 signaling	1	259.6×	0.011	STAT3
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	1	259.6×	0.011	STAT3

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
positive regulation of myeloid cell apoptotic process	1	8426.0×	0.002	ADIPOQ
positive regulation of glycogen (starch) synthase activity	1	8426.0×	0.002	ADIPOQ
positive regulation of metanephric podocyte development	1	8426.0×	0.002	ADIPOQ
positive regulation of renal albumin absorption	1	8426.0×	0.002	ADIPOQ
negative regulation of metanephric mesenchymal cell migration	1	8426.0×	0.002	ADIPOQ
positive regulation of interleukin-8 production	2	244.2×	0.002	STAT3, ADIPOQ
negative regulation of canonical NF-kappaB signal transduction	2	172.0×	0.002	STAT3, ADIPOQ
response to ethanol	2	146.5×	0.002	STAT3, ADIPOQ
glucose homeostasis	2	130.6×	0.002	STAT3, ADIPOQ
response to hypoxia	2	95.8×	0.002	STAT3, ADIPOQ
detection of oxidative stress	1	4213.0×	0.003	ADIPOQ
positive regulation of growth factor dependent skeletal muscle satellite cell proliferation	1	4213.0×	0.003	STAT3
negative regulation of platelet-derived growth factor receptor-alpha signaling pathway	1	4213.0×	0.003	ADIPOQ
positive regulation of canonical NF-kappaB signal transduction	2	72.6×	0.003	STAT3, ADIPOQ
negative regulation of cholesterol import	1	2808.7×	0.003	ADIPOQ
response to linoleic acid	1	2808.7×	0.003	ADIPOQ
eye photoreceptor cell differentiation	1	2106.5×	0.004	STAT3
negative regulation of hydrogen peroxide biosynthetic process	1	2106.5×	0.004	STAT3
negative regulation of primary miRNA processing	1	2106.5×	0.004	STAT3
response to sucrose	1	1685.2×	0.004	ADIPOQ
interleukin-11-mediated signaling pathway	1	1685.2×	0.004	STAT3
positive regulation of fatty acid metabolic process	1	1685.2×	0.004	ADIPOQ
T-helper 17 type immune response	1	1685.2×	0.004	STAT3
postsynapse to nucleus signaling pathway	1	1685.2×	0.004	STAT3
interleukin-23-mediated signaling pathway	1	1404.3×	0.004	STAT3
regulation of cellular response to hypoxia	1	1404.3×	0.004	STAT3
leptin-mediated signaling pathway	1	1203.7×	0.004	STAT3
response to leptin	1	1203.7×	0.004	STAT3
cellular response to interleukin-17	1	1203.7×	0.004	STAT3
negative regulation of granulocyte differentiation	1	1053.2×	0.004	ADIPOQ

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
STAT3	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
STAT3	18	4
ADIPOQ	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	STAT3
NITAZOXANIDE	4	STAT3
NICLOSAMIDE	4	STAT3
DIGOXIN	4	STAT3
BARICITINIB	4	STAT3
DIGITOXIN	4	STAT3
DEUCRAVACITINIB	4	STAT3
CURCUMIN	3	STAT3
BARDOXOLONE METHYL	3	STAT3
NIFUROXAZIDE	3	STAT3
DELGOCITINIB	3	STAT3
LESTAURTINIB	3	STAT3
NAPABUCASIN	3	STAT3
LEVOMENOL	2	STAT3
AZD-1480	2	STAT3
WP 1066	2	STAT3
C-188-9	2	STAT3
GENISTEIN	2	STAT3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
STAT3	1,319	Binding:1304, Functional:12, Unclassified:2, ADMET:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
STAT3	1,319

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

18 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)
MOMELOTINIB	4	STAT3
NITAZOXANIDE	4	STAT3
NICLOSAMIDE	4	STAT3
DIGOXIN	4	STAT3
BARICITINIB	4	STAT3
DIGITOXIN	4	STAT3
DEUCRAVACITINIB	4	STAT3
CURCUMIN	3	STAT3
BARDOXOLONE METHYL	3	STAT3
NIFUROXAZIDE	3	STAT3
DELGOCITINIB	3	STAT3
LESTAURTINIB	3	STAT3
NAPABUCASIN	3	STAT3
LEVOMENOL	2	STAT3
AZD-1480	2	STAT3
WP 1066	2	STAT3
C-188-9	2	STAT3
GENISTEIN	2	STAT3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	STAT3
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	ADIPOQ

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)
ADIPOQ	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.