Autoimmune polyendocrine syndrome type 1

Summary

Autoimmune polyendocrine syndrome type 1 (MONDO:0009411) is a disease caused by AIRE (GenCC Definitive), with 5 cohort genes and 2 clinical trials. Top therapeutic interventions include ruxolitinib.

At a glance

• Prevalence: 1-9 / 100 000 (Finland) [Orphanet-validated]
• Causal gene: AIRE (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 1,262
• Phenotypes (HPO): 38
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	4	Finland	Validated
Point prevalence	1-9 / 1 000 000	0.5	France	Validated
Point prevalence	1-9 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

38 HPO clinical features (Orphanet curated; top 38 by frequency):

HPO ID	Term	Frequency
HP:0000829	Hypoparathyroidism	Very frequent (80-99%)
HP:0002728	Chronic mucocutaneous candidiasis	Very frequent (80-99%)
HP:0002960	Autoimmunity	Very frequent (80-99%)
HP:0003118	Increased circulating cortisol level	Very frequent (80-99%)
HP:0004319	Decreased circulating aldosterone level	Very frequent (80-99%)
HP:0008207	Primary adrenal insufficiency	Very frequent (80-99%)
HP:0008221	Adrenal hyperplasia	Very frequent (80-99%)
HP:0100530	Abnormality of calcium-phosphate metabolism	Very frequent (80-99%)
HP:0100659	Abnormality of the cerebral vasculature	Very frequent (80-99%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000613	Photophobia	Frequent (30-79%)
HP:0000953	Hyperpigmentation of the skin	Frequent (30-79%)
HP:0000968	Ectodermal dysplasia	Frequent (30-79%)
HP:0001096	Keratoconjunctivitis	Frequent (30-79%)
HP:0006297	Enamel hypoplasia	Frequent (30-79%)
HP:0007759	Opacification of the corneal stroma	Frequent (30-79%)
HP:0008209	Premature ovarian insufficiency	Frequent (30-79%)
HP:0034055	Anti-side-chain cleavage enzyme antibody positivity	Frequent (30-79%)
HP:0034071	Anti-21-hydroxylase antibody positivity	Frequent (30-79%)
HP:0100502	Decreased circulating vitamin B12 concentration	Frequent (30-79%)
HP:0100651	Type I diabetes mellitus	Frequent (30-79%)
HP:0000123	Nephritis	Occasional (5-29%)
HP:0000135	Hypogonadism	Occasional (5-29%)
HP:0000554	Uveitis	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000872	Hashimoto thyroiditis	Occasional (5-29%)
HP:0001045	Vitiligo	Occasional (5-29%)
HP:0001053	Hypopigmented skin patches	Occasional (5-29%)
HP:0001596	Alopecia	Occasional (5-29%)
HP:0001746	Asplenia	Occasional (5-29%)
HP:0002024	Malabsorption	Occasional (5-29%)
HP:0002582	Atrophic gastritis	Occasional (5-29%)
HP:0006515	Interstitial pneumonitis	Occasional (5-29%)
HP:0007663	Reduced visual acuity	Occasional (5-29%)
HP:0008404	Nail dystrophy	Occasional (5-29%)
HP:0008720	Primary testicular failure	Occasional (5-29%)
HP:0012115	Hepatitis	Occasional (5-29%)
HP:0012804	Corneal ulceration	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autoimmune polyendocrine syndrome type 1
Mondo ID	MONDO:0009411
OMIM	240300
Orphanet	3453
DOID	DOID:0050167
NCIT	C129727
SNOMED CT	11244009
UMLS	C0085859
MedGen	39125
GARD	0008466
NORD	798
Is cancer (heuristic)	no

Also known as: AIRE autoimmune polyendocrinopathy · aire autoimmune polyendocrinopathy · APECED syndrome · APS type 1 · APS1 · autoimmune hypoparathyroidism-chronic candidiasis-Addison disease syndrome · autoimmune polyendocrine syndrome type 1 · autoimmune polyendocrine syndrome, type I, with or without reversible metaphyseal dysplasia · autoimmune polyendocrinopathy caused by mutation in AIRE · autoimmune polyendocrinopathy caused by mutation in aire · autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia · autoimmune polyendocrinopathy syndrome type 1 · autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy · autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) · autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome · Autoimmune Polyglandular Syndrome Type 1 · autoimmune polyglandular syndrome type 1 · ham syndrome · hypoparathyroidism-Addison disease-mucocutaneous candidiasis syndrome · MEDAC syndrome (+4 more)

Data availability: 1,262 ClinVar variants · 8 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › adrenal gland disorder › autoimmune polyendocrine syndrome type 1

Related subtypes (17): medulloadrenal hyperfunction, adrenal cortex disorder, adrenal medullary hyperplasia, pituitary dwarfism, pseudoleprechaunism syndrome, Patterson type, apparent mineralocorticoid excess, adrenomyodystrophy, corticosteroid-binding globulin deficiency, Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency, adrenogenital syndrome, hypoaldosteronism disease, primary pigmented nodular adrenocortical disease, adrenoleukodystrophy, adrenal gland neoplasm, ectopic ACTH secretion syndrome, endogenous Cushing syndrome, isolated micronodular adrenocortical disease

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:

313 likely benign, 165 uncertain significance, 52 pathogenic, 30 likely pathogenic, 15 benign, 13 conflicting classifications of pathogenicity, 8 pathogenic/likely pathogenic, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069340	NC_000021.8:g.(?45705880)(45707026_?)del	AIRE	Pathogenic	criteria provided, single submitter
1069666	NM_000383.4(AIRE):c.347del (p.Pro116fs)	AIRE	Pathogenic	criteria provided, single submitter
1071086	NM_000383.4(AIRE):c.1182C>A (p.Tyr394Ter)	AIRE	Pathogenic	criteria provided, single submitter
1071371	NC_000021.8:g.(?45705870)(45707494_?)del	AIRE	Pathogenic	criteria provided, single submitter
1071372	NC_000021.8:g.(?45705870)(45711113_?)del	AIRE	Pathogenic	criteria provided, single submitter
1074719	NM_000383.4(AIRE):c.560C>G (p.Ser187Ter)	AIRE	Pathogenic	criteria provided, single submitter
1075365	NM_000383.4(AIRE):c.489del (p.Lys164fs)	AIRE	Pathogenic	criteria provided, single submitter
1075801	NM_000383.4(AIRE):c.508_517dup (p.Gln173fs)	AIRE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075834	NM_000383.4(AIRE):c.784C>T (p.Gln262Ter)	AIRE	Pathogenic	criteria provided, single submitter
1076320	NM_000383.4(AIRE):c.747del (p.Ser249fs)	AIRE	Pathogenic	criteria provided, single submitter
1076711	NM_000383.4(AIRE):c.1192_1196dup (p.Pro400fs)	AIRE	Pathogenic	criteria provided, single submitter
1322985	NM_000383.4(AIRE):c.2T>A (p.Met1Lys)	AIRE	Pathogenic	criteria provided, single submitter
1359526	NM_000383.4(AIRE):c.868del (p.Gln290fs)	AIRE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1361985	NM_000383.4(AIRE):c.599dup (p.Ala202fs)	AIRE	Pathogenic	criteria provided, single submitter
1401394	NM_000383.4(AIRE):c.1259_1260del (p.Val420fs)	AIRE	Pathogenic	criteria provided, single submitter
1415983	NM_000383.4(AIRE):c.36del (p.Arg12fs)	AIRE	Pathogenic	criteria provided, single submitter
1430725	NM_000383.4(AIRE):c.1143_1144del (p.Glu383fs)	AIRE	Pathogenic	criteria provided, single submitter
1433366	NM_000383.4(AIRE):c.1233del (p.Ser412fs)	AIRE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1441280	NM_000383.4(AIRE):c.1429G>T (p.Gly477Ter)	AIRE	Pathogenic	criteria provided, single submitter
1451244	NM_000383.4(AIRE):c.2T>G (p.Met1Arg)	AIRE	Pathogenic	criteria provided, single submitter
1454525	NM_000383.4(AIRE):c.969_975del (p.Ser324fs)	AIRE	Pathogenic	criteria provided, single submitter
1454596	NM_000383.4(AIRE):c.205C>T (p.Gln69Ter)	AIRE	Pathogenic	criteria provided, single submitter
1455222	NM_000383.4(AIRE):c.1214del (p.Pro405fs)	AIRE	Pathogenic	criteria provided, single submitter
1456179	NM_000383.4(AIRE):c.1250_1251insTCTCCTCGGCCCTGCACCCCCT (p.Cys419fs)	AIRE	Pathogenic	criteria provided, single submitter
1456925	NM_000383.4(AIRE):c.193_197dup (p.Leu67fs)	AIRE	Pathogenic	criteria provided, single submitter
1458364	NM_000383.4(AIRE):c.340A>T (p.Lys114Ter)	AIRE	Pathogenic	criteria provided, single submitter
1458570	NM_000383.4(AIRE):c.14_15del (p.Ala5fs)	AIRE	Pathogenic	criteria provided, single submitter
1460122	NM_000383.4(AIRE):c.510_522del (p.Glu171fs)	AIRE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1480781	NM_000383.4(AIRE):c.173C>G (p.Ala58Gly)	AIRE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1522763	NM_000383.4(AIRE):c.253_255del (p.Tyr85del)	AIRE	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
AIRE	Definitive	Autosomal recessive	autoimmune polyendocrine syndrome type 1	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AIRE	Orphanet:189466	Familial isolated hypoparathyroidism due to impaired PTH secretion
AIRE	Orphanet:3453	Autoimmune polyendocrinopathy type 1
CFAP410	Orphanet:1872	Cone rod dystrophy
CFAP410	Orphanet:653709	Cone rod dystrophy-short stature syndrome
CFAP410	Orphanet:803	Amyotrophic lateral sclerosis
CYBA	Orphanet:379	Chronic granulomatous disease

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AIRE	HGNC:360	ENSG00000160224	O43918	Autoimmune regulator	gencc,clinvar
UBE2G2	HGNC:12483	ENSG00000184787	P60604	Ubiquitin-conjugating enzyme E2 G2	clinvar
CFAP410	HGNC:1260	ENSG00000160226	O43822	Cilia- and flagella-associated protein 410	clinvar
CYBA	HGNC:2577	ENSG00000051523	P13498	Cytochrome b-245 light chain	clinvar
DNMT3L	HGNC:2980	ENSG00000142182	Q9UJW3	DNA (cytosine-5)-methyltransferase 3-like	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AIRE	Autoimmune regulator	Transcription factor playing an essential role to promote self-tolerance in the thymus by regulating the expression of a wide array of self-antigens that have the commonality of being tissue-restricted in their expression pattern in the pe…
UBE2G2	Ubiquitin-conjugating enzyme E2 G2	Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins.
CFAP410	Cilia- and flagella-associated protein 410	Plays a role in cilia formation and/or maintenance.
CYBA	Cytochrome b-245 light chain	Subunit of NADPH oxidase complexes that is required for the NADPH oxidase activity that generates, in various cell types, superoxide from molecular oxygen utilizing NADPH as an electron donor.
DNMT3L	DNA (cytosine-5)-methyltransferase 3-like	Catalytically inactive regulatory factor of DNA methyltransferases that can either promote or inhibit DNA methylation depending on the context.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.2

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	2	3.3×	0.343
Enzyme (other)	1	2.4×	0.530
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AIRE	Transcription factor	no		SAND_dom, Znf_PHD, HSR_dom
UBE2G2	Enzyme (other)	yes	2.3.2.23	UBC, UBQ-conjugating_enzyme/RWD, UBQ-conjugating_AS
CFAP410	Other/Unknown	no		Leu-rich_rpt, U2A’_phosphoprotein32A_C, LRR_dom_sf
CYBA	Other/Unknown	no		Cyt_b558_asu
DNMT3L	Transcription factor	no		Znf_FYVE_PHD, Znf_RING/FYVE/PHD, ADD

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
diaphragm	1
gluteal muscle	1
triceps brachii	1
medial globus pallidus	1
middle frontal gyrus	1
tendon of biceps brachii	1
adenohypophysis	1
right frontal lobe	1
right uterine tube	1
granulocyte	1
leukocyte	1
monocyte	1
liver	1
male germ line stem cell (sensu Vertebrata) in testis	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AIRE	105	tissue_specific	marker	triceps brachii, diaphragm, gluteal muscle
UBE2G2	291	ubiquitous	marker	tendon of biceps brachii, middle frontal gyrus, medial globus pallidus
CFAP410	190	ubiquitous	marker	right uterine tube, adenohypophysis, right frontal lobe
CYBA	267	ubiquitous	marker	granulocyte, monocyte, leukocyte
DNMT3L	77	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, liver, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AIRE	3,001
CYBA	1,699
DNMT3L	1,589
UBE2G2	701
CFAP410	140

Structural data

PDB: 5 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNMT3L	Q9UJW3	29
UBE2G2	P60604	7
CYBA	P13498	7
AIRE	O43918	4
CFAP410	O43822	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 5 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
Cross-presentation of particulate exogenous antigens (phagosomes)	1	475.8×	0.022	CYBA
WNT5:FZD7-mediated leishmania damping	1	317.2×	0.022	CYBA
RHO GTPases Activate NADPH Oxidases	1	152.3×	0.023	CYBA
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	1	122.8×	0.023	UBE2G2
ROS and RNS production in phagocytes	1	112.0×	0.023	CYBA
Detoxification of Reactive Oxygen Species	1	100.2×	0.023	CYBA
DNA methylation	1	59.5×	0.032	DNMT3L
VEGFA-VEGFR2 Pathway	1	46.4×	0.032	CYBA
RAC2 GTPase cycle	1	42.3×	0.032	CYBA
RAC3 GTPase cycle	1	39.6×	0.032	CYBA
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	1	39.2×	0.032	DNMT3L
RAC1 GTPase cycle	1	20.4×	0.056	CYBA
Antigen processing: Ubiquitination & Proteasome degradation	1	12.4×	0.085	UBE2G2
Neutrophil degranulation	1	7.7×	0.124	CYBA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
peripheral T cell tolerance induction	1	3370.4×	0.005	AIRE
central tolerance induction to self antigen	1	3370.4×	0.005	AIRE
negative regulation of glomerular filtration by angiotensin	1	3370.4×	0.005	CYBA
smooth muscle hypertrophy	1	3370.4×	0.005	CYBA
regulation of thymocyte migration	1	3370.4×	0.005	AIRE
cytochrome complex assembly	1	1685.2×	0.006	CYBA
negative regulation of DNA methylation-dependent heterochromatin formation	1	1685.2×	0.006	DNMT3L
thymus epithelium morphogenesis	1	1685.2×	0.006	AIRE
epigenetic programing of female pronucleus	1	842.6×	0.009	DNMT3L
cellular response to L-glutamine	1	842.6×	0.009	CYBA
positive regulation of mucus secretion	1	674.1×	0.010	CYBA
chorionic trophoblast cell differentiation	1	561.7×	0.011	DNMT3L
autosome genomic imprinting	1	481.5×	0.012	DNMT3L
positive regulation of toll-like receptor 2 signaling pathway	1	421.3×	0.013	CYBA
positive regulation of defense response to bacterium	1	374.5×	0.013	CYBA
negative regulation of retrograde protein transport, ER to cytosol	1	374.5×	0.013	UBE2G2
response to aldosterone	1	337.0×	0.013	CYBA
negative thymic T cell selection	1	280.9×	0.013	AIRE
hydrogen peroxide biosynthetic process	1	280.9×	0.013	CYBA
transposable element silencing by heterochromatin formation	1	280.9×	0.013	DNMT3L
respiratory burst	1	259.3×	0.013	CYBA
mucus secretion	1	259.3×	0.013	CYBA
cellular response to phorbol 13-acetate 12-myristate	1	259.3×	0.013	CYBA
transposable element silencing by piRNA-mediated DNA methylation	1	224.7×	0.013	DNMT3L
positive regulation of reactive oxygen species biosynthetic process	1	224.7×	0.013	CYBA
negative regulation of gene expression via chromosomal CpG island methylation	1	210.7×	0.013	DNMT3L
superoxide metabolic process	1	198.3×	0.013	CYBA
genomic imprinting	1	198.3×	0.013	DNMT3L
oocyte development	1	187.2×	0.013	DNMT3L
regulation of release of sequestered calcium ion into cytosol	1	187.2×	0.013	CYBA

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 4 of 5 evidence-associated genes (80%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AIRE	0	0
UBE2G2	0	0
CFAP410	0	0
CYBA	0	0
DNMT3L	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DNMT3L	59	Binding:59
UBE2G2	6	Binding:6
CFAP410	1	Binding:1
CYBA	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
UBE2G2	2.3.2.23, 2.3.2.24	E2 ubiquitin-conjugating enzyme, (E3-independent) E2 ubiquitin-conjugating enzyme

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	UBE2G2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	AIRE, CFAP410, CYBA, DNMT3L

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AIRE	0	—
UBE2G2	6	—
CFAP410	1	—
CYBA	1	—
DNMT3L	59	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05398809	PHASE2	RECRUITING	Evaluate the Efficacy and Safety of Ruxolitinib on Hair Regrowth in Patients With Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED)-Associated Alopecia Areata
NCT00743782	PHASE2	COMPLETED	Comparing Pump With Subcutaneous Injection Delivery of PTH 1-34 in the Management of Chronic Hypoparathyroidism

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
RUXOLITINIB	4	1