Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: AIRE

Green List (high evidence)

Comment on mode of inheritance: Both mono and bi allelic variants have been reported to cause Autoimmune polyendocrinopathy syndrome, type I (APS-1) - primarily characterised by hypoparathyroidism, enamel hypoplasia, adrenal insufficiency, and recurrent candidiasis. There are at least 3 indiviuals reported with monoallelic AIRE variants, and numerous cases with biallelic variants. Monoallelic variants in AIRE result in an incompletely penetrant, milder phenotype. Based on the available evidence, the MOI should remain as BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.

Created: 5 Nov 2025, 3:23 p.m. | Last Modified: 5 Nov 2025, 3:39 p.m.

Panel Version: 8.73

MONOALLELIC REPORTS:
PMID: 11600535 Cetani et al., 2001
Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated.

PMID: 29129473 Abbott et al., 2017
17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent.

PMID: 37235056 Oftedal et al., 2023
11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance.
Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes.
Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes.

BIALLELIC REPORTS:
PMID 19393987 Pavlic and Waltimo-Sirén, 2009
Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1).
Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped.
Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE.
Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11.

BIALLELIC:
PMID: 25926518 Borgault et al., 2015
Report of 5 molecularly confirmed cases with APS1 (age range: 19 months–44 years).
P3: female, c.967_c.979del13/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyoidism, Adrenal insufficiency, Osteopenia, Vitiligo, Sicca syndrome, Multiple bacterial/fungal infections

PMID: 27253668 Bruserud et al., 2016
Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. No immunodeficiency noted.

PMID: 31905445 Suh et al., 2019
10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia & Hyperpigmentation.

PMID: 35521792 Cranston et al., 2022
Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis.
Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency.
No immunodeficiency or inflammatory bowel disease was reported in the cohort (40 patients).

AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).

Created: 5 Nov 2025, 1:43 p.m. | Last Modified: 5 Nov 2025, 3:34 p.m.

Panel Version: 8.73

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411

Publications

• 11600535
• 19393987
• 27253668
• 29129473
• 31905445
• 35521792
• 37993717
• 37235056

Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.

Created: 14 Oct 2020, 12:23 p.m. | Last Modified: 14 Oct 2020, 12:23 p.m.

Panel Version: 2.220

The following PubMed IDs were added to entity AIRE: 29483906;9735375;28257655;30565240;29949487. These publications have been associated with OMIM phenotype MIM#240300, which is listed for this entity, by the immunedysregulation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.

Created: 13 Oct 2020, 9:36 a.m. | Last Modified: 13 Oct 2020, 9:36 a.m.

Panel Version: 2.208

Publications

• 29483906
• 9735375
• 28257655
• 30565240
• 29949487

Green List (high evidence)

agree with green gene

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Green List (high evidence)

YES- this is covered on our targeted exome

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Green List (high evidence)

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Green List (high evidence)

Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): AIRE .PanelApp HGNC gene symbol check: AIRE . IUIS Disease: APECED (APS-1), autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy . IUIS Inheritance: AR or AD .T cells: N/A, .B cells: Normal, .IUIS Other affected cells: N/A. IUIS Associated features: Autoimmunity: hypoparathyroidism hypothyroidism, adrenal insufficiency, diabetes, gonadal dysfunction and other endocrine abnormalities, chronic mucocutaneous candidiasis, dental enamel hypoplasia, alopecia areata enteropathy, pernicious anemia. IUIS Major category: Diseases of Immune Dysregulation. IUIS Subcategory: Autoimmunity with or without Lymphoproliferation

Created: 2 Jul 2018, 10:35 a.m.

Comment on mode of inheritance: updated MOI from external expert review

Created: 13 Jun 2018, 1:43 p.m.

Comment on list classification: Changed from Amber to Green there are more than 3 unrelated cases to support the PID phenotype.

Created: 1 May 2018, 11:54 a.m.

Changed status from Amber to Green, there are more than 3 unrelated cases to support the phenotype. Recent papers PMID: 28911151 (2017)- largest cohort (112) of patients with clinically characterized APS-1 to date and PMID: 29108822 (2018)

Created: 1 May 2018, 11:50 a.m.

Comment on publications: added publications to support PID phenotype

Created: 1 May 2018, 11:39 a.m.

Comment on mode of inheritance: Changed MOI from AR to both since there is some evidence for monoallelic inheritance PMID: 11600535 (2001) identified an Italian family with autoimmune polyendocrinopathy syndrome and a pattern of inheritance suggestive of a dominant mechanism.

Created: 1 May 2018, 11:23 a.m.

from Orphanet: Autoimmune polyendocrinopathy type 1, or APECED syndrome, is a genetic disease that manifests in childhood or early adolescence with a combination of chronic mucocutaneous candidiasis, hypoparathyroidism and autoimmune adrenal failure.

Created: 1 May 2018, 11:18 a.m.

Comment on phenotypes: added OMIM MIMid and synonyms

Created: 1 May 2018, 11:12 a.m.

This gene was absent from the original PanelApp PID panel dataset (review April 2018). However it was listed in external expert immunodeficiency diagnostic gene list(s) GOSH or GRID. In this combined PID panel, this gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.

Created: 20 Apr 2018, 12:25 p.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: AIRE, PanelApp HGNC gene symbol check: AIRE, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Defects in innate immunity / Chronic mucocutaneous candidiasis (CMC) / Chronic mucocutaneous candidiasis (CMC); Diseases of immune dysregulation / Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) / Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED)

Created: 17 Apr 2018, 12:29 p.m.

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: AIRE, GRID_Gene_Symbol: AIRE, GRID_Transcript_ENS_Community submitted: ENST00000291582, GRID_Transcript_RefSeq: NM_000383.3, GRID_Transcript_ENS_used_on_Production: ENST00000291582

Created: 17 Apr 2018, 12:12 p.m.