Submission Details

Human pathogenic variants in the autoimmune regulator (AIRE) gene were first reported in association with autoimmune polyendocrinopathy -candidiasis-ectodermal dystrophy (APECED) also known as autoimmune polyendocrine syndrome type 1(APS-1) in 1997 (Ahonen et al, PMID:2348835; Aaltonen et al, PMID:9398840). Both autosomal recessive (Wang et al, PMID:9921903; Heino et al, PMID: 9888391; Cranston et al, PMID:35521792; Bjorses et al, PMID:8808604) and autosomal dominant (Cetani et al, PMID:11600535; Oftedal et al, PMID:26084028) forms have been reported.

Classical autosomal recessive AIRE-related APS-1 is typically caused by homozygosity or compound heterozygosity for variants in the CARD, SAND, PHD1, and PHD2 domains/exon-2,6,8,10 of AIRE with chronic mucocutaneous candidiasis, hypoparathyroidism, primary adrenal insufficiency, hypogonadism and other organ specific autoimmune manifestations usually seen in children aged 3-5 years (Husebye et al, PMID:19382991; Suh et al, PMID:31905445; Bjorses et al, PMID:10677297). The occasional autosomal dominant cases were caused by apparent dominant negative variants in the first plant homeodomain (PHD1) Zinc finger and SAND domain and characterized by later onset, milder phenotypes, and reduced penetrance compared to classical APS-1 (PMIDs: 116005356, 26084028).

Autoimmune diabetes has been reported as a rare manifestation of APS-1 with prevalence ranging from 1-18% in various populations (reviewed in PMID: 27420045). Thus it makes sense to consider the possibility of an AIRE variant when autoimmune diabetes is accompanied by other autoimmune disorders characteristic of APS-1.

At least 100 APS-1 - causing variants (primarily frameshift or nonsense) have been identified across AIRE in humans. Evidence supporting the association of this gene with APS-1 includes case-level data, segregation data, and experimental data. The aggregated score for case-level and segregation data is 12 points. Variants in this gene have been curated in at least 5 probands in 4 publications (PMIDs: 34991662, 34991662, 24988226, 28323927,18274776), with cases presenting as APS-1. More evidence is available to support the gene-disease association in the literature, but as the maximum score for genetic evidence (12 points) has been reached this has not been curated exhaustively. This gene-disease relationship is supported by functional assays (both individual and massively parallel), expression studies and functional alterations. Total points for the experimental evidence are 5.5. The total score for genetic and experimental evidence together is 17.5.

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern, mutational mechanism, and penetrance between the recessive and dominant forms of APS-1. Therefore, we curated AIRE related APS-1 with autosomal recessive inheritance (OMIM: 240300) as a split curation of autoimmune polyendocrine syndrome type 1 (MONDO: 0009411). Given the decreased penetrance and apparent dominant negative mutational mechanism of autosomal dominant APS-1, this entity may be curated as a split curation at a later date if more data accumulates.

In summary, AIRE is definitively associated with autoimmune polyendocrine syndrome type 1, with most cases presenting in children from birth or 3-5 years of age. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.