Dataset Information

Molecular and clinical characterization of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) in Iranian non-Jewish patients: report of two novel AIRE gene pathogenic variants.

ABSTRACT:

Objective

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) is a rare autosomal recessive systemic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Incidence of this genetic disorder is estimated at 1/90,000-200,000 worldwide and 1/6500-9000 in genetically isolated populations such as Iran. Here, we investigated AIRE gene mutations in eight independent Iranian non-Jewish families.

Methods

We sequenced the coding regions of the AIRE gene and documented mutations which were further confirmed in respective parents.

Results

In total, 11 cases from 8 independent families were recruited. Mucosal candidiasis, Addison's disease and hypoparathyroidism were the most common clinical manifestations in these patients. One novel homozygous splice acceptor mutation (c.308-1G>C), and one novel heterozygous stop-gain mutation (c.1496delC) combined with a known heterozygous c.232T>C missense mutation were found. Moreover, we observed previously described splice donor (c.1095+2T>A), frameshift (c.967-979del), stop-gain (c.415C>T), and missense (c.62C>T) mutations among the patients. All results were co-segregated in parents.

Conclusion

Here, we reported two novel mutations in the AIRE gene leading to APECED. Our data could provide insight into the phenotypic and genotypic spectrum of APECED in the non-Jewish Iranian population. These findings, in addition to future functional assays, can elucidate disease-causing mechanisms related to the AIRE gene and assist in genetic counseling and diagnosis.

SUBMITTER: Setoodeh A

PROVIDER: S-EPMC8734050 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by homozygous AIRE mutations. It classically presents with chronic mucocutaneous candidiasis and autoimmunity that primarily targets endocrine tissues; hypoparathyroidism and adrenal insufficiency are most common. Developing any two of these classic triad manifestations establishes the diagnosis. Although widely recognized in Europe, where nonendocrine autoimmune manifestations are uncommon, APECED is less defined in patients from the Western Hemisphere. We enrolled 35 consecutive American APECED patients (33 from the US) in a prospective observational natural history study and systematically examined their genetic, clinical, autoantibody, and immunological characteristics. Most patients were compound heterozygous; the most common AIRE mutation was c.967_979del13. All but one patient had anti-IFN-ω autoantibodies, including 4 of 5 patients without biallelic AIRE mutations. Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases. Development of a classic diagnostic dyad was delayed at mean 7.38 years. Eighty percent of patients developed a median of 3 non-triad manifestations before a diagnostic dyad. Only 20% of patients had their first two manifestations among the classic triad. Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations. Patients exhibited expanded peripheral CD4+ T cells and CD21loCD38lo B lymphocytes. In summary, American APECED patients develop a diverse syndrome, with dramatic enrichment in organ-specific nonendocrine manifestations starting early in life, compared with European patients. Incorporation of these new manifestations into American diagnostic criteria would accelerate diagnosis by approximately 4 years and potentially prevent life-threatening endocrine complications.