# A novel heterozygous pathogenic AIRE variant causing autoimmunity but not infectious susceptibility

## TL;DR

A new AIRE gene variant causes autoimmunity but not infections, expanding the understanding of APECED.

## Contribution

A novel heterozygous AIRE variant is identified as pathogenic via negative dominance, broadening autosomal dominant APECED.

## Key findings

- The AIRE variant c.1010G>T (p.Cys337Phe) is pathogenic via loss-of-function and dominant-negative mechanisms.
- Affected individuals show APECED-like autoimmunity without candidiasis or Th17 cytokine autoantibodies.
- The variant resides in the conserved PHD1 domain and demonstrates functional validation of pathogenicity.

## Abstract

We describe a novel heterozygous variant in AIRE in 3 individuals with mild APECED. This variant was validated as being pathogenic by a mechanism of negative dominance. This represents new cases of autosomal dominant APECED.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is characterized by the triad of hypoparathyroidism, Addison’s disease, and chronic mucocutaneous candidiasis due to biallelic deleterious variants in AIRE. However, emerging evidence has established that some monoallelic variants affecting specific functional domains may also drive autoimmunity by negative dominance. Here, we describe a novel heterozygous AIRE variant, c.1010G>T (p.Cys337Phe), in three individuals from a Taiwanese-Singaporean family presenting with hypoparathyroidism, vitiligo, anemia, and ectodermal abnormalities, but not candidiasis. Functional studies confirmed AIREC337F is both loss-of-function and dominant negative to wild-type AIRE. Detection of neutralizing autoantibodies against type I IFNs, but not Th17 cytokines, further supported an APECED-like immunological profile and potentially explained the lack of infections in affected individuals. Like other dominant negative AIRE variants, AIREC337F localizes to the highly conserved PHD1 domain. Thus, our findings identify a novel pathogenic heterozygous AIRE variant and broaden the phenotype of autosomal dominant APECED. We also highlight the importance of functional validation in interpreting variants of unknown significance, particularly when disease prevalence and variant profiles differ from typical cohorts.