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

Abstract

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 AIRE(C337F) 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, AIRE(C337F) 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.