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

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 . 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 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 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 variants, AIRE localizes to the highly conserved PHD1 domain. Thus, our findings identify a novel pathogenic heterozygous 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.

DOI: 10.70962/jhi.20250151, PMID: 41608501
Authors: Mounavi Vemula, Bergithe E Oftedal, Dorsa Iraji, Mélanie Migaud, Christopher Richmond, Syndia Lazarus, Jean-Laurent Casanova, Anna Sullivan, Anne Puel, Stuart G Tangye, Alberto Pinzon-Charry