Limited penetrance of dominantly inherited AIRE variants in a population-based cohort.

Pathogenic variants in the autoimmune regulator gene (AIRE) cause Autoimmune polyendocrine syndrome type 1 (APS-1). The majority of disease-causing variants are inherited recessively, while several heterozygous AIRE variants have been reported in the literature as having dominant-negative or partially inhibitory effects. Additionally, some heterozygous AIRE variants have been implicated in milder and more common autoimmune phenotypes in disease cohort studies. The contribution of these variants to disease risk in unselected populations has not been assessed at scale. We aimed to investigate the prevalence and phenotypic impact of rare coding variants in AIRE in 449 075 participants from the UK Biobank (UKB). A literature review identified 25 rare heterozygous AIRE variants previously reported in association with autoimmunity, including variants described as dominant-negative or partially inhibitory, 13 of which were observed in UKB, collectively carried by 2123 participants. Filtering and annotation of rare coding AIRE variants identified a further 180 rare coding AIRE variants in 1934 UKB participants. Phenotype association analysis revealed no significant associations between rare heterozygous AIRE variants previously reported in association with autoimmunity and APS-1-associated traits after multiple-testing correction. Similarly, no statistically significant associations were observed for other heterozygous carriers of missense variants, frameshift/protein-truncating variants, or domain-specific groupings. These findings are consistent with a predominantly recessive model of AIRE-associated disease and indicate limited penetrance of rare heterozygous variants in the UKB population. Our work highlights the need for cautious interpretation of heterozygous AIRE variants in clinical settings.