Systematic and proactive evaluation of AIRE missense variant effects.

AIRE increases the expression and presentation of tissue-specific genes encoding self-antigens in the developing T cell niche, triggering the elimination of self-reactive T cells and preventing autoimmunity.

Pathogenic variants in AIRE cause autoimmune polyendocrine syndrome type 1, a rare primary immunodeficiency combining hypoparathyroidism, adrenal insufficiency and chronic mucocutaneous candidiasis, increasingly diagnosed by AIRE sequencing; yet two-thirds of reported clinical variants are missense and more than half of these are VUS. Rather than testing variants reactively, often years after clinical presentation, the authors proactively assessed the function of 9,790 AIRE missense variants using an insulin-promoter-driven reporter. The resulting variant effect map validates and extends current biochemical knowledge, concords with pathogenicity annotations and provides proactive evidence for 70% of previously reported VUS. Placed in the context of an international APS-1 cohort and the UK Biobank, it reveals quantitative genotype-phenotype correlations and resolves 32% of current VUS.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This is the model of functional data produced before the clinical question rather than after: for a gene dominated by missense variation, having a value for a never-before-seen variant removes the delay of a bespoke assay. The limitation lies in what the assay measures, a single activity read on a reporter, so that a variant deleterious through another mechanism — splicing, protein instability — may look functional; the genotype-phenotype correlations also remain quantitative rather than predictive at the individual level. With 32% of VUS resolved, the yield exceeds that of most ACMG criteria taken individually, and the approach is transferable to any gene whose function can be measured with a reporter.

Analysis by Dr Thibaut Benquey