Systematic and proactive evaluation of AIRE missense variant effects

Area of Science:

• Genetics and Immunology
• Molecular Biology
• Autoimmune Diseases

Background:

• Pathogenic variants in the autoimmune regulator (AIRE) gene cause autoimmune polyendocrine syndrome type 1 (APS-1), a rare primary immunodeficiency.
• AIRE's function is crucial for central tolerance by promoting self-antigen presentation to developing T cells, preventing autoimmunity.
• Current diagnostic challenges include a high proportion of variants of uncertain significance (VUSs) among AIRE missense variants, often requiring delayed functional assays.

Purpose of the Study:

• To proactively assess the functional impact of a comprehensive set of AIRE missense variants.
• To create a predictive resource for variant classification and improve the diagnosis of APS-1.
• To correlate AIRE variant function with clinical phenotypes in APS-1 cohorts.

Main Methods:

• Utilized an insulin-promoter-driven reporter system to functionally assay 9,790 AIRE missense variants.
• Developed a large-scale AIRE variant effect map.
• Integrated variant data with an international APS-1 cohort and the UK Biobank for genotype-phenotype correlation analysis.

Main Results:

• The AIRE variant effect map validated existing knowledge and provided functional evidence for 70% of previously reported VUSs.
• Quantitative genotype-phenotype correlations were identified by contextualizing the map with clinical data.
• The resource resolved 32% of current AIRE VUSs, offering immediate functional insights.

Conclusions:

• The proactive AIRE variant effect map serves as a powerful tool for immediate variant classification and diagnosis.
• This resource has the potential to significantly improve patient outcomes through accelerated and more definitive APS-1 diagnosis.
• Proactive functional assessment of genetic variants can overcome limitations of reactive assays in rare disease diagnostics.