Systematic and proactive evaluation of AIRE missense variant effects

Area of Science:

• Genetics
• Immunology
• Endocrinology

Background:

• Autoimmune Polyendocrine Syndrome Type 1 (APS-1) is a rare primary immunodeficiency caused by pathogenic variants in the autoimmune regulator (AIRE) gene.
• AIRE is crucial for preventing autoimmunity by promoting the elimination of self-reactive T cells.
• Diagnosing APS-1 through AIRE sequencing is common, but many variants are of uncertain significance (VUSs), hindering diagnosis.

Purpose of the Study:

• To proactively assess the functional impact of AIRE missense variants.
• To create a comprehensive AIRE variant effect map to guide genetic diagnosis.
• To improve the classification of AIRE variants, including VUSs, for earlier and more accurate APS-1 diagnosis.

Main Methods:

• Utilized an insulin-promoter-driven reporter system to functionally assay 9,790 AIRE missense variants.
• Developed a proactive AIRE variant effect map.
• Correlated variant effects with an international APS-1 cohort and UK Biobank data.

Main Results:

• The AIRE variant effect map validated and expanded biochemical knowledge, aligning with pathogenicity annotations.
• Proactive evidence was generated for 70% of previously reported AIRE VUSs.
• The map resolved 32% of current AIRE VUSs and revealed quantitative genotype-phenotype correlations.

Conclusions:

• The proactive AIRE variant effect map provides a valuable resource for understanding AIRE variant impacts.
• This resource can significantly improve patient outcomes through more rapid and definitive APS-1 diagnosis.
• The study demonstrates the utility of proactive functional variant assessment in rare disease diagnosis.