Systematic and proactive evaluation of AIRE missense variant effects

Area of Science:

• Genetics
• Immunology
• Molecular Biology

Background:

• Pathogenic variants in the Autoimmune Regulator (AIRE) gene cause Autoimmune Polyendocrine Syndrome Type 1 (APS-1), a rare primary immunodeficiency.
• AIRE is crucial for preventing autoimmunity by eliminating self-reactive T cells.
• Many AIRE variants are classified as variants of uncertain significance (VUS), hindering diagnosis.

Purpose of the Study:

• To proactively assess the functional impact of AIRE missense variants.
• To create a comprehensive AIRE variant effect map for improved genetic diagnosis.
• To provide evidence for classifying VUS and enhancing APS-1 diagnosis.

Main Methods:

• Utilized an insulin promoter-driven reporter system to functionally assay 9790 AIRE missense variants.
• Generated an AIRE variant effect map.
• Correlated variant data with an international APS-1 cohort and UK BioBank data.

Main Results:

• The AIRE variant effect map validated and extended biochemical knowledge.
• The map provided proactive evidence for 70% of previously reported VUS.
• Quantitative genotype-phenotype correlations were identified, enabling classification for 32% of VUS.

Conclusions:

• The proactive AIRE variant effect map offers a valuable resource for improving patient outcomes.
• This resource facilitates more rapid and definitive diagnosis of APS-1.
• The study enhances understanding of AIRE variant pathogenicity and its clinical implications.