438: Mapping AIRE: a proactive atlas of 9,790 missense variants

Axakova A et al., The American Journal of Human Genetics - Axakova et al. generated a variant effect map for AIRE using an insulin‑promoter GFP reporter in HEK293 cells to measure the functional impact of 9,790 missense substitutions and provide calibrated evidence for clinical variant interpretation. Key terms: AIRE, missense variants, variant effect map, APS-1, functional assay.

Study Highlights:
The authors used an insulin‑promoter‑driven GFP reporter in HEK293 cells and a DT‑POPCode mutagenesis library to assay 9,790 AIRE missense variants. The resulting map recapitulated known functional regions (CARD, SAND, PHD2, C‑terminal), revealed both loss‑ and gain‑of‑function changes, and exposed a blind spot for PHD1 in this assay. Benchmarking against ClinVar and computational predictors enabled calibrated evidence for 70% of ClinVar VUSs and supported reclassification of 32% (109/345) of VUSs. The map also correlated quantitatively with APS‑1 severity in an international cohort and associated damaging variants with hypoparathyroidism and vitamin B12 deficiency anemia in UK Biobank.

Conclusion:
This proactive, calibrated AIRE variant effect map provides immediate functional evidence to improve missense variant classification and expedite APS‑1 diagnosis, while highlighting assay limitations (PHD1 blind spot, cDNA-based design) that warrant follow-up studies.

Music:
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Article title:
Systematic and proactive evaluation of AIRE missense variant effects

First author:
Axakova A

Journal:
The American Journal of Human Genetics

DOI:
10.1016/j.ajhg.2026.07.008

Reference:
Axakova A., Berger A.H., van Loggerenberg W., et al. Systematic and proactive evaluation of AIRE missense variant effects. The American Journal of Human Genetics 113, 1–21 (2026). https://doi.org/10.1016/j.ajhg.2026.07.008

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Episode link: https://basebybase.com/episodes/s2-e438-aire-variant-effect-map

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-10.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantively audited the sections describing the AIRE variant-effect map, high-throughput mutagenesis and screening, structural-domain interpretation (CARD/SAND/PHD1/PHD2), gain-of-function findings, CAM-score genotype-phenotype correlations, and population-level associations (APS-1 cohort and UK Biobank). Also review
- transcript topics: AIRE and APS-1 background; Insulin promoter GFP reporter assay in HEK293 cells; DT-POPCode library and missense variant generation; Variant effect map results and validation; Structural-domain mapping (CARD, SAND, PHD1, PHD2, C-terminal); Gain-of-function variants and disordered regions

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
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