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Background <p>Alagille syndrome (ALGS) is a rare multisystem disorder primarily caused by pathogenic variants in JAG1 and NOTCH2. Although its genetic basis is well established, existing variant repositories often lack comprehensive clinical annotation, sufficient ethnic representation, and open accessibility. These limitations reduce their translational relevance and hinder genotype–phenotype correlation and evidence-based molecular diagnosis. To address this gap, we developed AGEX (Alagille Genetics Exploration Database), a curated, open-access resource integrating genetic variants with phenotype and population frequency data.</p> Methods <p>AGEX (<a href="http://agexbase.iitd.ac.in">http://agexbase.iitd.ac.in</a>) was constructed through a systematic literature review from 1999–2025, supplemented with unpublished case reports from Indian ALGS patients. Variants were curated and classified according to ACMG/AMP guidelines, with pathogenicity predictions derived from multiple in silico tools. Population allele frequency data were integrated from gnomAD, All of Us, and IndiGenome databases. Domain-level mutation mapping was performed to assess variant distribution across functional protein regions. Additionally, a prototype ALGS Severity Tier Calculator was developed to integrate genotype and phenotype parameters for semi-quantitative clinical stratification.</p> Results <p>AGEX compiles 260 variants, including 231 in JAG1 and 29 in NOTCH2, reported across 20 global populations. Four previously unreported variants were identified. Domain-level analysis revealed recurrent clustering of mutations within the DSL and EGF-like domains of JAG1, emphasizing their importance in Notch signaling. The database provides an interactive interface enabling variant browsing, phenotype-linked queries, and population-level analyses, along with a prototype severity scoring framework.</p> Conclusion <p>AGEX represents the first dedicated integrative database for ALGS, enabling variant browsing, population-specific analyses, and phenotype-linked searches. While further longitudinal clinical validation is required, AGEX represents the first dedicated, integrative database for ALGS. By centralizing variant and clinical data, AGEX aims to accelerate diagnosis, improve patient stratification, and facilitate precision medicine strategies targeting Notch pathway dysregulation, serving as a scalable model for other rare disorder genomics.</p>

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AGEX: a comprehensive database of clinically relevant genetic variants associated with Alagille syndrome across diverse populations

  • 期刊论文

  • 发表日期：

    2026年3月21日

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  • Priya Sharma,
  • Vishnu Prasad,
  • Bhanu Teja Korra,
  • Rohan Grotra,
  • Rohan Malik,
  • Rahul Kumar,
  • Deepti Abbey

摘要

Background

Alagille syndrome (ALGS) is a rare multisystem disorder primarily caused by pathogenic variants in JAG1 and NOTCH2. Although its genetic basis is well established, existing variant repositories often lack comprehensive clinical annotation, sufficient ethnic representation, and open accessibility. These limitations reduce their translational relevance and hinder genotype–phenotype correlation and evidence-based molecular diagnosis. To address this gap, we developed AGEX (Alagille Genetics Exploration Database), a curated, open-access resource integrating genetic variants with phenotype and population frequency data.

Methods

AGEX (http://agexbase.iitd.ac.in) was constructed through a systematic literature review from 1999–2025, supplemented with unpublished case reports from Indian ALGS patients. Variants were curated and classified according to ACMG/AMP guidelines, with pathogenicity predictions derived from multiple in silico tools. Population allele frequency data were integrated from gnomAD, All of Us, and IndiGenome databases. Domain-level mutation mapping was performed to assess variant distribution across functional protein regions. Additionally, a prototype ALGS Severity Tier Calculator was developed to integrate genotype and phenotype parameters for semi-quantitative clinical stratification.

Results

AGEX compiles 260 variants, including 231 in JAG1 and 29 in NOTCH2, reported across 20 global populations. Four previously unreported variants were identified. Domain-level analysis revealed recurrent clustering of mutations within the DSL and EGF-like domains of JAG1, emphasizing their importance in Notch signaling. The database provides an interactive interface enabling variant browsing, phenotype-linked queries, and population-level analyses, along with a prototype severity scoring framework.

Conclusion

AGEX represents the first dedicated integrative database for ALGS, enabling variant browsing, population-specific analyses, and phenotype-linked searches. While further longitudinal clinical validation is required, AGEX represents the first dedicated, integrative database for ALGS. By centralizing variant and clinical data, AGEX aims to accelerate diagnosis, improve patient stratification, and facilitate precision medicine strategies targeting Notch pathway dysregulation, serving as a scalable model for other rare disorder genomics.