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Generative AI Accelerates Genotype-Phenotype Characterization of a 1600-Case Leigh Syndrome Virtual Cohort from
1Pathology Informatics, Bioinformatics, and Data Science, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
Biology
|February 26, 2026
Summary
Generative AI rapidly created the largest Leigh Syndrome Spectrum cohort, revealing key genetic causes and phenotypes. Mitochondrial translation defects are linked to poor prognosis and early onset in this rare disease.
Area of Science:
- Genetics and Genomics
- Artificial Intelligence in Medicine
- Rare Disease Research
Background:
- Leigh Syndrome Spectrum (LSS) is a rare, heterogeneous disease with small cohorts limiting statistical power.
- Manual data standardization from literature for meta-analyses is burdensome and inefficient.
Purpose of the Study:
- To develop a novel workflow combining Generative AI (GenAI) and human curation to create large-scale, harmonized virtual cohorts for rare disease analysis.
- To characterize the phenotypic and genetic architecture of LSS and perform large-scale survival analysis.
Main Methods:
- Utilized Google's Gemini-2.5-pro for rapid processing of over 2300 published LSS cases.
- Employed human-in-the-loop curation for accurate mapping of raw clinical data to Human Phenotype Ontology (HPO) terms (>90% accuracy).
- Generated a harmonized LSS virtual cohort of 1679 cases for analysis.
Main Results:
- Identified autosomal recessive (932 cases) and mitochondrial (752 cases) inheritance as most common.
- Found SURF1 (240 cases), MT-ATP6 (199), and MT-ND3 (183) as frequently mutated genes.
- Survival analysis revealed defects in mitochondrial translation are associated with poorest prognosis (84% mortality) and early onset (0.23 years).
Conclusions:
- GenAI-driven methodology enables rapid creation of analysis-ready virtual cohorts from heterogeneous literature, accelerating rare disease research.
- The largest LSS virtual cohort facilitates robust characterization of LSS genetics, phenotypes, and survival outcomes.
- Mitochondrial translation defects and Complex V mutations are associated with significantly poorer prognosis in LSS.
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