Generative AI Accelerates Genotype-Phenotype Characterization of a 1600-Case Leigh Syndrome Virtual Cohort from...

Leigh Syndrome Spectrum (LSS) is a rare and heterogeneous disease continuum with most published cohorts in small sizes that limit the statistical power. Large-scale meta-analyses with published case-level clinical data extracted from the literature are essential for robust population analysis but are hindered by the burden of manually standardizing the unstructured, heterogeneous, and sparse case-level data from the literature. We developed a novel workflow which is among the first to combine Generative AI (GenAI) with human-in-the-loop curation to overcome this barrier. This pipeline utilized Google's Gemini-2.5-pro and rapidly processed over 2300 cases from published case data tables in two weeks and achieved >90% accuracy in mapping raw clinical data to Human Phenotype Ontology (HPO) terms. This process rapidly yielded a harmonized LSS virtual cohort of 1679 data-rich cases, which is the largest LSS virtual cohort reported so far, and thus enables characterization of LSS phenotypic and genetic architectures, revealing that autosomal recessive (932 cases) and mitochondrial (752 cases) inheritance are the most common. The most frequently mutated genes were SURF1 (240 cases), MT-ATP6 (199), and MT-ND3 (183). HPO term consolidation identified common hallmark phenotypes, including lactic acidosis, hypotonia, bilateral basal ganglia lesions, and mitochondrial respiratory chain deficiency. The cohort's scale enabled large-scale survival analysis, revealing that defects in mitochondrial translation are associated with the poorest prognosis (84% mortality in this group) and early onset (0.23 years). Among the deceased group, patients with Complex V mutations were linked to a significantly shorter mean survival time (1.77 years) than those with Complex I (3.70 years) or IV (3.57 years) mutations. This GenAI-driven methodology establishes a scalable framework for rapidly creating analysis-ready virtual cohorts from heterogeneous literature and accelerating population-level study for rare diseases including Leigh Syndrome and other mitochondrial diseases.