Systematic Curation and Development of an Evidence-Tiered Virtual Gene Panel for Molecular Diagnosis of Inherited Metabolic Hyperlactatemia

Background/ Objectives: Hyperlactatemia is a nonspecific biochemical phenotype with a broad acquired and inherited differential, complicating genomic interpretation. We aimed to identify and curate genes associated with inherited metabolic hyperlactatemia and develop an evidence-tiered virtual diagnostic panel. Methods: NCBI Gene was searched on 8 August 2026 using four lactate-related terms. Human records were deduplicated by GeneID and curated for gene–disease validity, inheritance, mechanism, and lactate-specific clinical relevance. Targeted review of ClinGen, OMIM, GenCC, PanelApp, GeneReviews, and primary literature identified established causes missed by keyword retrieval. Results: The searches yielded 802 raw records. After removal of duplicate export blocks, 401 human query records resolved to 240 unique genes. Submission-version reconciliation identified 34 search-derived genes in the 85-gene active panel, while 206 search-derived genes were not retained and remain available for audit and future reanalysis. Targeted review contributed 51 additional active genes. The final panel comprised 40 Tier 1, 26 Tier 2, and 19 Tier 3 genes. Conclusions: Phenotype-keyword retrieval showed low specificity and incomplete sensitivity. Integrating gene–disease validity with lactate-specific relevance provides a transparent, updateable framework for phenotype-informed genomic prioritization.