Integrating Genomics and Deep Phenotyping for Diagnosing Rare Pediatric Neurological Diseases: Potential for Sustainable Healthcare

Background: Rare pediatric neurological diseases (RPND) often elude timely diagnosis, resulting in prolonged and costly diagnostic odysseys. Integration of Human Phenotype Ontology (HPO)-based deep phenotyping with exome sequencing (ES) and reverse phe-notyping may improve diagnostic yield and efficiency, especially in resource-limited set-tings. Objectives: To assess the diagnostic yield and clinical impact of an integrated ap-proach combining deep phenotyping, ES, and reverse phenotyping in children with sus-pected RPND in a multi-center, resource-limited setting. Methods: Eighty-one children with suspected RPND from 11 hospitals in South Kazakhstan were enrolled via the Cen-tral Asian and Transcaucasian Rare Pediatric Neurological Diseases Genomic Consorti-um (CAT-RPND). ES was performed by 3Billion (South Korea). All patients underwent HPO-based deep phenotyping, with variant classification according to American College of Medical Genetics and Genomics (ACMG) guidelines. Reverse phenotyping and inter-disciplinary case discussions supported interpretation. Results: Molecular diagnoses were achieved in 43 of 81 patients (53%), including 18 pathogenic, 12 likely pathogenic, and 9 variants of uncertain significance (VUS). Reverse phenotyping refined or expanded phenotypes in 33% of diagnosed cases and supported likely pathogenicity in 8 of 9 VUS. The integrated approach reduced the median diagnostic odyssey from 72 to < 5 months and the median number of procedures from 20 to 2 (Wilcoxon p = 1.91×10⁻⁶; Cohen’s d = 2.43). Conclusions: Combining deep phenotyping, ES, and reverse phenotyping improved diagnostic outcomes and shortened the diagnostic journey. This approach minimizes unnecessary procedures and delays, offering scalable value for sustainable healthcare in resource-limited settings.