Ending the Diagnostic Odyssey in Rare Genetic Diseases: A Clinical and Genomic Roadmap to Accelerating Diagnosis Worldwide

This text proposes a patient-centered redesign of the diagnostic system for rare genetic diseases. Resolving the prolonged "diagnostic odyssey" requires integrating family phenotypic data with whole-genome sequencing, multidisciplinary teams, and continuous re-analysis, rather than just adopting new technologies.The framework spans four chapters:Chapter 1: Shows how advanced sequencing is absorbed into outdated clinical workflows, necessitating systemic reorganization.Chapter 2: Reframes diagnostics around patients, using the Human Phenotype Ontology to translate qualitative narratives into computational data.Chapter 3: Analyzes systemic bottlenecks and reviews innovations (e.g., long-read sequencing, AI) that elevate diagnostic yields.Chapter 4: Proposes a lifelong care architecture involving longitudinal consent, continuous results delivery, and seamless care transitions.Empirical benchmarks from pioneering programs (e.g., Karolinska, Solve-RD) prove this integrated approach is feasible. The ultimate goal is to expand these models to historically excluded populations while securing sustainable financial and policy frameworks.