Genotype before phenotype? Reversing the diagnostic odyssey in genomic medicine

For decades, the diagnosis of rare genetic disorders has relied on a phenotype-driven approach, often resulting in a prolonged "diagnostic odyssey." The widespread use of whole-exome and whole-genome sequencing has transformed this paradigm, increasingly enabling genotype-first diagnoses before a clear clinical phenotype is recognized. This shift may contribute to a reversal of the diagnostic odyssey, in which genetic findings guide subsequent clinical evaluation through reverse phenotyping. Large-scale biobank studies and newborn genomic screening programs are further accelerating this paradigm shift. Although this approach has improved diagnostic yield, it also introduces interpretative challenges, including the risk of phenotype reinterpretation bias and the persistent burden of variants of uncertain significance (VUS), particularly when genetic variants only partially explain the clinical presentation. This article discusses the emergence of genotype-driven diagnosis and emphasizes the need for balanced integration of genomic and clinical data in modern precision medicine.