Attaining Diagnostic Excellence: How the Structure and Function of a Rare Disease Service Contribute to Ending the Diagnostic Odyssey

Patients with rare or otherwise undiagnosed disorders frequently find themselves on a diagnostic odyssey, the often-prolonged journey toward diagnosis that can be characterized by significant physical, emotional, and financial hardship, as well as by diagnostic errors and delays. The wider availability of clinical exome sequencing has helped end many diagnostic odysseys, though diagnostic success rates of around 35% for exome sequencing leave many patients undiagnosed. Diagnostic yields can be improved via the implementation of advanced genetic testing modalities, though both these modalities and exome sequencing perform significantly better when paired with high-quality phenotypic data. Diagnostic centers of excellence can improve outcomes for patients on a diagnostic odyssey by providing a process and environment that address shortfalls in diagnostic access while providing high-quality phenotyping. Features of successful undiagnosed and rare disease evaluation teams are discussed and an illustrative case is provided.