An accurate diagnosis is essential for effective medical management; in the case of rare genetic disease, it also guides genetic counseling. Nevertheless, clinical assessments and conventional genetic testing lead to a diagnosis in less than half of patients.¹ The introduction of whole-exome sequencing has substantially improved our ability to provide patients with a molecular diagnosis and is increasingly the approach of choice for patients with rare diseases. With the genes known for more than half of the predicted 7000 rare diseases,² such hypothesis-free approaches to diagnosis are attractive and have the potential to end the “diagnostic odyssey.”

As clinicians, we . . .