A Zebra in Horse's Clothing: Rethinking the Diagnosis of Rare Diseases

Rare diseases sometimes present with deceptively common symptoms, complicating diagnosis and decisions about genetic testing. While testing for rare disease offers important benefits, it also carries risks that warrant careful consideration.

We review illustrative cases of rare diseases, along with current screening and diagnostic practices, to reexamine guiding principles for genetic testing. The analysis focuses on balancing clinical utility, patient-centered care, and broader policy implications.

We propose a number of recommendations to guide testing, including ruling out common causes before proceeding, ensuring the presentation is atypical for other common conditions, confirming consistency with a specific, treatable rare disease entity or group, assessing patient or family capacity for informed decision-making, and matching test invasiveness to expected diagnostic utility. Comparison with newborn screening and diagnostic testing highlights discrepancies between these principles and common practices, highlighting the difficulty of achieving consistency.

Establishing uniform guidelines for genetic testing remains challenging, particularly given the limited knowledge surrounding rare disorders. Coordinated efforts are needed to protect patient interests, assess the utility of diagnoses across varied contexts, and ensure that both clinical practice and policy development maximize benefits while minimizing harms.