This month in The Journal

Rare diseases affect more than 5% of the population in the United States. Classically, rare diseases are diagnosed through a phenotype-first approach in which individuals with distinct clinical features undergo genetic testing to identify the underlying genetic basis of their disorder. This approach can lead to ascertainment bias toward individuals with more severe or well-characterized phenotypes, leaving many affected individuals without a diagnosis. A genotype-first approach could increase diagnoses and provide insight into the phenotypic spectrum and prevalence of rare diseases, but this approach is difficult to apply at scale.