2014 ASHG: Using an Augmented Exome to Improve Diagnostic Yield: Case Studies in Retinal Disorders

Identifying the genetic etiology for retinal disorders, like many other Mendelian disorders, is challenging because of allelic, phenotypic, and locus heterogeneity, as well as environmental toxicities resulting in phenocopies. Patients often endure long diagnostic odysseys involving many single gene and/or gene panel tests, with a genetic etiology remaining undetermined in a large percentage of cases (30-50%). Whole exome sequencing (WES) is a highly appealing alternative to panels which require frequent revision as new causative genes are discovered (Figure 1); however, incomplete coverage of relevant genes means standard WES is also non-ideal. To address these limitations, we developed an augmented exome (ACE Exome), which improves sensitivity to detect variants by enhancing coverage over genes of biomedical relevance.