High Diagnostic Yield of Whole Exome Sequencing in Participants With Retinal Dystrophies in a Clinical Ophthalmology Setting

Abstract

Purpose: To assess the diagnostic yield and the practicality of implementing whole exome sequencing within a clinical ophthalmology setting.

Design: Evaluation of a diagnostic protocol.

Methods: setting: Patient participants were enrolled during clinical appointments in a university-based ophthalmic genetics clinic.

Patient population: Twenty-six patients with a variety of presumed hereditary retinal dystrophies.

Intervention: Participants were offered whole exome sequencing in addition to clinically available sequencing gene panels between July 2012 and January 2013 to determine the molecular etiology of their retinal dystrophy.

Main outcome measures: Diagnostic yield and acceptability of whole exome sequencing in patients with retinal disorders.

Results: Twenty-six of 29 eligible patients (∼90%) who were approached opted to undergo molecular testing. Each participant chose whole exome sequencing in addition to, or in lieu of, clinically available sequencing gene panels. Time to obtain informed consent was manageable in the clinical context. Whole exome sequencing successfully identified known pathogenic mutations or suspected deleterious variants in 57.7% of participants. Additionally, 1 participant had 2 autosomal dominant medically actionable incidental findings (unrelated to retinopathy) that were reported to enable the participant to take preventive action and reduce risk for future disease.

Conclusions: In this study, we identified the molecular etiology for more than half of all participants. Additionally, we found that participants were widely accepting of whole exome sequencing and the possibility of being informed about medically actionable incidental findings.

Copyright © 2015 Elsevier Inc. All rights reserved.

Figures

Figure 1. Selected pedigrees of participants with a variety of retinal dystrophies evaluated by whole exome sequencing

(Top Left) Participant 4 with BRCA2 and MSH2 mutations with only paternal grandfather with a history of cancer. (Top Right) Participant 24 withPRPH2 mutation with two sisters with Stargardt disease and mother with diagnosis of age related macular degeneration. (Bottom Right) Participant 25 withRPGR mutation with family history consistent with X-linked inheritance.