MARGARET HILL
Capstone Project Committee: Lauren Doyle, MGC, CGC; Mary Hricik, M.S., CGC; Alessandro Iannaccone, M.D.
Purpose: Inherited retinal dystrophies (IRDs) display great genetic heterogeneity and molecular diagnosis remains challenging. Given the variability of IRD next-generation sequencing (NGS) panels, the choice of which panel to order can be a difficult one. Here, we compared the predicted diagnostic yields for various clinically available IRD panels.
Design: Retrospective chart review.
Methods: A total 128 patients with IRD who had molecular testing were included. For each patient, demographics, molecular test ordered, test results, and final diagnoses were curated. Three CLIA-certified labs were selected and, for each available NGS panel applicable for this patient cohort, the predicted diagnostic rates were calculated.
Results: In this cohort, 47.7% of patients had received a molecular diagnosis. The most common diagnoses in this sample was AD retinitis pigmentosa (RP), followed by cone-rod dystrophy (CORD) and Usher syndrome. For the largest available NGS panels, Blueprint Genetics had the greatest diagnostic yield at 45.31%. Diagnostic yields for smaller, targeted NGS panels were high and, with the exception of Stargardt disease and blue cone monochromacy, were comparable across the three labs. Differences depended on detection of large deletions.
Conclusion: Large NGS panels had comparable predicted diagnostic yields. Given the presence of a pathogenic variant in a mitochondrial gene, sequencing of mitochondrial DNA may be an appropriate second-tier test. When available, targeted NGS panels performed extremely well, with predicted diagnostic yields of 100% for achromatopsia, Bardet-Biedl syndrome, CORD, X-linked RP, and Usher syndrome.