The Diagnostic Yield of Next Generation Sequencing in Inherited Retinal Diseases: A Systematic Review and Meta-analysis

center dot PURPOSE: Accurate genotyping of individuals with in-herited retinal diseases (IRD) is essential for patient man-agement and identifying suitable candidates for gene ther-apies. This study evaluated the diagnostic yield of next generation sequencing (NGS) in IRDs.center dot DESIGN: Systematic review and meta-analysis.center dot METHODS: This systematic review was prospectively registered (CRD42021293619). Ovid MEDLINE and Ovid Embase were searched on 6 June 2022. Clinical studies evaluating the diagnostic yield of NGS in individ-uals with IRDs were eligible for inclusion. Risk of bias assessment was performed. Studies were pooled using a random-effects inverse variance model. Sources of het-erogeneity were explored using stratified analysis, meta-regression, and sensitivity analysis.center dot RESULTS: This study included 105 publications from 28 countries. Most studies (90 studies) used targeted gene panels. The diagnostic yield of NGS was 61.3% (95% confidence interval: 57.8-64.7%; 51 studies) in mixed IRD phenotypes, 58.2% (51.6-64.6%; 41 stud-ies) in rod-cone dystrophies, 57.7% (46.8-68.3%; eight studies) in macular and cone/cone-rod dystrophies, and 47.6% (95% CI: 41.0-54.3%; four studies) in familial exudative vitreoretinopathy. For mixed IRD phenotypes, a higher diagnostic yield was achieved pooling studies published between 2018-2022 (64.2% [59.5-68.7%]), studies using exome sequencing (73.5% [58.9-86.1%]), and studies using the American College of Medical Ge-netics variant interpretation standards (65.6% [60.8- 70.4%]).center dot CONCLUSION: The current diagnostic yield of NGS in IRDs is between 52-74%. The certainty of the evi-dence was judged as low or very low. A key limitation of the current evidence is the significant heterogeneity be-tween studies. Adoption of standardized reporting guide-lines could improve confidence in future meta-analyses. (Am J Ophthalmol 2023;249: 57-73.(c) 2022 Elsevier Inc. All rights reserved.)

Automated summary

This study evaluates the diagnostic yield of next-generation sequencing (NGS) in inherited retinal diseases (IRDs) and finds that the current diagnostic yield of NGS in IRDs is between 52-74%.