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Updated: Aug 15, 2025
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
The Diagnostic Yield of Next Generation Sequencing in Inherited Retinal Diseases: A Systematic Review and
Alexis Ceecee Britten-Jones1, Sena A Gocuk1, Kai Lyn Goh2
1From the Department of Optometry and Vision Sciences (A.C.B.-J., S.A.G., L.N.A.), Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia; Department of Surgery (Ophthalmology) (A.C.B.-J., S.A.G., K.L.G., T.L.E.., L.N.A.), Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia; Centre for Eye Research Australia (A.C.B.-J., S.A.G., K.L.G., T.L.E., L.N.A.), Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
Purpose:
Accurate genotyping of individuals with inherited retinal diseases (IRD) is essential for patient management and identifying suitable candidates for gene therapies. This study evaluated the diagnostic yield of next generation sequencing (NGS) in IRDs.
Design:
Systematic review and meta-analysis.
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 individuals with IRDs were eligible for inclusion. Risk of bias assessment was performed. Studies were pooled using a random...effects inverse variance model. Sources of heterogeneity were explored using stratified analysis, meta-regression, and sensitivity analysis.
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 studies) 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 Genetics variant interpretation standards (65.6% [60.8-70.4%]).
Conclusion:
The current diagnostic yield of NGS in IRDs is between 52-74%. The certainty of the evidence was judged as low or very low. A key limitation of the current evidence is the significant heterogeneity between studies. Adoption of standardized reporting guidelines could improve confidence in future meta-analyses.
