Mital Shah1,2, Morag Shanks3, Emily Packham3, Jonathan Williams3, Jesse Haysmoore3, Robert E MacLaren1,2, Andrea H Németh4,5, Penny Clouston3, Susan M Downes1,2. 1. Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust , Oxford, UK. 2. Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford , Oxford, UK. 3. Oxford Medical Genetics Laboratories, Churchill Hospital , Oxford, UK. 4. Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. 5. Nuffield Department of Clinical Neurosciences, University of Oxford , Oxford, UK.
Abstract
INTRODUCTION: Diagnostic next generation sequencing (NGS) services for patients with inherited retinal diseases (IRD) traditionally use gene panel based approaches, which have cost and resource implications. Phenotype-based gene panels use a targeted strategy with further testing protocols, if initial results are negative. We present the molecular findings of the Oxford phenotype-based NGS panels for genetic testing in IRD. METHODS: Results of 655 consecutive patients referred for phenotype-based panel testing over 54 months were analysed to assess diagnostic yield. RESULTS: Variants were identified in 450 patients (68.7%). The overall diagnostic yield from phenotype-based panels was 42.8%. The diagnostic yield was highest from panels representing distinct clinical phenotypes: Usher panel 90.9% and congenital stationary night blindness panel 75.0%. Retinitis pigmentosa/rod-cone dystrophy was the commonest presenting phenotype (n = 243) and Usher syndrome was the commonest presenting syndromic disease (n = 39). Patients presenting with late-onset (≥50 years) macular disease had a lower diagnostic yield (18.0%) compared with patients <50 years (24.2%). Additionally, a diagnostic yield of 1.8% was attributable to copy number variants. CONCLUSIONS: Phenotype-based genetic testing panels provide a targeted testing approach and reduce bioinformatics demand. The overall diagnostic yield achieved in this study reflects the wide range of phenotypes that were referred. This pragmatic approach provides a high yield for early-onset and clearly defined genetically determined disorders but clinical utility is not as clear for late-onset macular disorders. This phenotype-based panel approach is clinician-referrer orientated, and can be used as a front-end virtual panel, when whole genome sequencing is introduced into diagnostic services for IRD.
INTRODUCTION: Diagnostic next generation sequencing (NGS) services for patients with inherited retinal diseases (IRD) traditionally use gene panel based approaches, which have cost and resource implications. Phenotype-based gene panels use a targeted strategy with further testing protocols, if initial results are negative. We present the molecular findings of the Oxford phenotype-based NGS panels for genetic testing in IRD. METHODS: Results of 655 consecutive patients referred for phenotype-based panel testing over 54 months were analysed to assess diagnostic yield. RESULTS: Variants were identified in 450 patients (68.7%). The overall diagnostic yield from phenotype-based panels was 42.8%. The diagnostic yield was highest from panels representing distinct clinical phenotypes: Usher panel 90.9% and congenital stationary night blindness panel 75.0%. Retinitis pigmentosa/rod-cone dystrophy was the commonest presenting phenotype (n = 243) and Usher syndrome was the commonest presenting syndromic disease (n = 39). Patients presenting with late-onset (≥50 years) macular disease had a lower diagnostic yield (18.0%) compared with patients <50 years (24.2%). Additionally, a diagnostic yield of 1.8% was attributable to copy number variants. CONCLUSIONS: Phenotype-based genetic testing panels provide a targeted testing approach and reduce bioinformatics demand. The overall diagnostic yield achieved in this study reflects the wide range of phenotypes that were referred. This pragmatic approach provides a high yield for early-onset and clearly defined genetically determined disorders but clinical utility is not as clear for late-onset macular disorders. This phenotype-based panel approach is clinician-referrer orientated, and can be used as a front-end virtual panel, when whole genome sequencing is introduced into diagnostic services for IRD.
Entities:
Keywords:
Retinal dystrophy; copy number variants; genetic testing; next generation sequencing; phenotype
Authors: Sena A Gocuk; Yuanzhang Jiao; Alexis Ceecee Britten-Jones; Nathan M Kerr; Lyndell Lim; Simon Skalicky; Richard Stawell; Lauren N Ayton; Heather G Mack Journal: Clin Ophthalmol Date: 2022-04-13
Authors: Kirk A J Stephenson; Julia Zhu; Adrian Dockery; Laura Whelan; Tomás Burke; Jacqueline Turner; James J O'Byrne; G Jane Farrar; David J Keegan Journal: Int J Mol Sci Date: 2022-01-17 Impact factor: 5.923