Next generation sequencing using phenotype-based panels for genetic testing in inherited retinal diseases

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.

KEYWORDS:

• Retinal dystrophy
• next generation sequencing
• copy number variants
• genetic testing
• phenotype

Acknowledgments

The authors would like to thank Dr Anneke Seller for her assistance in the development of the phenotype-based genetic testing panels.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

This work was supported by the Thames Valley & South Midlands Clinical Research Network and the NIHR Oxford Biomedical Research Centre.