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

Area of Science:

• Ophthalmology
• Genetics
• Molecular Biology

Background:

• Traditional gene panel approaches for inherited retinal diseases (IRD) present cost and resource challenges.
• Phenotype-based gene panels utilize a targeted strategy with additional testing if initial results are negative.

Purpose of the Study:

• To present the molecular findings of phenotype-based next-generation sequencing (NGS) panels for genetic testing in IRD.
• To assess the diagnostic yield of phenotype-based NGS panels in a clinical setting.

Main Methods:

• Analysis of molecular findings from 655 consecutive patients undergoing phenotype-based panel testing over 54 months.
• Evaluation of diagnostic yield across different clinical phenotypes and age groups.

Main Results:

• Variants were identified in 68.7% of patients, with an overall diagnostic yield of 42.8% from phenotype-based panels.
• Highest diagnostic yields were observed for Usher syndrome (90.9%) and congenital stationary night blindness (75.0%) panels.
• Late-onset macular disease showed a lower diagnostic yield (18.0%) compared to younger patients (24.2%). Copy number variants contributed 1.8% to the diagnostic yield.

Conclusions:

• Phenotype-based genetic testing panels provide a targeted approach, reducing bioinformatics demands and offering a high yield for early-onset, well-defined genetic disorders.
• The clinical utility for late-onset macular disorders requires further evaluation.
• This clinician-referrer-oriented approach can serve as a front-end strategy for future whole-genome sequencing services in IRD diagnostics.