Target 5000: a standardized all-Ireland pathway for the diagnosis and management of inherited retinal degenerations

Abstract

Introduction: Inherited retinal degenerations (IRD) are rare genetic disorders with > 300 known genetic loci, mani- festing variably progressive visual dysfunction. IRDs were historically underserved due to lack of effective interven- tions. Many novel therapies will require accurate diagnosis (phenotype and genotype), thus an efficient and effective pathway for assessment and management is required. Methods: Using surveys of existing practice patterns and advice from international experts, an all-Ireland IRD service (Target 5000) was designed. Detailed phenotyping was followed by next generation genetic sequencing in both a research and accredited laboratory. Unresolved pedigrees underwent further studies (whole gene/whole exome/ whole genome sequencing). Novel variants were interrogated for pathogenicity (cascade screening, in silico analysis, functional studies). A multidisciplinary team (MDT; ophthalmologists, physicians, geneticists, genetic counsellors) reconciled phenotype with genotype. A bespoke care plan was created for each patient comprising supports, existing interventions, and novel therapies/clinical trials. Results and discussion: Prior to Target 5000, a significant cohort of patients were not engaged with healthcare/sup- port services due to lack of effective interventions. Pathogenic or likely pathogenic variants in IRD-associated genes were detected in 62.3%, with 11.6% having variants of unknown significance. The genotyping arm of Target 5000 allowed a 42.73% cost saving over independent testing, plus the value of MDT expertise/processing. Partial funding has transferred from charitable sources to government resources. Conclusion: Target 5000 demonstrates efficacious and efficient clinical/genetic diagnosis, while discovering novel IRD-implicated genes/variants and investigating mechanisms of disease and avenues of intervention. This model could be used to develop similar IRD programmes in small/medium-sized nations.