Target 5000: Evolution of the Irish National Program for Inherited Retinal Degenerations

Abstract

Purpose : Inherited retinal degenerations (IRD) are rare genetic eye diseases with >300 implicated genes, many manifesting as progressive visual loss in children/young adults. The IRD population was historically underserved and disillusioned with healthcare services due to lack of interventions. Many novel therapies (e.g., gene and cell-based therapies) will require accurate genetic/clinical diagnosis, thus an efficient and effective pathway for assessment and management of IRDs is required. Here we describe the development of a national pathway for the management of the Irish IRD population.

Methods : Surveys of past Irish practice and international experts advice were used to design an all-Ireland IRD service (Target 5000). Assessment included clinical phenotyping (history, examination, multimodal imaging, perimetry, and electrophysiology) and next generation genetic sequencing in research-grade and accredited laboratories. 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). Weekly multidisciplinary team (MDT; ophthalmologists, physicians, clinical and molecular geneticists, genetic counsellors) meetings reconciled phenotype with genotype. Bespoke care plans were created for each patient comprising supports, existing interventions, and novel therapies/clinical trials.

Results : The survey revealed that, prior to Target 5000, a significant cohort of patients were not engaging with healthcare and support services due to lack of effective interventions. Pathogenic/likely-pathogenic genetic variants in IRD-implicated genes were confirmed in 62.3% of cases, with 11.6% had variants of unknown significance. The genotyping strategy (research grade testing with validation in an accredited laboratory) of Target 5000 saved 42.73% vs independent testing, not accounting for MDT expertise access, which is unavailable outside the program. This has leveraged funding from government resources, where previously this was largely charitably sourced.

Conclusions : The Target 5000 program has demonstrated a move toward a more efficacious & efficient model of care. This enables harmonized clinical & genetic diagnosis while investigating novel genes/variants, disease mechanisms and therapies. This template could be helpful in developing similar IRD programm in small/medium nations.

This is a 2021 ARVO Annual Meeting abstract.