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, manifesting variably progressive visual dysfunction. IRDs were historically underserved due to lack of effective interventions. 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/support 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.

Pseudodominant inheritance of retinitis pigmentosa in a family with mutations in the Eyes Shut Homolog (EYS) gene

“…[11,16] In the course of the normal clinical practice for the complex management of patients with IRDs, NGS custom panels operationally represent unbiased choice for the molecular characterization of genetically heterogeneous disorders such as RP, other than a viable compromise between diagnostic yield, time consumption, and running costs. [30][31][32] On the other hand, the composite diagnostic pathway reported by ours on also emphasizes the recommendations of Zampaglione and co-workers, [28] about the need of CNVs study for arriving at a tailored molecular diagnosis in a signi cant percentage of IRD cases erroneously labeled as "genetically unsolved" after the carrying out of NGS and/or WES. A deep genotyping attitude can be decisive to strengthen the close teamwork between ophthalmologists and geneticists, and to address the unmet patients' needs.…”

<i>MFRP</i>-Associated Retinopathy and Nanophthalmos in Two Irish Probands: A Case Report

“…The first approved gene therapy is available for biallelic RPE65 -associated retinopathy (Luxturna™), and examples of ongoing clinical trials include for retinopathy associated with the RPGR, USH2A, ABCA4, CEP290, CHM genes [3]. Even without immediate, gene-therapy implications, optimizing visual potential (e.g., correction of refractive error, glaucoma screening), and treating symptomatic complications (e.g., cataract, CML), with molecular characterization as the cornerstone [3, 15] leads to better outcomes. The ophthalmologist often coordinates multidisciplinary team input (i.e., ophthalmic physician/surgeon, molecular and clinical geneticists, genetic counsellors, other medical specialties as appropriate), efficient and equitable access to treatment, visual rehabilitation strategies, and genetic counselling for parents/families [8, 9, 15].…”

Clinical and Genetic Re-Evaluation of Inherited Retinal Degeneration Pedigrees following Initial Negative Findings on Panel-Based Next Generation Sequencing

“…Visual electrophysiology (ERG, Metrovision, Perenchies, France) was assessed where diagnostically relevant. All clinically assessed patients had undergone a research grade pNGS of 250 IRD-implicated genes at the Ocular Genetics Unit, Trinity College Dublin [4,5,16].…”

“…The panel-based NGS approach in a research-based academic laboratory with validation in an accredited laboratory adopted by Target 5000, as outlined in previous publications, accrued substantial cost savings (Table 3) [5,16]. Using pNGS compared to WES as a first-pass approach for 'gene hunting' is favorable, as it reduces bioinformatic demand, identifies the molecular diagnosis for the majority of IRD patients, and frees resources for 2nd-tier testing of more difficult cases as necessary (Figure 1B).…”

“…The 'cost-effectiveness' of genetic testing for IRDs includes not only the direct costs of genetic sequencing but also the surrounding infrastructure (e.g., genetic counsellor, MDT meeting, molecular geneticist/scientist time/training, clinic use). The broader the scope of a test (e.g., WGS), the greater the yield of non-diagnostic (potentially misleading) findings, including secondary findings, which must be reported [10,16,43]. The expenditure of limited resources on the use and interpretation of 1st-tier WGS in a health service of limited size reduces the number of patients/pedigrees that can be served.…”