Mater Clinical Ophthalmic Genetics Unit, Mater Misericordiae University Hospital, Dublin, Ireland.
The Research Foundation, Royal Victoria Eye and Ear Hospital, Dublin, Ireland.
Orphanet J Rare Dis. 2021 May 5;16(1):200. doi: 10.1186/s13023-021-01841-1.
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.
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.
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.
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.
遗传性视网膜变性（IRD）是一种罕见的遗传疾病，有超过 300 个已知的遗传位点，表现为不同程度的进行性视觉功能障碍。由于缺乏有效的干预措施，IRD 历史上服务不足。许多新疗法将需要准确的诊断（表型和基因型），因此需要一种有效的评估和管理途径。
通过对现有实践模式的调查和国际专家的建议，设计了一个全爱尔兰的 IRD 服务（目标 5000）。在研究和认证实验室中，先进行详细的表型分析，然后进行下一代基因测序。未解决的家系进行进一步研究（全基因/全外显子/全基因组测序）。对新变体进行致病性分析（级联筛查、计算机分析、功能研究）。一个多学科团队（MDT；眼科医生、内科医生、遗传学家、遗传咨询师）将表型与基因型协调一致。为每位患者创建了一个定制的护理计划，包括支持、现有干预措施和新疗法/临床试验。
在目标 5000 之前，由于缺乏有效的干预措施，相当一部分患者没有参与医疗保健/支持服务。在与 IRD 相关的基因中发现了致病性或可能致病性的变体，占 62.3%，其中 11.6%的变体意义不明。目标 5000 的基因分型部分使独立测试的成本节省了 42.73%，加上 MDT 专业知识/处理的价值。部分资金已从慈善来源转移到政府资源。
目标 5000 证明了有效的和高效的临床/基因诊断，同时发现了新的 IRD 相关基因/变体，并研究了疾病的机制和干预途径。这种模式可用于在小/中型国家开发类似的 IRD 计划。
