Abstract
The Irish national registry for inherited retinal degenerations (Target 5000) is a clinical and scientific program to identify individuals in Ireland with inherited retinal disorders and to attempt to ascertain the genetic cause underlying the disease pathology. Potential participants first undergo a clinical assessment, which includes clinical history and analysis with multimodal retinal imaging, electrophysiology, and visual field testing. If suitable for recruitment, a sample is taken and used for genetic analysis. Genetic analysis is conducted by use of a retinal gene panel target capture sequencing approach. With over 1000 participants from 710 pedigrees now screened, there is a positive candidate variant detection rate of approximately 70% (495/710). Where an autosomal recessive inheritance pattern is observed, an additional 9% (64/710) of probands have tested positive for a single candidate variant. Many novel variants have also been detected as part of this endeavor. The target capture approach is an economic and effective means of screening patients with inherited retinal disorders. Despite the advances in sequencing technology and the ever-decreasing associated processing costs, target capture remains an attractive option as the data produced is easily processed, analyzed, and stored compared to more comprehensive methods. However, with decreasing costs of whole genome and whole exome sequencing, the focus will likely move towards these methods for more comprehensive data generation.
Highlights
Inherited retinal degenerations (IRDs) are a broad set of clinically and genetically diverse conditions that represent the leading cause of visual dysfunction in those of working age
Over 270 genes have been associated with a wide variety of IRDs across a phenotypic spectrum [6], which are routinely divided into large subcategories in order to readily distinguish the specific retinal regions and cell types affected; for example, retinitis pigmentosa (RP) versus macular dystrophy, which initially cause predominantly peripheral and central vision loss, respectively
We present novel findings from both newly recruited participants and retrospective analysis of 750 individuals previously screened, resulting over 1000 individuals across 710 pedigrees genetically screened to date. 458 individuals have been sequenced for variants in 210 genes, 689 individuals have been sequenced for variants in 254 genes, and confirmation sequencing is ongoing for other affected family members
Summary
Inherited retinal degenerations (IRDs) are a broad set of clinically and genetically diverse conditions that represent the leading cause of visual dysfunction in those of working age. IRDs are typically caused by improper development or death of photoreceptor cells and have a substantial effect on both the quality of life of those affected and health economics. Inheritance patterns include autosomal recessive, autosomal dominant and X-linked, as well as rarer mitochondrial and digenic forms [1,2]. Over 270 genes have been associated with a wide variety of IRDs across a phenotypic spectrum [6], which are routinely divided into large subcategories in order to readily distinguish the specific retinal regions and cell types affected; for example, retinitis pigmentosa (RP) versus macular dystrophy, which initially cause predominantly peripheral and central vision loss, respectively.
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