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Adrian Dockery, Niamh C Wynne, Kirk Stephenson, Laura Whelan, Peter Humphries, Giuliana Silvestri, Matthew Carrigan, David J Keegan, Paul F Kenna, G. Jane Farrar; Target 5000: Target Capture Genotyping of Retinal Degenerations in Ireland. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2812.
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© ARVO (1962-2015); The Authors (2016-present)
Although a number of clinical trials are in progress for patients with inherited retinal degenerations (IRDs), Typically such trials require patients to have a known causative mutation to participate. The Target 5000 research project aims to genetically characterise the estimated 5,000 people in Ireland affected by IRDs.
The IRD patient cohort used in the study has been obtained via a collaborative network of ophthalmologists whereby if an IRD is suspected, given consent, a DNA sample is taken and provided to a central laboratory for genetic analysis. The study seeks to detect previously identified, together with as yet undiscovered, pathological mutations in a panel of known IRD genes utilizing target capture next generation sequencing (NGS). The study to date includes data from over 1000 IRD patients.
Target 5000 offers not only a chance to discover new pathogenic mutations but is vital to providing patients with information regarding the underlying genetic pathogenesis of their disease. Over 80 novel IRD mutations have been discovered to date, this includes several novel large structural variants including inversions and deletions spanning several hundred kilobases, for example in the CHM gene. Our findings have also proved beneficial in a clinical setting where candidate variants have helped to resolve some previously ambiguous disease phenotypes. The study has also led to the identification of several actionable variants in our cohort where there is active recruitment for natural history studies or clinical trials of new therapeutics.
The aim of the study is to characterise the genetic architecture of IRDs in Ireland and, in principle, potentially enable clinical trials to be more accessible for some patients where appropriate. To date, genetic analysis of IRD patients has helped to resolve ambiguous phenotypes and to identify candidate variants in nearly 70% of cases. The continuous expansion of our cohort has enabled us to better interrogate the sequencing data and interpret the potential pathogenicity of novel variants when detected. In addition to this, the increasing wealth of data from NGS studies of IRDs globally are helping to facilitate better correlations between genotypes and phenotypes. In turn, this information allows for the further refinement of methods for diagnoses and prognoses.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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