Exploring the Genetics of Unresolved Inherited Retinal Diseases in Ireland

Abstract

The Target 5000 study was established in 2009 with a primary goal to develop a national care pathway for inherited retinal disease patients in Ireland. 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 blood/saliva sample is taken and used for genetic analysis. First tier genetic testing 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). However, it is imperative that more comprehensive sequencing methods are employed in order to provide the 30% of individuals who remain unresolved following preliminary testing with an accurate genetic diagnosis. This doctoral thesis presents data from a pilot study on whole genome sequencing as a diagnostic tool for 100 previously unresolved individuals, with a positive diagnostic yield of 24%. In addition another pilot study on cost effective whole-gene sequencing of ABCA4 for 162 Irish Stargardt/cone-rod dystrophy cases is presented, with a positive diagnostic yield of 61% and 59% for pre-screened and unscreened cases respectively. Lastly, three case studies are presented illustrating the application of knowledge gained regarding pathogenic splice altering variants from both pilot studies when applied to existing target capture data. The results highlight the significant value of a panel target capture sequencing strategy as a first tier genetic test, with remaining elusive cases undergoing more extensive genetic testing in addition to functional analyses of putative pathogenic variants.