The 100,000 Genomes Project - Uncovering Pathogenic Variants in Inherited Optic Neuropathies with Whole-Genome Sequencing (PDF)

Inherited optic neuropathies (ION) are a genetically heterogeneous group of disorders characterised by progressive and irreversible loss of retinal ganglion cells. Reaching a confirmed molecular diagnosis can be challenging given the number of disease-associated genes that have been identified within both the nuclear and mitochondrial genomes. In addition, routine genetic testing will also not identify novel causes of optic atrophy. In this study, we applied whole-genome sequencing (WGS) to investigate a cohort of patients with a clinical diagnosis of ION.

Tuesday, March 10th from 10:15 - 10:30 am The 100,000 Genomes Project - Uncovering Pathogenic Variants in inherited Optic Neuropathies with Whole-Genome Sequencing Neringa Jurkute1, Gavin Arno2, Amy Slater3, Nikolas Pontikos2, Marcela Votruba4, Savita Nutan5, Andrew Webster2, Patrick Yu-WaiMan6 NIHR Biomedical Research Centre at MoorfieldsEye Hospital and UCL IoO, London, United Kingdom of Great Britain and Northern Ireland, 2Moorfields Eye Hospital and UCL IoO, London, United Kingdom of Great Britain and Northern Ireland, 3Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom of Great Britain and Northern Ireland, 4School of Optometry and Vision Sciences, Cardiff University, Cardiff, United Kingdom of Great Britain and Northern Ireland, 5Great Ormond Street Hospital, London, United Kingdom of Great Britain and Northern Ireland, 6Moorfields Eye Hospital, UCLIoO, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland 1 Introduction: Inherited optic neuropathies (ION) are a genetically heterogeneous group of disorders characterised by progressive and irreversible loss of retinal ganglion cells. Reaching a confirmed molecular diagnosis can be challenging given the number of disease-associated genes that have been identified within both the nuclear and mitochondrial genomes. In addition, routine genetic testing will also not identify novel causes of optic atrophy. In this study, we applied whole-genome sequencing (WGS) to investigate a cohort of patients with a clinical diagnosis of ION. Methods: As part of the 100,000 Genomes project, we have so far analysed 61 probands with ION. Variant calling was conducted using an automated bioinformatics pipeline. In the first instance, variant prioritisation in a curated virtual gene panel (https://panelapp.genomicsengland.co.uk/panels/186/) was performed, followed by clinical variant interpretation and a discussion at a multidisciplinary meeting. For unsolved cases, we looked specifically for non-coding and structural variants in the gene panel and new gene/disease associations. Potential pathogenic variants were selected for functional analysis by applying an integrated analysis pipeline incorporating deep clinical phenotyping, variant filtering and interpretation tools. Results: To date, 61/137 (44.5%) probands with optic atrophy have been analysed. Using our integrated bioinformatics approach, we have identified likely pathogenic variants in 34/61 (56%) probands. Of these, 29 (85%) cases harbor variants in known optic atrophy genes whereas 5 (15%) cases harboured likely pathogenic variants outside of the gene panel. 24/61 (39%) undiagnosed cases currently undergoing expanded variant discovery analysis, where we expect to identify novel optic atrophy genes. Conclusions: Implementation of WGS as part of a clinical genomic pipeline is a powerful strategy leading to a molecular diagnosis in over half of all cases investigated. Furthermore, we identified novel optic atrophy genes and new gene/disease associations in the undiagnosed cases. References: None. Keywords: Genetic disease, Optic neuropathy Financial Disclosures: The authors had no disclosures. Grant Support: None. Contact Information: For more information contact: [e-mail] 310 | North American Neuro-Ophthalmology Society