Understanding the Molecular Pathology of Inherited Retinal Disease: Harnessing Large Patient Cohorts and Long-Read Sequencing

Background Inherited retinal diseases (IRDs) are a group of genetic eye conditions that affect the retina, which is the light-sensitive tissue at the back of the eye that converts light into electrical signals processed by the brain to create the images that we see. IRD can cause blindness from birth or gradual vision loss over time. In the UK, IRD affects over 1 in 3000 people, making it the leading cause of blindness among working-age adults and the second most common cause of blindness in children (1). Globally, more than 5.5 million people are affected, with significant economic, societal, emotional, and psychological impacts (2,3). IRD is caused by mutations (errors in the DNA sequence) in over 300 genes that are important for normal retinal function (4). Identifying the specific gene mutation in a patient is essential for accurately diagnosing their condition, predicting disease progression, and accessing emerging gene-therapy treatments and personalised care (5). However, despite genetic testing, 40-50% of IRD patients remain without a genetic diagnosis (6). This is mainly due to (i) limitations in current sequencing methods used to read and analyse DNA, and (ii) significant gaps in understanding the genes and disease mechanisms linked to IRD. Goals This project aims to improve the diagnosis and understanding of IRD by combining clinical, computational and laboratory approaches, addressing a significant unmet need. Leveraging my expertise in genomic data analysis (PhD, University of Exeter) and IRD clinical experience (IRD Genetics Fellowship, Moorfields Eye Hospital; MEH), and supported by preliminary data from Fight for Sight and Sight Research UK awards, this research builds on my success in improving patient care by identifying genetic diagnoses for over 50 previously undiagnosed patients. The main goals of the project are to: Improve IRD diagnosis, by: (a) Detecting disease-causing mutations missed by standard genetic testing (b) Discovering new genes causing IRD (c) Clarifying the disease-causing potential of uncertain mutations 2. Improve understanding of IRD, by: (a) Determining the impact of new IRD genes on retinal structure and function (b) Exploring how IRD gene changes affect gene activity and disease severity State-of-the-art long-read sequencing (LRS) technology, capable of analysing very long stretches of DNA as single molecules, will be used to overcome limitations of conventional “short-read” methods, enabling investigation of previously inaccessible gene regions and mutations. LRS will also be used to study gene activity, and be adapted for simultaneous targeting of multiple genes, representing innovative approaches in IRD research. Conducted at MEH and University College London Institute of Ophthalmology (UCL-IoO), this research accesses a large and ethnically diverse IRD patient group (>5000; 25% African and South Asian), ensuring broad relevance across diverse populations. Extensive clinical data (MEH) and genetic sequencing data (Genomics England, NIHR BioResource) are available for these patients. Established collaborations will expand access to more patients and molecular biology expertise, ensuring the necessary data and expertise for planned experiments in the project. Why this matters This project aims to improve how we analyse genetic data in real-world clinical practice, leading to quicker and more accurate diagnoses for patients and facilitating access to appropriate treatments. Additionally, this study aims to deepen our understanding of disease pathways in IRD, potentially identifying targets for future treatments that could help prevent blindness.