Approved research

Understanding the impact of rare DNA variants in molecular phenotypes & ophthalmic disease risk

Lay summary

Rare eye disorders are a major cause of visual impairment and blindness in children and young adults. Over 1000 such disorders have been described (most of which are genetic) and although each individual condition is rare, collectively they are common and their cumulative impact on affected families and healthcare systems is substantial. Advances in DNA sequencing technologies over the past decade have transformed our ability to read DNA. This catalysed the development of powerful genetic tests that transformed our ability to reach an early, precise diagnosis in people affected by rare eye disorders. It has also become possible to start translating our growing knowledge of the genetic mechanisms of eye disease into targeted treatments. However, several challenges remain. A central problem is that of understanding how specific genetic changes affect different molecules in a cell in a way that leads to disease. In other words, our ability to predict the effect of specific genetic changes at the level of the cell or the individual is limited. In this project we would like to analyse UK Biobank data in combination with data from patient cohorts available to our group and with other large publicly available datasets to understand how genetic changes affect vision. A key aim would be to identify and to study genetic changes that are associated with significant inter-individual differences in effect (i.e. variable expressivity and incomplete disease penetrance). Another aim would be to understand which genes are mainly causing eye disease through a 'loss-of-function' mechanisms (i.e. genes in which mutations result in reduced or abolished protein function) and which genes are causing disease through more complex mechanisms such as 'gain-of-function' effects (i.e. genes in which mutations confer new or enhanced activity on a protein). This project is expected to last for many years (minimum 3 years) as we plan to analyse and monitor the clinical effects of specific genetic alterations in our patient cohort long-term. Through this study, we hope to (i) provide to the public a better understanding of how genetic changes contribute to eye disease risk, (ii) develop a resource that would help interpret genetic (diagnostic, reproductive, predictive) test result for eye disorders, (iii) inform the design of future gene-based treatment trials.