Identifying variants impacting non-coding regions of genes underpinning inherited retinal disease

Brief plain language background

Inherited retinal dystrophies (IRDs) are a group of eye diseases caused by genetic mutations passed down through families. There are more than 270 disease-associated genes identified, yet up to half of individuals with IRDs do not receive a genetic diagnosis for their condition. People who inherit these faulty genes develop progressive visual impairment that can lead to loss of sight.

What problem/knowledge gap does it help address

A genetic test is required to diagnose IRDs, which can be done by examining part (genetic) or all (genomic) of someone’s DNA. Most tests focus on variations in a person's DNA that directly affect protein creation – the encoding parts of genes.

However, recent evidence highlights the need to study all aspects of the genome that impact how genes function, including when they're activated (gene expression) and their specific structure and how they are joined together (splicing). Variations in DNA can affect these processes and lead to IRDs.

Despite knowing many genes causing IRDs, some individuals remain undiagnosed even after extensive genetic testing. Until recently, there hasn't been a chance to analyse all the potential parts of the genome, influencing gene expression or splicing – which are known as the non-coding parts of genes.

Aim of the project

To identify differences in non-coding parts of genes that cause or contribute to inherited retinal disease.

This award will also contribute to building capacity in inherited retinal research as it will lead to a PhD for an early career researcher.

Key procedures/objectives

The PhD student will:

1. Characterise the non-coding regions of genes found in the retina and identify whether they are unique in the retina or shared across tissues in the body.
2. Identify common genomic variants that influence the splicing of genes in the retina and examine how these variants contribute to the onset of IRDs.
3. Identify individuals without a genetic diagnosis that have gene variants likely to disrupt the way genes in the retina are spliced and expressed.
4. Define the impact of these variants and their potential to be treated.

Potential impact on people with sight loss

The identification of new genetic causes of IRDs and how, or when, these occur could result in more genetic diagnoses and in turn, better clinical management. An increased and precise understanding of the development and progression of IRDs could identify new avenues for treatment.