Dr Adrian Dockery and Prof. Jane Farrar
Dr Adrian Dockery started work on this award while working in Professor Jane Farrar’s laboratory in Trinity College Dublin. Dr Dockery move to a new position and a number of Prof Farrar’s team took over the research project including- Laura Whelan, Ciara Shortall and Ella Kopčić. This project is part of the Target 5000 programme.
Project: ‘Enhancing and expanding the utility of Target 5000’
Start date: 2020
Amount: €50,000. This project was co-funded with Janssen.
Two of the key aims of the Target 5000 programme is to ‘provide a genetic and clinical diagnosis to individuals with an IRD in Ireland’ and ‘to discover new genes responsible for IRDs’. This project addresses these two aims.
This study aimed to identify changes or variants in the DNA sequence of 150 patients that could be the cause of the disease. The researchers used a sophisticated technique called whole exome sequencing (WES)* to find these DNA changes. WES looks at changes in the regions of DNA that encode proteins.
The project has recently ended, and we asked the researchers to give us an update on the project and the results.
- What are the overall aims of the project you are working on, including how it could have an impact on those affected by sight loss?
- What are the results of the project?
- Could you tell us about your next steps?
1. What are the overall aims of the project you are working on, including how it could have an impact on those affected by sight loss?
Over the past decade or so, significant advances in DNA sequencing has enabled the rapid sequencing of DNA to determine the underlying genetic cause of many disorders. This study aimed to identify disease-causing variant—changes in the DNA sequence—in 150 patients via whole exome sequencing (WES)*, which includes the regions of DNA that encode proteins.
While the whole exome (i.e., all exons)* was sequenced, analysis focused on over 250 genes known to be involved in eye disease. As variants were identified, their potential to cause disease was evaluated through the use of computational tools, extensive mining of the scientific literature and population databases, and performing functional tests in the lab.
2. What are the results of the project?
This study identified the variants that are likely to be causing disease in approximately half of patients included in the study. These variants were found via whole exome sequencing , which includes the regions of DNA that encode proteins.
- There were several previously-unseen variants identified in the studies, in genes such as BBS7, which encodes a protein involved in cell signalling, and in RAX2, which encodes a protein involved in the development of the retina.
- Some variants identified were run through computer algorithms that suggested that they may affect the process our cells use to chop out genetic material not required to make a given protein (called ‘splicing’). Therefore, variants that affect this process may result in pieces being included when not required or being excluded when essential.
The variants identified by these computer algorithms as potentially splice-altering are being investigated further in the lab to confirm that this is indeed what is taking place and that these variants are potentially contributing to disease.
Over the course of this project, 150 whole exome sequences were Results from this project are being included in several collaborative research papers, including papers on Usher syndrome, PROM1 and ABCA4 (a gene involved in Stargardt disease).
3. Could you tell us about your next steps?
Our current study, FB22FAR follows on from this project, interrogating a further 150 whole exomes. Additionally, we are continually returning to the sequence of anybody who was included in the original cohort of 150 patients but was not solved in our first tier of analysis.
As the scientific community learns more about inherited retinal degeneration, more genes are being linked to eye disease. As these are identified, we return to our whole exome sequence* to see if these genes might be involved in causing disease in our currently unresolved cohort.
While whole exome sequencing is providing many insights, some patients will require whole genome sequencing—sequencing of their entire DNA sequence—to elucidate the cause of retinal degeneration. Our current Fighting Blindness project includes whole genome sequencing of 150 patients.
*To find more information on what the exomes and whole exome sequencing are, please click here