Gene variant found enriched in Irish Stargardt disease patients

A new collaborative study by our funded researchers is published in the scientific journal ‘Scientific Reports’. The study is aiming to help provide a more accurate genetic diagnosis for people with Stargardt disease and therefore is paving the way for better access to the correct therapy needed in each case. The publication can be found here.

Stargardt Disease is an inherited retinal degeneration which causes progressive loss of central vision as a result of damage to the central region of the retina known as the macula. It is often diagnosed in childhood or adolescence.

Stargardt Disease is mostly caused by mutations in genes ABCA4 and ELOVL4, both of these genes are associated with vision. The majority of people with Stargardt Disease have the recessive form of disease (STGD1) involving mutations in the ABCA4 gene. That recessive form occurs when the individual’s mother and father have both passed on a mutation in the ABCA4 gene.

The number of people affected by Stargardt disease is estimated to be 1 in-10,000, however the exact amount is difficult to calculate due to high level of clinical variation in the population. For example, Stargardt Disease can be variable in that the age of onset and rate of progression of vision loss can differ between individuals.

The researchers analysed Irish patients with Stargardt disease checking for different disease causing ABCA4 gene variants in their DNA. In a healthy human, the ABCA4 gene provides instructions to make the ABCA4 protein which has an important role in transporting toxic substances out of photoreceptor cells. Therefore, if ABCA4 function is impaired, these toxic substances accumulate causing dysfunction and cell death followed by impairment and eventually loss of photoreceptors. Photoreceptors are essential for vision.

All genes are made up of DNA, some parts of the DNA are used to make protein (exons*) and some don’t (introns). The researchers in this study looked at the DNA in both the exons and introns of the ABCA4 gene to spot any disease-causing changes in the DNA.

They found that 25 of the participants in the study had one particular variant in an intron in ABCA4. This variant has been seen in 15 individuals identified in other studies worldwide but the results from this study suggest that it is particularly enriched in the Irish population. Interestingly of the 25 participants in the Irish study, 2 individuals had two copies of the particular variant which has not been previously seen.

The researchers in this study also looked more closely at the eyes of the 25 participants (through testing, imaging and looking at clinical history) which provided evidence that the variant is associated with disease of mild to intermediate severity.

The importance of this study:

  • It is adding to the knowledge of the genetic variants associated with Stargardt disease. Thus, helping both doctor and geneticists give a more accurate diagnosis.
  • It highlights that this particular variant is enriched in Irish Stargardt patients and therefore should be considered as a potential variant in Stargardt patients of Irish descent worldwide.
  • It also emphasizes the importance of sequencing the introns as well as exons in previously unresolved STGD1 cases.
  • An accurate diagnosis means that patients are clinical trial ready, should a trial become active in their specific disease.

As the researchers mention in the publication: ”Given the widespread availability of DNA sequencing in this era of genomic medicine, it is imperative that patients’ interests are at the forefront, with access to novel therapies dependent on a genetic diagnosis.”

Thank you to all the researchers who worked on this study: 

LauraWhelan1, Adrian Dockery1,2, KirkA. J. Stephenson3,4, Julia Zhu4, Ella Kopčić1, Iris J. M. Post1, Mubeen Khan5,6,7, Zelia Corradi5,8, NiamhWynne3, James J. O’ Byrne4,7,9,10, Emma Duignan3, Giuliana Silvestri11,12,13, Susanne Roosing5,8, Frans P. M. Cremers5,8, David J. Keegan4, Paul F. Kenna1,3 & G. Jane Farrar1.

Based on the institutes below:

1. The School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland.

2. Next Generation Sequencing Laboratory, Pathology Department, The Mater Misericordiae University Hospital, Dublin 7, Ireland.

3. Department of Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin 2, Ireland.

4. Mater Clinical Ophthalmic Genetics Unit, The Mater Misericordiae University Hospital, Dublin 7, Ireland.

5. Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.

6. Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.

7. International Max Planck Research School for Language Sciences, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.

8. Academic Alliance Genetics, Radboud University Medical Center, Nijmegen, and Maastricht University Medical Center+, Maastricht, The Netherlands.

9. National Centre for Inherited Metabolic Disorders, The Mater Misericordiae University Hospital, Dublin 7, Ireland.

10. School of Medicine, Trinity College Dublin, Dublin 2, Ireland.

11. Centre for Experimental Medicine, Queen’s University Belfast, Belfast, Northern Ireland, UK.

12. School of Medicine, University College Dublin, Dublin 4, Ireland.

13. Department of Ophthalmology, The Royal Victoria Hospital, Belfast, Northern Ireland, UK


*To find more information on what exons are, please click here