Genetics Research

Genetics is the study of genes and heredity. As our understanding of genetics and hereditary conditions develops, the potential for preventative treatments is exponentially expanded and catapults us to a new level of perception on how and why conditions are passed on through families.

The Research Foundation has a long standing interest in inherited retinal degenerations since its inception. The Foundation is the premier centre in Ireland for the clinical characterisation of patients with a variety of inherited diseases such as Retinitis Pigmentosa(RP), Choroideraemia, Stargardts Disease and X-Linked Retinoschisis, amongst many others. Patients are referred from Ophthalmology units throughout the country for these highly specialised investigations.

At present, patients with inherited retinal degenerations face inexorable loss of vision, in many cases resulting in total blindness. However, as a result of the molecular genetic advances with which the Foundation has been intimately involved, realistic prospects now exist to give hope that treatments will become available in the foreseeable future. At the Foundation, we aim to continue to be at the forefront of research which will eventually result in the development of sight-saving treatments for these patients. The Foundation has collaborated closely with the Ocular Genetics Unit at Trinity College Dublin for Three decades in the genetic characterisation of patients attending the Foundation. This collaboration has resulted in the identification of novel disease causing genes responsible for some of these inherited retinopathies.

Amongst the pioneering discoveries resulting from this collaboration were the identification of Rhodopsin, the first disease associated gene ever identified in any form of RP and now known to be the most frequent case of autosomal dominant forms of RP, the first reporting of a mutation in the Peripherin/RDS gene in a form of autosomal dominant ROP, the first implication of the mitochondrial second serine transfer RNA gene (MTTS2) in patients with RP and hearing loss, and the first documentation of a dominantly acting mutation in the RPE65 gene in a late onset form of RP. None of these discoveries would have been possible without the generous cooperation of patients ascertained and clinically investigated at the Foundation.

Researchers at the Foundation continue this effort with the goal of achieving the core aim of the Foundation, namely, ‘development of new treatments for eye and eye conditions which will ‘eliminate hearing and sight loss’.


Age-related macular degeneration (AMD)

Age-related macular degeneration is one of the most common causes of visual impairment in the Irish population. Although many risk factors for the condition have been identified, recent research has highlighted the significance of genetic factors in increasing the risk of an individual developing this disease. A large-scale study into the genetics of AMD is presently underway at the Foundation to characterise the importance of genetic risk factors in the Irish AMD population.

Retinitis Pigmentosa (RP)ADRP with Choroidal Involvement associated with Asp477gly Mutation within the Rpe65 Gene

In a collaborative research effort between the Research Foundation at the Royal Victoria Eye and Ear Hospital and the Ocular Genetics Unit at Trinity College Dublin investigators identified a new gene responsible for a form of autosomal dominant Retinitis Pigmentosa. The results were published in October 2011. Linkage testing using Affymetrix 6.0 SNP Arrays mapped the disease locus in TCD-G, an Irish family with autosomal dominant retinitis pigmentosa (adRP) ascertained and clinically characterized at the Foundation to an 8.8 Mb region on 1p31. Candidate gene and exome sequencing resulted in the identification of an Asp477Gly mutation in exon 13 of the RPE65 gene tracking with the disease in TCD-G. The Asp477Gly mutation was not present in Irish controls, but was found in a second Irish family identified at the Foundation, provisionally diagnosed with Choroideraemia, but in whom no Choroideraemia gene mutation had been found. Mutations in RPE65 are a known cause of recessive Leber congenital amaurosis (LCA) and recessive RP, but no dominant mutations have been reported. This important paper (A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement. Bowne SJ, Humphries MM, Sullivan LS, Kenna PF, et. al. Eur J Hum Genet. 2011 Oct;19(10):1074-81. doi: 10.1038/ejhg.2011.86. Epub 2011 Jun 8) documented for the first time a dominantly acting mutation in this gene in 2 families with a clinical picture somewhat reminiscent of Choroideraemia. Approximately 20% of patients with a diagnosis of Choroideraemia do not have mutations in the X-linked gene for Choroideraemia. It is likely that mutations in RPE65 may be responsible for the disease in these patients.

Gene therapy for LCA patients with RPE65 mutations has shown great promise, raising the possibility of related therapies for dominant-acting mutations in this gene.


Registry of Irish Patients with Leber Congenital Amaurosis and Early Onset Severe Retinal DystrophyWellcome Trust – HRB Centre for Clinical Research, Molecular Medicine Ireland, P. Kenna (RVEEH) , M. Cahill (RVEEH), D. Keegan (MMH), I. Flitcroft (MMH).This collaborative research co-ordinated by Mr. P. Kenna of the Research Foundation at the Eye and Ear Hospital and Mr. David Keegan of the Mater Misericordiae Hospital aims to identify Irish patients with Leber Congenital Amaurosis or Early Onset Severe Retinal Dystrophy (EOSRD), conditions in which gene mutations in the RPE65 gene have been identified. The aim is to document the incidence of these rare inherited disorders in the Irish population and to identify those individuals who might benefit from the encouraging results of the on-going clinical trials of gene therapy in these conditions.


Genetic Characterisation of a population of Irish Retinal degeneration patientsThe study, funded by the Health Research Board of Ireland aims to analyse the DNA of a cohort of Irish patients with a variety of inherited retinal degenerations using next generation gene sequencing technology. This is a collaborative effort between Mr. P. Kenna of the Research Foundation, The Royal Victoria Eye and Ear Hospital and Prof. G. Jane Farrar at the Genetics Department, Trinity College Dublin.

As a result of this work a Phase 1b trial of an orally delivered 9-cis retinal analogue involving Irish patients with this condition and sponsored by QLT Inc. of Canada has just commenced. This is the first gene-informed treatment trial for any form of autosomal dominant Retinitis Pigmentosa and further highlights the importance of the long-standing work of the Foundation in this area.

Patients with a variety of inherited retinal degenerations who have been clinically characterised at the Foundation have been recruited over the past 2 years into a research project funded by the Health Research Board for next generation genome sequencing. This ambitious project will hopefully result in the identification of disease-associated gene mutations in these patients. While the study is designed to give a picture of the spectrum of genes causing inherited retinopathies in a cohort of Irish patients the results will be of value to the participants and allow them to consider participating in future gene-based treatment trials. Undoubtedly, over the next 5 to 10 years, as a result of the progress in elucidating the genetic basis of many of these currently untreatable disorders, treatment options are likely to become available. The Foundation is proud of its contribution over many years to this pioneering work.

Mr. Eoin Hanney, an Irish clinical genetics student at the University of Wales, is conducting a survey of patients attending the Foundation with Retinitis Pigmentosa into their experiences and attitudes to genetic testing. This important study will hopefully influence the development of future genetic testing services in Ireland. This is undoubtedly going to become a major clinical need for Irish patients as more treatment options, many based on knowledge of the disease causing gene, become available.

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