Target 5000 research sheds light on inherited retinal degenerations

Target 5000 was established many years ago with an ambition to shed light on the different genetic causes of inherited retinal degenerations (IRDs), affecting people in Ireland.

At the start of the year, we welcomed the publication of key research findings from Target 5000 in a scientific journal. The paper, entitled “Findings from a Genotyping Study of Over 1000 People with Inherited Retinal Disorders in Ireland” is a culmination of the generous participation of people living with an IRD and many years of hard work by the research team at Trinity College Dublin, led by Prof Jane Farrar.

Analysing DNA samples from over 1000 study participants, a wide spectrum of inherited retinal degenerations was observed. In fact, close to 20 different IRD conditions have been captured to date in this study. Using a technique known as next-generation sequencing, research grade genetic testing identified the potential cause of disease in approximately 70% of cases. Specifically, the research team were able to pinpoint the exact IRD causing variant (previously referred to as mutation) within the gene. Below we endeavour to break down some of the key observations from this research study to date.

Retinitis Pigmentosa (RP)

The most common condition observed on initial clinical assessment was retinitis pigmentosa (RP). There are three main types of inheritance patterns associated with RP: autosomal dominant, autosomal recessive, and X-linked. With respect to this study, autosomal dominant was the most common form of inheritance, accounting for over 45% of all RP samples analysed. Specifically, variants in the rhodopsin gene were largely observed in dominant forms of RP. The most commonly observed candidate gene for autosomal recessive forms of RP was USH2A while variants in the RPGR gene were the most frequent cause of x-linked RP.

Macular Dystrophies

Stargardt disease was the most frequent form of macular dystrophy presenting in Target 5000 clinics, followed by Best disease and cone-rod dystrophy.

Accounting for over 97% of Stargardt disease samples, variants in the ABCA4 gene was the most frequently observed. Other genes associated with this condition include PROM1 and ELOVL4.

It is important to note that ABCA4 is a particularly large and complex gene and pinpointing the exact variant (mutation) within it can be difficult. Through extensive research efforts, the team at TCD have detected six potentially new disease causing variants associated with the ABCA4 gene. This study has also highlighted that disease causing variants may be hidden in other areas of the gene not typically captured by current genetic testing technologies. This is because these techniques primarily focus on areas of the gene that are responsible for coding (producing) important proteins for vision, known as exonic regions. However, there are areas outside of here that do not code for proteins, known as intronic regions. The team, in collaboration with Prof Frans Cremers at Radboud University in The Netherlands have been searching the intronic regions of the ABCA4 gene. As a result, they have been able to increase their ability to truly pin down the exact genetic cause in these cases.

Syndromic Inherited Retinal Degenerations

Usher Syndrome was the most common syndromic retinal degeneration clinically diagnosed in the study, followed by Bardet-Biedel syndrome.

Usher Syndrome can be divided into three groups based on severity of symptoms, ranging from the most severe in Type 1 and the least severe in Type 3. In this study to date, Type 2 was most commonly observed with variants in the USH2A gene most frequent. Variants in MYO7A gene were the most frequent cause of Usher type I, while variants in CLRN1 and MTTS2 genes contributed equally to cases of Usher Type 3. Variants in the BBS1 gene were the most frequent cause of Bardet-Biedel syndrome.

Novel Findings

IRDs are amongst the most complex of all genetic conditions, with close to 300 different genes known to be associated with these conditions. Through significant efforts at TCD, the research team have now identified several novel variants within these known genes that may contribute to IRDs. The team will now perform a wide range of animal and cell studies to confirm whether these new findings are in fact disease-causing (pathogenic).

Conclusion

The results of this research study thus far highlight the unique genetic architecture of IRDs in Ireland. Without a doubt, it also showcases the calibre of researchers in Ireland and their significant contribution at a global level towards greater understanding of inherited retinal degenerations. It has also emphasised the need for genetic testing to support a clinical diagnosis. Over recent years, significant steps have been accomplished in ensuring these research grade results are clinically validated and delivered back to study participants with the support of a genetic counsellor. For the 30% of cases where the disease causing gene has yet to be discovered, research groups in Trinity College and across the world are actively trying to resolve these cases using a variety of research approaches.

Target 5000 is now a unique programme delivering important clinical and genetic services to everyone in Ireland living with an inherited retinal degeneration (IRD). If you are a participant of Target 5000, you may email research@fightingblindness.ie or contact your clinic directly for more information.

The full research paper published in the scientific journal called Genes is now available online.