| dc.description.abstract | Aim: To elucidate the molecular diagnosis and perform deep phenotyping on patients with inherited retinal degenerations (IRDs)
Methods: Patients were identified through self-referral or referral by an ophthalmologist and data was collected prospectively. I performed deep phenotyping of over 150 patients in the Research Foundation of the Royal Victoria Eye and Ear Hospital, Dublin, contributing to the Target 5000 project, a national project, to build a database of standardised information describing the characteristics of these patients, of which there are estimated to be 5000 on the island of Ireland. Deep phenotyping included extensive history taking, clinical examination, psychophysical testing, performing electrophysiological tests, fundus photography and optical coherence tomography (OCT). I obtained blood samples which were analysed in the Smurfit Institute of Genetics, Trinity College Dublin, by next generation sequencing (NGS) using a targeted gene panel of genes associated with retinal degeneration.
Results: A molecular diagnosis was identified in 68% of cases. Retinitis pigmentosa (RP) was the most commonly identified phenotype. Autosomal dominant RP was most commonly caused by a mutation of the RHO gene and recessive RP most commonly due to mutation of the USH2A gene. Of all patients with an IRD, ABCA4 was the single most frequently affected gene. Of the patients that I assessed, three pedigrees are detailed in this thesis to demonstrate the importance of the data collected to individual patients and how this data adds to our ability to solve future cases. A patient with a novel GNAT1 variant is described with a late onset retinitis pigmentosa phenotype. GNAT1 mutations have only been described in the literature to date to cause congenital stationary night blindness. A patient with cone-rod dystrophy, likely due to biallelic PROM1 mutation, is described where the molecular diagnosis remains uncertain, demonstrating the difficulty in interpreting variants of unknown significance. Finally, a choroideraemia pedigree is described which was found to harbour three patients with a bilallelic RPE65-mediated retinal dystrophy after NGS, with implications for the wider family in terms of genetic counselling.
Conclusion: The proportion of patients solved molecularly in this series is in keeping with other international groups. Identifying the molecular diagnosis in these patients and collecting accurate and precise phenotype information allows us to provide patients with a more specific diagnosis and prognosis. It allows us to confirm the inheritance pattern of disease, facilitating detailed genetic counselling and family planning. The expansion of knowledge underlying the genetic aetiology of these disorders with the discovery of novel genes and variants that have thus far evaded NGS analysis such as deep intronic mutations, copy number variants, structural variants and splice site mutations allow us to increase our rate of solving future cases. Finally, a gene-based therapy for one form of retinal degeneration is now licenced in Europe. Many clinical trials of further therapies, both gene-based and gene-independent, are ongoing. These data allow us to identify patients who would benefit from these therapies and to ensure that the optimum treatment window for these treatments can be delivered. | en |
