Inherited retinal diseases in Norway - Studies on phenotype and genotype characteristics
Year: 2021
Type: dissertation
Study design: Observational Study
Abstract: Inherited retinal diseases are a leading cause of vision loss in children and young adults. The majority of inherited retinal diseases are untreatable, consequently leading to irreversible retinal damage and blindness. Recent advances in the understanding of the underlying molecular causes, has increased knowledge of the diseases and facilitated the development of the first gene therapy for an inherited retinal disease.1 Inherited retinal diseases are a heterogeneous group of diseases, consisting of approximately 60 clinical diagnoses,2 caused by monogenetic variants in over 270 genes.3 Consequently, the clinical expression and visual prognosis of inherited retinal diseases varies significantly.\nFew studies on the inherited retinal disease population in Norway have been performed, therefore increased knowledge of this patient population was warranted. The aim of this thesis was to increase knowledge of inherited retinal diseases in Norway by estimating prevalence and providing a detailed analysis of the clinical expressions (phenotypes) and the molecular causes (genotypes) of inherited retinal disease in Norway.\nTo achieve this aim, a patient registry of inherited retinal diseases was established, including detailed clinical and genetic data of 900 patients. A population based study was performed by utilising phenotype and genotype data from the registry.\nPrevalence of inherited retinal disease in the South-East region of Norway was estimated with a minimum prevalence of 1:3,856, meaning that an estimated minimum of 1,400 patients in Norway live with an inherited retinal disease. The clinical spectrum demonstrated heterogeneity, with over 40 clinical diagnoses registered. Non-syndromic retinitis pigmentosa was the most common clinical diagnosis and was further observed as the most genetically heterogenic diagnosis, associated with more than 20 genes. In contrast, the prevalence of patients with clinical diagnosis choroideremia was low, in comparison to other countries.4-10 The diagnostic yield of routine genetic testing from 2007 to 2018 was low (32%), compared to other genetic studies of inherited retinal diseases.2, 5-9, 11-18 The most common genes found in the study population were ABCA4, USH2A, BEST1, RHO and RS1. Additional descriptive studies were performed on the clinical subgroups autosomal dominant retinitis pigmentosa and ABCA4-retinal dystrophies.\nIn total 15 patients with autosomal dominant retinitis pigmentosa were analysed with gene panels that resulted in a genetic diagnosis in 11 of 15 patients (diagnostic yield 73%). The genetic cause was found in 10 genes, one of which was the ARL3 gene. The ARL3 gene had previously been suspected of causing autosomal dominant retinitis pigmentosa. The study was able to confirm the phenotype association to the ARL3 p.(Tyr90Cys) variant, resulting in a change in the phenotype classification of ARL3. The phenotype was given the name retinitis pigmentosa type 83 [MIM# 618173].\nThe study of ABCA4-retinal dystrophies was a national collaboration, including in total 106 patients. The study demonstrated that the clinical diagnosis of Stargardt disease did not correlate well with the prognosis for development of peripheral degeneration in the retina. A phenotype-genotype subclassification system was implemented for classification of long-term prognosis based on the clinical expression, disease duration and the underlying genetic variants. Further, the study demonstrated a high carrier frequency of the loss of function splice variant c.5461-10T>C in the Norwegian population, compared to other studies of the ABCA4 gene.19 A genetic diagnostic yield of 89% was established, which was in the high range compared to other ABCA4 studies.20-23 The diagnostic yield was achieved by facilitating a tiered genetic analysis, including whole-gene sequencing of the ABCA4 gene. In total 84 variants were detected, of those 15 were novel, including a novel deletion and several novel rare deep intronic variants.\nThis thesis describes the first ever population based study that includes all inherited retinal disease diagnoses in Norway. The studies significantly increase our knowledge of this patient population and ensures knowledge required for updated clinical recommendations for genetic diagnostics, clinical follow-up as well as improved prognostic guidance.
Author: Josephine Prener Holtan
Language: English
Subfield: Ophthalmology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3200975161