Lauren N. Ayton

Objectives: We sought to investigate the visual function, retinal features, and genotype-phenotype correlations of an Australian cohort of RPGR carriers. Methods: In this cross-sectional study, we evaluated RPGR carriers seen in Melbourne and Perth between 2013 and 2023 and healthy women seen between 2022 and 2023 in Melbourne. Visual acuity tests, fundus-tracked microperimetry, and retinal imaging were performed. RPGR carriers were classified into four retinal phenotypes (normal, radial, focal pigmentary retinopathy, and male pattern phenotype) and compared against healthy controls. Genotype-phenotype relationships in the RPGR carriers were investigated. Results: Thirty-five female RPGR carriers and thirty healthy controls were included in this study. The median ages were 40 and 48.5 years for RPGR carriers and controls, respectively (p = 0.26). Most RPGR carriers (89%) had a genetic diagnosis. Best-corrected visual acuity (BCVA), low luminance visual acuity, retinal sensitivity, central inner retinal thickness (IRT, 1°), and photoreceptor complex (PRC) thickness across the central 1-7° of the retina differed between phenotypes of RPGR carriers. On average, RPGR carriers with ORF15 variants (n = 25 carriers) had reduced LLVA, a greater IRT at 1°, and thinner PRC thickness at 7° from the fovea (all p < 0.05) compared to those with exon 1-14 variants. Conclusions: Female RPGR carriers with severe retinal phenotypes had significantly decreased visual function and changes in retinal structure in comparison to both the controls and carriers with mild retinal disease. BCVA, LLVA, retinal sensitivity, and retinal thickness are biomarkers for detecting retinal disease in RPGR carriers. The genetic variant alone did not influence retinal phenotype; however, RPGR carriers with ORF15 variants exhibited reduced retinal and visual measurements compared to those with exon 1-14 variants.

Genotyping patients with inherited retinal diseases (IRD) is important for diagnosis, genetic counselling, and future treatments. However, in Australia less than 10% of patients with IRD have undergone genetic testing. Recognised barriers to testing include cost, access, and trust in the treating clinician. We aimed to assess uptake and outcomes to an offer of sponsored (free) genetic testing with home DNA collection, thereby removing typical barriers to genetic testing. Participation in a sponsored genetic testing program (Invitae Corporation) was offered to adults from a private retinal practice in Australia in July 2022. Email invitations were sent to 233 patients clinically diagnosed with an IRD phenotype by the senior author. Potential participants were ≥18 years old, had no previous diagnostic genetic testing, and had supplied an email address for communication. Emails were successfully delivered to 205 individuals. Response rate to invitation were low, with no reply in the 62% cases (128/205). Of the 58 participants for whom testing was ordered, 47 (47/58, 81%) supplied at-home collected DNA. The solve rate was 34% (16/47), rising to 53% (25/47) when probable solves were included. One of the thirteen families accepted the offer of family studies to clarify the genotype. The most frequent identified IRD-associated gene was PRPH2 (4/16 cases), followed by RHO (2/16 cases). Overall low response, DNA return and acceptance of family testing rates suggest ill-defined human factors affected DNA genetic testing uptake. Improved patient education and follow-up of offers of genetic testing are required to improve patient genotyping.

Objective: This review explores the prevalence, diagnostic challenges, associated comorbidities, and potential complications of early-onset glaucoma in individuals with Stickler syndrome. By addressing these aspects, this review aims to enhance clinical awareness, improve patient outcomes and highlight research opportunities within the paediatric Stickler syndrome population. Results: Of 185 unique studies, 51 duplicates were removed, leaving 15 studies for analysis. The review included data from 679 patients, of whom 82 were reported as being diagnosed with glaucoma, yielding an overall prevalence of 12.1%. The prevalence was 7.5% in patients aged 0-10 years and remained stable through age 20. It then increased to 18% in patients aged 21-40 years, before slightly decreasing to 16.5% in those over 40. Paediatric patients with Stickler syndrome and glaucoma exhibited a higher risk of cataract (56% vs 22%, OR 4.5, p<0.05) and hearing loss (70% vs 31% OR 5.2, p<0.05) compared with those without glaucoma. Conclusions: Early identification of clinical signs is critical for effective intervention. Paediatric patients with Stickler syndrome, particularly those with cataract or hearing loss, are at higher risk of glaucoma and, therefore, should be closely monitored, in addition to regular retinal assessments. Given the limitations of this review-including small sample sizes and variable diagnostic methods-larger standardised studies are needed to refine glaucoma prevalence estimates and clinical guidelines for Stickler syndrome.

Accurate diagnosis of both age-related macular degeneration (AMD) and inherited retinal diseases (IRD) with macular atrophy is important because treatments for both conditions are emerging. Phenotypical similarities between macular atrophy associated with AMD (geographic atrophy, GA) and IRD-associated atrophy exist, which can make accurate diagnosis challenging in clinical practice. Misdiagnosis may lead to inappropriate treatment strategies and missed opportunities for disease-specific interventions. A retrospective clinical review of medical records of people diagnosed with AMD between 1995 and 2023 from a large multidisciplinary private ophthalmic practice in Australia was undertaken to identify cases of patients diagnosed with geographic atrophy without drusen, which was then further assessed for potentially missed IRD with macular atrophy. Flagged cases were presented to experts in AMD and IRD to establish a most-likely diagnosis. Cases without consensus between graders were grouped into most-likely diagnosis by a third senior retinal clinician. Of the 1136 cases reviewed, the possible rate of misdiagnosis observed was 1.9%, with 1.0% representing potentially missed IRDs, most commonly pattern dystrophy (0.5%). A multi-modal approach, including clinical features and patient history, is important to limit the possibility of misdiagnosis of GA, and identify a subset of patients who might benefit from genetic testing prior to considering possible treatments.

Purpose: To design and build a new disease registry to track the natural history and outcomes of approved gene therapy in patients with inherited retinal diseases. Methods: A core committee of six members was convened to oversee the construction of the Fight Inherited Retinal Blindness! module. A further 11 experts formed a steering committee, which discussed disease classification and variables to form minimum datasets using a consensus approach. Results: The web-based Fight Inherited Retinal Blindness! registry records baseline demographic, clinical, and genetic data together with follow-up data. The Human Phenotype Ontology and Monarch Disease Ontology nomenclature were incorporated within the Fight Inherited Retinal Blindness! architecture to standardize nomenclature. The registry software assigns individual diagnoses to one of seven broad phenotypic groups, with minimum datasets dependent on the broad phenotypic group. In addition, minimum datasets were agreed on for patients undergoing approved gene therapy with voretigene neparvovec (Luxturna). New patient entries can be completed in 5 minutes, and follow-up data can be entered in 2 minutes. Conclusion: Fight Inherited Retinal Blindness! is an organized, web-based system that uses observational study methods to collect uniform data from patients with inherited retinal disease to track natural history and (uniquely) treatment outcomes. It is free to users who have control over their data.