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Sena A Gocuk,1 Yuanzhang Jiao,2 Alexis Ceecee Britten-Jones,1,3,4 Nathan M Kerr,5 Lyndell Lim,3,5 Simon Skalicky,5 Richard Stawell,5 Lauren N Ayton,1,3,4 Heather G Mack3– 5 1Department of Optometry and Vision Sciences, University of Melbourne, Melbourne, Victoria, Australia; 2University Hospital Geelong, Geelong, Victoria, Australia; 3Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia; 4Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia; 5Eye Surgery Associates, East Melbourne, Victoria, AustraliaCorrespondence: Lauren N Ayton, Email layton@unimelb.edu.auBackground: To assess the prevalence of genetic testing for inherited retinal diseases (IRDs) in a tertiary practice setting.Methods: Single-centre retrospective analysis of patients with diagnosed or suspected IRD.Results: Four hundred and sixty-four patient records were analysed. Patients had received care for different IRDs grouped as follows: panretinal pigmentary retinopathies (283, 61%), macular dystrophies (136, 29.3%), stationary diseases (23, 5%), hereditary vitreoretinopathies (14, 3%), and other IRDs (8, 1.7%). The suspected pattern of inheritance of patients’ IRD was predominantly autosomal recessive (205, 44.2%). Genetic testing was performed with the corresponding results available for 44 patients (9.5%). Diagnostic yield was 65.9% for the results received. Genetic test results were available mostly for younger patients (13.1% for < 45 years vs 6.2% ≥ 45 years of age, p = 0.01) and those who received greater than 12 months of care (16% for ≥ 12 months vs 4% for < 12 months, p < 0.01). For patients without genetic testing results, reasons include awaiting a geneticist consultation (17.9%), awaiting test results (4.5%), or patient refusal (8.4%). Most clinical records (69.2%) did not document genetic testing status.Conclusion: Genetic testing is increasingly being utilised in the work-up for patients with IRD worldwide. This large Australian private practice IRD cohort shows a low uptake of testing (around 10%), reflecting historical management patterns and accessibility of genetic counselling and testing. The results show that younger patients and those with a longer duration of care were more likely to have received genetic testing. As the importance of IRD genetic testing continues to increase, we expect to see a change in patient management within the Australian private ophthalmology system and testing rates to increase. Further research is required to identify and address clinician and patient barriers to improving genetic testing rates for IRD.Keywords: inherited retinal disease, retinitis pigmentosa, macular dystrophy, genetic testing

X-linked genetic disorders typically affect females less severely than males owing to the presence of a second X Chromosome not carrying the deleterious variant. However, the phenotypic expression in females is highly variable, which may be explained by an allelic skew in X-Chromosome inactivation. Accurate measurement of X inactivation skew is crucial to understand and predict disease phenotype in carrier females, with prediction especially relevant for degenerative conditions. We propose a novel approach using nanopore sequencing to quantify skewed X inactivation accurately. By phasing sequence variants and methylation patterns, this single assay reveals the disease variant, X inactivation skew, and its directionality and is applicable to all patients and X-linked variants. Enrichment of X Chromosome reads through adaptive sampling enhances cost-efficiency. Our study includes a cohort of 16 X-linked variant carrier females affected by two X-linked inherited retinal diseases: choroideremia and RPGR -associated retinitis pigmentosa. As retinal DNA cannot be readily obtained, we instead determine the skew from peripheral samples (blood, saliva, and buccal mucosa) and correlate it to phenotypic outcomes. This reveals a strong correlation between X inactivation skew and disease presentation, confirming the value in performing this assay and its potential as a way to prioritize patients for early intervention, such as gene therapy currently in clinical trials for these conditions. Our method of assessing skewed X inactivation is applicable to all long-read genomic data sets, providing insights into disease risk and severity and aiding in the development of individualized strategies for X-linked variant carrier females., (© 2024 Gocuk et al.; Published by Cold Spring Harbor Laboratory Press.)

Background/aims: Female choroideremia carriers present with a spectrum of disease severity. Unlike in men, the rate of disease progression has not been well characterised in carriers. This longitudinal study aimed to determine the rate of retinal degeneration in choroideremia carriers, using multimodal imaging and microperimetry., Methods: Choroideremia carriers previously seen at Oxford Eye Hospital (United Kingdom) between 2012 and 2017 returned for testing between 2015 and 2023, providing up to 11 years' follow-up data. Participants had optical coherence tomography, fundus-tracked microperimetry and fundus autofluorescence (FAF) imaging performed., Results: Thirty-four eyes of 17 choroideremia carriers were examined using multimodal imaging. Median age was 44 (range: 15-73) years at baseline and median follow-up duration was 7 (range: 1-11) years. At baseline, phenotype was classified as fine (n=5 eyes), coarse (n=13 eyes), geographic (n=12 eyes) or male pattern (n=4 eyes). Thirteen patients showed no change in phenotype classification, four showed slight changes associated with choroideremia-related retinal degeneration. Despite this, carriers with severe retinal phenotypes had a statistically significant decline in average retinal sensitivity (-0.7 dB and -0.8 dB per year, respectively, p<0.001), area of geographic loss defined by FAF (+2.5 mm 2 and +3.7 mm 2 per year, respectively, p<0.001) and thinning of the photoreceptor complex (up to -2.8 microns and -10.3 microns per year, p<0.001)., Conclusion: Choroideremia carriers, particularly those with severe retinal phenotypes, exhibit progressive retinal degeneration, as evident by multimodal imaging biomarkers and functional testing. Clinicians should not rely on retinal severity classification alone to assess disease progression., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Female carriers of X-linked inherited retinal diseases (IRDs) can show highly variable phenotypes and disease progression. Vascular reactivity, a potential disease biomarker, has not been investigated in female IRD carriers. In this study, functional optical coherence tomography angiography (OCT-A) was used to dynamically assess the retinal microvasculature of X-linked IRD carriers., Methods: Genetically confirmed female carriers of IRDs (choroideremia or X-linked retinitis pigmentosa), and healthy women were recruited. Macular angiograms (3x3mm, Zeiss Plex Elite 9000) were obtained in 36 eyes of 15 X-linked IRD female carriers and 21 age-matched control women. Two tests were applied to test vascular reactivity: (i) mild hypoxia and (ii) handgrip test, to induce a vasodilatory or vasoconstrictive response, respectively. Changes to vessel density (VD) and vessel length density (VLD) were independently evaluated during each of the tests for both the superficial and deep capillary plexuses., Results: In the control group, the superficial and deep VD decreased during the handgrip test (p<0.001 and p=0.037, respectively). Mean superficial VLD also decreased during the handgrip test (p=0.025), while the deep plexus did not change significantly (p=0.108). During hypoxia, VD and VLD increased in the deep plexus (p=0.027 and p=0.052, respectively) but not in the superficial plexus. In carriers, the physiologic vascular responses seen in controls were not observed in either plexus during either test, with no difference in VD or VLD noted (all p>0.05)., Conclusions: Functional OCT-A is a useful tool to assess dynamic retinal microvascular changes. Subclinical impairment of the physiological vascular responses seen in carriers of X-linked IRDs may serve as a valuable clinical biomarker., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Gocuk, Hadoux, Catipon, Cichello, Kumar, Jolly, van Wijngaarden, Llewelyn Edwards, Ayton and Sousa.)

Purpose: To describe visual function and retinal features of female carriers of choroideremia (CHM), using multimodal imaging and microperimetry., Design: Cross-sectional cohort study., Participants and Controls: Choroideremia carriers seen in Australia (Melbourne or Perth) or the United Kingdom (Oxford or Cambridge) between 2012 and 2023. Healthy age-matched controls seen in Melbourne, Australia, between 2022 and 2023., Methods: Participants had visual acuity, fundus-tracked microperimetry, OCT, and fundus autofluorescence imaging performed. Choroideremia carriers were either genetically or clinically confirmed (i.e., obligate carriers). Choroideremia carriers were grouped according to their retinal phenotype and compared with healthy controls. Statistical analyses were performed on StataBE (v18.0)., Main Outcome Measures: Best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), average retinal sensitivity, volume of macular hill of vision (HoV), inner retinal thickness, and photoreceptor complex (PRC) thickness., Results: Eighty-six eyes of 43 CHM carriers and 60 eyes of 30 healthy controls were examined using multimodal imaging and microperimetry. Median age was 54 and 48.5 years for CHM carriers and controls, respectively (P = 0.18). Most CHM carriers (86%) were genetically confirmed. Choroideremia carriers and controls had strong intereye correlation between eyes for BCVA and average retinal sensitivity (P < 0.001). Low-luminance visual acuity and macular HoV tests were sensitive tests to detect changes in CHM carriers with mild phenotypes (i.e., fine and coarse). Choroideremia carriers with geographic or male-pattern phenotypes had reduced BCVA, LLVA, retinal sensitivity, and retinal thinning, compared with healthy controls. Retinal thickening of the inner retina was observed in the central 1°, despite generalized thinning of the PRC in the central 7°, indicating retinal remodeling in CHM carriers, compared with controls. There were no genotype-phenotype correlations observed., Conclusions: Female carriers of CHM with severe retinal phenotypes (i.e., geographic or male pattern) have significantly decreased visual function and retinal structural changes when compared with age-matched controls and those carriers with milder phenotypes. Low-luminance visual acuity and volumetric measures of the macular HoV were found to be the most sensitive functional tests to detect milder retinal disease (fine and coarse phenotypes) in CHM carriers., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Female carriers of X-linked inherited retinal diseases (IRDs) are burdened with potentially passing their disease-causing variant to future generations, as well as exhibiting signs of retinal disease themselves. This study aimed to investigate carriers' experiences of genetic testing, emotions relating to having affected children, and their knowledge regarding genetic testing and gene therapy. An online survey was advertised to self-identified carriers worldwide. Two hundred and twenty-eight carriers completed the survey with mean age of 51 years (SD ± 15.0). A majority of respondents resided in the United States of America (51%), Australia (19%), and the United Kingdom (14%). Most carriers identified with feelings of guilt (70%), concern (91%), and anxiety (88%) for their child. Female carriers who had given birth to children had significantly greater gene therapy knowledge compared to carriers who had not (p < 0.05). Respondents agreed that their eyecare provider and general practitioner helped them understand their condition (63%), however, few carriers reported receiving psychological counselling (9%) or family planning advice (5%). Most respondents (78%) agreed that gene therapy should be available to carriers. This study emphasises the importance of providing appropriate counselling to female carriers and illustrates the motivation of many to participate in emerging treatment options, such as gene therapy., (© 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Dementia comprises a group of brain disorders characterised by loss of cognitive function. Sensory loss, predominantly vision (the focus of this review) and hearing, is a significant problem for people living with dementia. Eyecare practitioners such as optometrists therefore play an important role in identifying and addressing vision-related care needs. To support provision of high quality "dementia-friendly" eyecare, this scoping review summarises recent primary research findings and available clinical practice guidelines, to identify research gaps relating to vision and dementia, and make recommendations for future research and clinical practice. The review set a priori guidelines for the population, concept and context based on the review questions. Primary research papers (2016-2021) were included via 3-step search strategy: preliminary search to index terms, full search, search reference lists of included articles for further inclusions. Additionally, websites of eyecare professional bodies in English-speaking countries were searched to identify current clinical eyecare practice guidelines relating to dementia. Study characteristics (e.g. country, study design) were reported descriptively. Patterns within findings/recommendations from included sources were identified using thematic analysis and reported as themes. 1651 titles/abstracts and 161 full-text articles were screened for eligibility. Three clinical practice guidelines were also identified. The final review included 21 sources: 18 primary research papers and 3 clinical practice guidelines. The thematic analysis reported five key themes: Diagnosis/Screening, dementia progression, findings on clinical visual testing, tailored approach to care, improving care . This scoping review demonstrated limited information about current practices of optometrists working with people living with dementia. Recent evidence reinforces the continuing need for improved eyecare for people living with dementia, taking into account their specific needs with an individualised approach. Up-to-date practical recommendations are synthesised for eyecare providers before, during and after a consultation with a person living with dementia, to better support their care.

Inherited retinal diseases (IRDs) are a group of heterogeneous conditions that cause progressive vision loss, typically due to monogenic mutations. Female carriers of X-linked IRDs have a single copy of the disease-causing gene, and therefore, may exhibit variable clinical signs that vary from near normal retina to severe disease and vision loss. The relationships between individual genetic mutations and disease severity in X-linked carriers requires further study. This review summarises the current literature surrounding the spectrum of disease seen in female carriers of choroideremia and X-linked retinitis pigmentosa. Various classification systems are contrasted to accurately grade retinal disease. Furthermore, genetic mechanisms at the early embryonic stage are explored to potentially explain the variability of disease seen in female carriers. Future research in this area will provide insight into the association between genotype and retinal phenotypes of female carriers, which will guide in the management of these patients. This review acknowledges the importance of identifying which patients may be at high risk of developing severe symptoms, and therefore should be considered for emerging treatments, such as retinal gene therapy., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Accurate genotyping of individuals with inherited retinal diseases (IRD) is essential for patient management and identifying suitable candidates for gene therapies. This study evaluated the diagnostic yield of next generation sequencing (NGS) in IRDs., Design: Systematic review and meta-analysis., Methods: This systematic review was prospectively registered (CRD42021293619). Ovid MEDLINE and Ovid Embase were searched on 6 June 2022. Clinical studies evaluating the diagnostic yield of NGS in individuals with IRDs were eligible for inclusion. Risk of bias assessment was performed. Studies were pooled using a random...effects inverse variance model. Sources of heterogeneity were explored using stratified analysis, meta-regression, and sensitivity analysis., Results: This study included 105 publications from 28 countries. Most studies (90 studies) used targeted gene panels. The diagnostic yield of NGS was 61.3% (95% confidence interval: 57.8-64.7%; 51 studies) in mixed IRD phenotypes, 58.2% (51.6-64.6%; 41 studies) in rod-cone dystrophies, 57.7% (46.8-68.3%; eight studies) in macular and cone/cone-rod dystrophies, and 47.6% (95% CI: 41.0-54.3%; four studies) in familial exudative vitreoretinopathy. For mixed IRD phenotypes, a higher diagnostic yield was achieved pooling studies published between 2018-2022 (64.2% [59.5-68.7%]), studies using exome sequencing (73.5% [58.9-86.1%]), and studies using the American College of Medical Genetics variant interpretation standards (65.6% [60.8-70.4%])., Conclusion: The current diagnostic yield of NGS in IRDs is between 52-74%. The certainty of the evidence was judged as low or very low. A key limitation of the current evidence is the significant heterogeneity between studies. Adoption of standardized reporting guidelines could improve confidence in future meta-analyses., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Age-related macular degeneration (AMD) is a leading cause of vision impairment. This randomised placebo-controlled trial investigated whether point-of-care tools can improve optometrists' AMD knowledge and/or care provision., Methods: Australian optometrists (n = 31) completed a demographics survey and theoretical AMD case study multiple-choice questions (MCQs) to assess their confidence in AMD care provision and AMD knowledge. Participants were then randomly assigned to one of three point-of-care tools (online 'Classification of Age-related macular degeneration and Risk Assessment Tool' (CARAT), paper CARAT, or 'placebo') to use when providing care to their subsequent 5-10 AMD patients. Participants self-audited the compliance of their AMD care to best practice for these patients, and a similar number of consecutive patients seen prior to enrolment. Post-intervention, participants retook the AMD knowledge MCQs and confidence survey., Results: A total of 29 participants completed the study. At the study endpoint, clinical confidence relative to baseline improved with the paper CARAT, relative to placebo, for knowledge of AMD risk factors, asking patients about these factors and referring for medical retinal sub-specialist care. There were no between-group differences for the change in AMD knowledge scores. Considering record documentation for patients with any AMD severity, there were no significant between-group differences for documenting patient risk factors, AMD severity, clinical examination techniques or management. In a sub-analysis, the change from baseline in compliance for documenting discussions about patient smoking behaviours for early AMD patients was higher with use of the online CARAT relative to placebo (p = 0.04). For patients with intermediate AMD, the change from baseline in documenting the risk of progression to late AMD was greater among practitioners who used the paper CARAT, relative to placebo (p = 0.04)., Conclusions: This study demonstrates that point-of-care clinical tools can improve practitioner confidence and aspects of the documentation of AMD clinical care by optometrists as assessed by self-audit., (© 2022 The Authors. Ophthalmic and Physiological Optics published by John Wiley & Sons Ltd on behalf of College of Optometrists.)

Purpose: This study aimed to systematically review and summarize gene therapy treatment for monogenic retinal and optic nerve diseases., Methods: This review was prospectively registered (CRD42021229812). A comprehensive literature search was performed in Ovid MEDLINE, Ovid Embase, Cochrane Central, and clinical trial registries (February 2021). Clinical studies describing DNA-based gene therapy treatments for monogenic posterior ocular diseases were eligible for inclusion. Risk of bias evaluation was performed. Data synthesis was undertaken applying Synthesis Without Meta-analysis guidelines., Results: This study identified 47 full-text publications, 50 conference abstracts, and 54 clinical trial registry entries describing DNA-based ocular gene therapy treatments for 16 different genetic variants. Study summaries and visual representations of safety and efficacy outcomes are presented for 20 unique full-text publications in RPE65-mediated retinal dystrophies, choroideremia, Leber hereditary optic neuropathy, rod-cone dystrophy, achromatopsia, and X-linked retinoschisis. The most common adverse events were related to lid/ocular surface/cornea abnormalities in subretinal gene therapy trials and anterior uveitis in intravitreal gene therapy trials., Conclusion: There is a high degree of variability in ocular monogenic gene therapy trials with respect to study design, statistical methodology, and reporting of safety and efficacy outcomes. This review improves the accessibility and transparency in interpreting gene therapy trials to date., Competing Interests: Conflict of Interest Thomas L. Edwards is the recipient of a Novartis Pharma medical research grant. All other authors declare no conflicts of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Purpose: Age-related macular degeneration (AMD) is a major cause of vision loss. This study investigated whether performing clinical audit and receiving analytical performance feedback altered documentation of the AMD care provided by optometrists., Methods: Australian optometrists were recruited and completed a survey about their demographics and confidence in AMD care, and a three-month audit of their practice records using an AMD audit tool (termed the pre-audit evaluation). After receiving analytical feedback, participants identified areas for improvement and re-audited their practices after three months to analyse changes in performance (termed the post-audit evaluation). Paired t-tests and Wilcoxon signed-rank tests, as appropriate, were used to compare pre- and post-audit data., Results: Twenty optometrists, most practising in Victoria, Australia, completed the study. Participants primarily worked in corporate practice and/or rural settings and had a range of optometric experience (2-40 years). At baseline, participants felt confident in their: knowledge of AMD risk factors (65%), advice to patients about these factors (55%) and management of earlier stages of AMD (55%). Each clinician completed (median [IQR]): 15 [IQR: 10-19] and 12 [IQR: 8-16] audits of unique patient records, pre- and post-audit, respectively. Post-audit, average record documentation (per optometrist) improved for asking about: AMD family history (94% to 100%, p = 0.03), smoking status (21% to 58%, p < 0.01), diet (11% to 29%, p < 0.01) and nutritional supplementation (20% to 51%, p < 0.01). For clinical examination, compliance with documenting pinhole visual acuity, performing an in-office Amsler grid (upon indication) and using optical coherence tomography improved post-audit (p < 0.05). Accuracy of severity documentation improved for earlier stages of AMD (p < 0.05). For earlier stages of AMD, documentation of counselling about modifiable risk factors significantly improved post-audit (p < 0.05). Aspects well-performed pre-audit that did not change included documenting: medical histories (100% at both time points, p = 0.06) and retinal imaging (77% at both time points, p = 0.97)., Conclusions: Self-audit with analytical feedback improved clinical record documentation of: AMD risk factors, clinical examination, AMD severity classification and management advice. These findings support a role for audit to improve optometric clinical care of AMD, as evidenced by improved documentation of the AMD care delivered., (© 2020 The Authors Ophthalmic and Physiological Optics © 2020 The College of Optometrists.)