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To assess the impact of baseline data on psychophysical and morphological outcomes of subretinal voretigene neparvovec (VN) (Luxturna, Spark Therapeutics, Inc.) treatment. Single-center, retrospective, longitudinal, consecutive case series. Patients with RPE65 -biallelic mutation–associated inherited retinal degeneration (RPE65 -IRD) treated between February 2020 and March 2022 with VN and oral immunosuppression according to the manufacturer's recommendation by one surgeon (F.G.H.). Retrospective analysis of surgical and clinical records, ancillary testing, and retinal imaging after VN therapy for RPE65 -IRD. Descriptive statistics compared data at baseline up to 32 months post-treatment. Best-corrected visual acuity (BCVA), low-luminance VA (LLVA), Goldmann visual fields (GVFs), chromatic full-field stimulus threshold (FST) testing (FST), scotopic and photopic 2-color threshold perimetry (2CTP), and multimodal retinal imaging. Thirty eyes of 19 patients were analyzed (10 pediatric patients < 20 years; 20 adult patients > 20 years of age; overall range: 8–40 years) with a median follow-up of 15 months (range, 1–32). The fovea was completely or partially detached in 16 eyes, attached in 12 eyes, and not assessable in 2 eyes on intraoperative imaging. Median BCVA at baseline was better in the pediatric group (P < 0.05) and did not change significantly independent of age. Meaningful loss of BCVA (≥ 0.3 logarithm of the minimal angle of resolution [logMAR]) occurred in 5 of 18 adult eyes, and a meaningful gain (≥–0.3 logMAR) occurred in 2 of 18 adult and 2 of 8 pediatric eyes. The LLVA and scotopic 2CTP improved considerably in pediatric patients. Scotopic blue FST improved at all ages but more in pediatric patients (8/8 eyes gained ≥ 10 decibels [dB]; P < 0.05). In pediatric patients, median GVF improved by 20% for target V4e and by 50% for target III4e (target I4e not detected). Novel atrophy developed in 13 of 26 eyes at the site of the bleb or peripheral of vascular arcades. Improvements in FST did not correlate with development of chorioretinal atrophy at 12 months. Mean central retinal thickness was 165.87 μm (± 26.26) at baseline (30 eyes) and 157.69 μm (± 30.3) at 12 months (26 eyes). Eight adult patients were treated unilaterally. The untreated eyes did not show meaningful changes during follow-up. These data in a clinical setting show the effectiveness of VN therapy with stable median BCVA and mean retinal thickness and improvements of LLVA, FST, and 2CTP up to 32 months. Treatment effects were superior in the pediatric group. We observed new chorioretinal atrophy in 50% of the treated eyes. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Patients with cone dystrophy (CD) can present with virtually normal retinal appearance, which may delay diagnosis. This study describes the inconspicuous clinical features of POC1B-associated CD in two Saudi families. This is a retrospective case study. Clinical data analyzed included multimodal retinal imaging and electroretinography of the affected individuals. Genetic analysis was done for all probands. Three affected males from two Saudi families with POC1B-associated CD were included. The ages at presentation ranged from 18 to 34 years. Ophthalmic examination showed decreased Snellen visual acuities (range: 20/100–20/300) and color vision bilaterally. Fundus examination showed only mild vascular attenuation. Macular optical coherence tomography showed reduced reflectivity of the external limiting membrane, ellipsoid, and interdigitation zones. Full-field electroretinography demonstrated undetectable light-adapted responses and normal dark-adapted responses in all patients. Next-generation sequencing showed one proband to be homozygous for a previously unpublished nonsense variant in POC1B (NM_172240):c.672C>G; p(Tyr224*). Whole exome sequencing for the second proband showed a novel homozygous frameshifting variant in POC1B: c.991del; p(Arg331Glufs*13). We described two novel variants in POC1B and the associated subtle, yet significant retinal features. POC1B-associated CD is a rare cause of visual loss in patients with relatively normal fundus appearance. Deep phenotyping is necessary in formulating appropriate differential diagnosis. [ABSTRACT FROM AUTHOR]

This retrospective study examines the clinical characteristics and underlying genetic variants that exist in a Leber congenital amaurosis (LCA) patient cohort evaluated at the inherited retinal disease (IRD) clinic at the University of Minnesota (UMN)/M Health System. Our LCA cohort consisted of 33 non-syndromic patients and one patient with Joubert syndrome. We report their relevant history, clinical findings, and genetic testing results. We monitored disease presentation utilizing ocular coherence tomography (OCT) and fundus autofluorescence (FAF). Electroretinogram testing (ERG) was performed in patients when clinically indicated. Next-generation sequencing (NGS) and genetic counseling was offered to all evaluated patients. Advanced photoreceptor loss was noted in 85.7% of the subjects. All patients who underwent FAF had findings of either a ring of macular hypo/hyper AF or peripheral hypo-AF. All patients had abnormal ERG findings. A diagnostic genetic test result was identified in 74.2% of the patients via NGS single-gene testing or panel testing. Two patients in our cohort qualified for Luxturna® and both received treatment at the time of this study. These data will help IRD specialists to understand the genetic variants and clinical presentations that characterize our patient population in the Midwest region of the United States. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to investigate the clinical characteristics and genetic spectrum of adult-onset cone/cone-rod dystrophy (AOCD/AOCRD) in Korean individuals. Methods: This is a single-center, retrospective cross-sectional study. We analyzed 22 individuals with genetically confirmed cone dystrophy, with symptoms beginning after 30 years of age. All patients underwent comprehensive ophthalmic and electrophysiological examinations. Exome sequencing of 296 genes associated with inherited retinal disease was performed. The clinical features of patients with AOCD/AOCRD and the causative genes and variants detected by exome sequencing were analyzed. Results: The median age at the first visit was 52 years (range, 31–76 years), and the most common initial symptom was reduced visual acuity. In most cases, fundus photography showed a bull's eye pattern with foveal sparing, consistent with perifoveal photoreceptor loss on optical coherence tomography. We identified disease-causing variants in six genes: RP1, CRX, CDHR1, PROM1, CRB1, and GUCY2D. Pathogenic variants in RP1, CRX, and CDHR1 were identified in 77% of the AOCD/AOCRD cases, including p.Cys1399LeufsTer5, p.Arg1933Ter, and p.Ile2061SerfsTer12 in RP1; p.Ter300GlnextTer118 in CRX; and p.Glu201Lys in CDHR1. No characteristic imaging differences were observed for any of the causative genes. Most of the RP1-related AOCD/AOCRD cases showed a decreased amplitude only in the photopic electroretinogram (ERG), whereas CRX-related AOCD/AOCRD cases showed a slightly decreased amplitude in both the scotopic and photopic ERGs. Conclusion: In case of visual impairment with bull's eye pattern of RPE atrophy recognized after the middle age, a comprehensive ophthalmic examination and genetic test should be considered, with the possibility of AOCD/AOCRD in East Asians. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa is an inherited disease, in which mutations in different types of genes lead to the death of photoreceptors and the loss of visual function. Although retinitis pigmentosa is the most common type of inherited retinal dystrophy, a clear line of therapy has not yet been defined. In this review, we will focus on the therapeutic aspect and attempt to define the advantages and disadvantages of the protocols of different therapies. The role of some therapies, such as antioxidant agents or gene therapy, has been established for years now. Many clinical trials on different genes and mutations causing RP have been conducted, and the approval of voretigene nepavorec by the FDA has been an important step forward. Nonetheless, even if gene therapy is the most promising type of treatment for these patients, other innovative strategies, such as stem cell transplantation or hyperbaric oxygen therapy, have been shown to be safe and improve visual quality during clinical trials. The treatment of this disease remains a challenge, to which we hope to find a solution as soon as possible. [ABSTRACT FROM AUTHOR]

Introduction: The GNB1 (guanine nucleotide-binding protein, β1) gene encodes for the ubiquitous β1 subunit of heterotrimeric G proteins, which are associated with G-protein-coupled receptors (GPCRs). GNB1 mutations cause a neurodevelopmental disorder characterized by a broad clinical spectrum. A novel variant has recently been confirmed in a case of rod-cone dystrophy. Case Presentation: We describe the second confirmed case of a classical rod-cone dystrophy associated with a mutation located in exon 6 of GNB1 [NM_002074.5:c.217G>C, p.(Ala73Pro)] in a 56-year-old patient also presenting mild intellectual disability, attention deficit/hyperactivity disorder, and truncal obesity. Conclusion: This paper confirms the role of GNB1 in the pathogenesis of a classic rod-cone dystrophy and highlights the importance of including this gene in the genetic analysis panel for inherited retinal diseases. [ABSTRACT FROM AUTHOR]

PurposeLeber congenital amaurosis due to CEP290 mutations (LCA10) is an inherited retinal disease that often results in severe visual impairment or blindness in early childhood. Currently, there are no approved treatments, highlighting the considerable unmet medical need associated with LCA10. We aimed to review the clinical characteristics of LCA10, its impact on patients and society, and the investigational treatment strategies currently in development.MethodsReview of the current literature.ResultsLCA10 is an autosomal recessive ciliopathy, for which the CEP290 intronic variant c.2991+1655A>G (p.Cys998X) is the most common mutation. Usually diagnosed in early childhood, most patients with LCA10 have severe visual impairment during their first decade of life, which significantly affects the quality of life and development. LCA10 also has a significant societal burden (direct and indirect costs). RNA editing using antisense oligonucleotides or Staphylococcus aureus CRISPR-associated protein-9 nuclease is currently under investigation for treatment of p.Cys998X LCA10. Specifically, the antisense oligonucleotide therapy QR-110 (sepofarsen) has demonstrated encouraging safety and efficacy data in a first-in-human trial; a phase 3 clinical trial is ongoing.ConclusionInterventions that can preserve or improve vision in patients with LCA10 have considerable potential to improve the patient quality of life and reduce burden of disease.

Advances in molecular genetics over the past three decades have helped identify a substantial number of genetic variants causing inherited eye diseases that can be identified rapidly by appropriate genetic tests in a clinically useful window. With this progression of knowledge, the roles of genetics and ophthalmology in patient care have become increasingly intertwined, and the necessity for subspecialists in the field of ophthalmic genetics is of paramount importance. As a result of continual medical specialization, technological progress in genetics and knowledge garnered by over a century and a half of cataloguing eye pathology, ophthalmic genetics has become an emerging subspecialty within ophthalmology. By virtue of its rapidly changing advances, genetics and genomics serves a large role within ophthalmology, and subspecialists with the same level of detailed and broad knowledge as any other ophthalmology subspecialty are now required in order to meet the growing needs of the expanding population.

Splicing defects from deep-intronic variants significantly contribute to the mutational spectrum in ABCA4-associated inherited retinal diseases, necessitating functional validation for their pathological classification. Typically, minigene assays in HEK293(T) can qualitatively assess splicing defects, yet they often fail to quantitatively reproduce the resulting mis-splicing patterns, leaving uncertainty on severity and pathogenicity. As a potential cellular model derived from patient cells, photoreceptor precursor cells (PPCs) play a pivotal role in assessing the severity of specific splicing mutations. Nevertheless, the accessibility of biosamples is commonly constrained, and their establishment is costly and laborious. In this study, we combined and investigated the use of a minigene assay and isogenic PPCs, as superior qualitative and more accessible cellular models for the assessment of splicing defects. Specifically, we focused on the clustered c.5196+1013A>G, c.5196+1056A>G, and c.5196+1216C>A deep-intronic variants in intron 36 of ABCA4, comparing their resulting (mis)splicing patterns in minigene-transfected cells and isogenic CRISPR-Cas9-knocked-in PPCs harboring these pathogenic variants in homozygous state. Moreover, we demonstrate the successful correction of these three splicing defects in homozygous mutant PPCs using a single pair of guide RNAs to target Cas9 cleavage, thereby identifying an efficient gene editing strategy for therapeutic applications.

Objective: To cluster the diverse phenotypic features of Stargardt disease (STGD) using unsupervised clustering of multimodal retinal structure and function data. Design: Retrospective cross-sectional study. Subjects: Eyes of subjects with STGD and fundus autofluorescence (FAF), OCT, electroretinography (ERG), and microperimetry (MP) data available within 1 year of the baseline evaluation. Methods: A total of 46 variables from FAF, OCT, ERG, and MP results were recorded for subjects with STGD as defined per published criteria. Factor analysis of mixed data identified the most informative variables. Unsupervised hierarchical clustering and silhouette analysis identified the optimal number of clusters to classify multimodal phenotypes. Main Outcome Measures: Phenotypic clusters of STGD subjects and the corresponding cluster features. Results: We included 52 subjects and 102 eyes with a mean visual acuity (VA) at the time of multimodal testing of 0.69 ± 0.494 logarithm of minimum angle of resolution (20/63 Snellen). We identified 4 clusters of eyes. Compared to the other clusters, cluster 1 (n = 16) included younger subjects, VA greater than that of clusters 2 and 3, normal or moderately low total macular volume (TMV), greater preservation of scotopic and photopic ERG responses and fixation stability, less atrophy, and fewer flecks. Cluster 2 (n = 49) differed from cluster 1 mainly with less atrophy and relatively stable fixation. Cluster 3 (n = 10) included older subjects than clusters 1 and 2 and showed the lowest VA, TMV, ERG responses, and fixation stability, with extensive atrophy. Cluster 4 (n = 27) showed better VA, TMV similar to clusters 1 and 2, moderate ERG activity, stable fixation, and moderate-high atrophy and flecks. Conclusions: Reflecting the phenotypic complexity of STGD, an unsupervised clustering approach incorporating phenotypic measures can be used to categorize STGD eyes into distinct clusters. The clusters exhibit differences in structural and functional measures including quantity of flecks, extent of retinal atrophy, visual fixation accuracy, and ERG responses, among other features. If novel pharmacologic, gene, or cell therapy modalities become available in the future, the multimodal phenomap approach may be useful to individualize treatment decisions, and its utility in aiding prognostication requires further evaluation. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.

Accurate diagnosis of macular atrophy is paramount to enable appropriate treatment when novel treatments for geographic atrophy and macular dystrophies become available. Genetic testing is useful in distinguishing between the two conditions but is not feasible for the majority of patients in real-world clinical practice. Therefore, we aimed to investigate the potential misdiagnosis of inherited macular dystrophy as age-related macular degeneration (AMD) in real-world ophthalmic practice to assist in the development of guidelines to improve diagnostic accuracy while minimizing genetic testing for targeted patients. Retrospective review of the medical records of patients diagnosed with AMD, which included imaging, between 1995 and 2023 from a large multidisciplinary private ophthalmic practice in Australia. We will use a stepwise method to screen for probable cases of macular dystrophy, followed by a consensus review by an expert panel. The outcomes are (1) to determine the potential misdiagnosis rate of macular dystrophy as atrophic AMD by retinal specialists and general ophthalmologists; (2) to identify clinical imaging modalities that are most useful for differentiating macular dystrophy from atrophic AMD; and (3) to establish preliminary guidance for clinicians to improve the diagnosis of macular atrophy from AMD in practice, and thereby target cost-efficient genetic testing. Improving the diagnostic accuracy of both AMD and macular dystrophy, while ensuring cost-efficient genetic testing, will improve the targeted treatment of macular diseases when emerging treatments become available. [ABSTRACT FROM AUTHOR]

(1) Purpose: ABCA4-associated retinal degeneration (ABCA4-RD) is a phenotypically diverse disease that often evades diagnosis, even by experienced retinal specialists. This may lead to inappropriate management, delayed genetic testing, or inaccurate interpretation of genetic testing results. Here, we illustrate the phenotypic diversity of ABCA4-RD using a series of representative cases and compare these to other conditions that closely mimic ABCA4-RD. (2) Methods: Genetically confirmed ABCA4-RD cases with representative phenotypes were selected from an inherited retinal disease cohort in Singapore and compared to phenocopies involving other retinal diseases. (3) Results: ABCA4-RD phenotypes in this series included typical adolescent-onset Stargardt disease with flecks, bull's eye maculopathy without flecks, fundus flavimaculatus, late-onset Stargardt disease, and severe early-onset Stargardt disease. Phenocopies of ABCA4-RD in this series included macular dystrophy, pattern dystrophy, cone dystrophy, advanced retinitis pigmentosa, Leber congenital amaurosis, drug toxicity, and age-related macular degeneration. Key distinguishing features that often suggested a diagnosis of ABCA4-RD were the presence of peripapillary sparing, macular involvement and centrifugal distribution, and a recessive pedigree. (4) Conclusions: ABCA4-RD demonstrates a remarkable phenotypic spectrum that makes diagnosis challenging. Awareness of the clinical spectrum of disease can facilitate prompt recognition and accurate diagnostic testing. [ABSTRACT FROM AUTHOR]

Genetic counselors (GCs) have practiced in Inherited Retinal Disease (IRD) clinics for several decades. In this small subspecialty of genetic counseling, GCs are critical for patient understanding of genetic information, which can have prognostic, systemic, family planning and therapeutic implications. Recently, both access to genetic testing for IRDs and the number of genes associated with IRDs (>350) has increased dramatically. However, the practice models and roles of IRD GCs have not been previously described. GCs working in academic IRD clinics were surveyed to assess their experience, clinical practices, and roles performed. The collected data was compared to the broader genetic counseling profession and to other specialties using publicly available data on GC professional practices. While roles of IRD GCs were overlapping with those of the overall genetic counseling profession, all survey respondents reported diverse roles that included both clinical and non-clinical duties, spending up to half their time on research and educational responsibilities. Most respondents (89%) felt that their clinic's MD to GC ratio was too high, while clinical load varied. IRD GCs report varying degrees of prior genetic counseling and ophthalmology-specific experience but unanimously desire additional subspecialty-specific training. This descriptive assessment of a small subspecialty suggests a need for growth in the number of GCs practicing in IRD clinics and could help to inform development of new GC positions in IRD centers. It also highlights the desire for additional GC-specific education and may be relevant to curriculum development within GC programs. [ABSTRACT FROM AUTHOR]

Purpose: To describe the natural history of autosomal dominant (AD) GUCY2D-associated cone–rod dystrophies (CRDs), and evaluate associated structural and functional biomarkers. Methods: Retrospective analysis was conducted on 16 patients with AD GUCY2D-CRDs across two sites. Assessments included central macular thickness (CMT) and length of disruption to the ellipsoid zone (EZ) via optical coherence tomography (OCT), electroretinography (ERG) parameters, best corrected visual acuity (BCVA), and fundus autofluorescence (FAF). Results: At first visit, with a mean age of 30 years (range 5–70 years), 12 patients had a BCVA below Australian driving standard (LogMAR ≥ 0.3 bilaterally), and 1 patient was legally blind (LogMAR ≥ 1). Longitudinal analysis demonstrated a deterioration of LogMAR by − 0.019 per year (p < 0.001). This accompanied a reduction in CMT of − 1.4 µm per year (p < 0.0001), lengthened EZ disruption by 42 µm per year (p = < 0.0001) and increased area of FAF by 0.05 mm2 per year (p = 0.027). Similarly, cone function decreased with increasing age, as demonstrated by decreasing b-wave amplitude of the light-adapted 30 Hz flicker and fused flicker (p = 0.005 and p = 0.018, respectively). Reduction in CMT and increased EZ disruption on OCT were associated with functional changes including poorer BCVA and decreased cone function on ERG. Conclusion: We have described the natural long-term decline in vision and cone function associated with mutations in GUCY2D and identified a set of functional and structural biomarkers that may be useful as outcome parameters for future therapeutic clinical trials. [ABSTRACT FROM AUTHOR]

Inherited retinal diseases (IRDs) can induce severe sight-threatening retinal degeneration and impose a considerable economic burden on patients and society, making efforts to cure blindness imperative. Transgenic animals mimicking human genetic diseases have long been used as a primary research tool to decipher the underlying pathogenesis, but there are still some obvious limitations. As an alternative strategy, patient-derived induced pluripotent stem cells (iPSCs), particularly three-dimensional (3D) organoid technology, are considered a promising platform for modeling different forms of IRDs, including retinitis pigmentosa, Leber congenital amaurosis, X-linked recessive retinoschisis, Batten disease, achromatopsia, and best vitelliform macular dystrophy. Here, this paper focuses on the status of patient-derived iPSCs and organoids in IRDs in recent years concerning disease modeling and therapeutic exploration, along with potential challenges for translating laboratory research to clinical application. Finally, the importance of human iPSCs and organoids in combination with emerging technologies such as multi-omics integration analysis, 3D bioprinting, or microfluidic chip platform are highlighted. Patient-derived retinal organoids may be a preferred choice for more accurately uncovering the mechanisms of human retinal diseases and will contribute to clinical practice. [ABSTRACT FROM AUTHOR]

Retinal diseases are a leading cause of blindness in developed countries, accounting for the largest share of visually impaired children, working-age adults (inherited retinal disease), and elderly individuals (age-related macular degeneration). These conditions need specialised clinicians to interpret multimodal retinal imaging, with diagnosis and intervention potentially delayed. With an increasing and ageing population, this is becoming a global health priority. One solution is the development of artificial intelligence (AI) software to facilitate rapid data processing. Herein, we review research offering decision support for the diagnosis, classification, monitoring, and treatment of retinal disease using AI. We have prioritised diabetic retinopathy, age-related macular degeneration, inherited retinal disease, and retinopathy of prematurity. There is cautious optimism that these algorithms will be integrated into routine clinical practice to facilitate access to vision-saving treatments, improve efficiency of healthcare systems, and assist clinicians in processing the ever-increasing volume of multimodal data, thereby also liberating time for doctor-patient interaction and co-development of personalised management plans. [ABSTRACT FROM AUTHOR]

Choroideremia (CHM) is an X-linked chorioretinal dystrophy leading to progressive retinal degeneration that results in blindness by late adulthood. It is caused by mutations in the CHM gene encoding the Rab Escort Protein 1 (REP1), which plays a crucial role in the prenylation of Rab proteins ensuring correct intracellular trafficking. Gene augmentation is a promising therapeutic strategy, and there are several completed and ongoing clinical trials for treating CHM using adeno-associated virus (AAV) vectors. However, late-phase trials have failed to show significant functional improvements and have raised safety concerns about inflammatory events potentially caused by the use of viruses. Therefore, alternative non-viral therapies are desirable. Episomal scaffold/matrix attachment region (S/MAR)-based plasmid vectors were generated containing the human CHM coding sequence, a GFP reporter gene, and ubiquitous promoters (pS/MAR-CHM). The vectors were assessed in two choroideremia disease model systems: (1) CHM patient-derived fibroblasts and (2) chmru848 zebrafish, using Western blotting to detect REP1 protein expression and in vitro prenylation assays to assess the rescue of prenylation function. Retinal immunohistochemistry was used to investigate vector expression and photoreceptor morphology in injected zebrafish retinas. The pS/MAR-CHM vectors generated persistent REP1 expression in CHM patient fibroblasts and showed a significant rescue of prenylation function by 75%, indicating correction of the underlying biochemical defect associated with CHM. In addition, GFP and human REP1 expression were detected in zebrafish microinjected with the pS/MAR-CHM at the one-cell stage. Injected chmru848 zebrafish showed increased survival, prenylation function, and improved retinal photoreceptor morphology. Non-viral S/MAR vectors show promise as a potential gene-augmentation strategy without the use of immunogenic viral components, which could be applicable to many inherited retinal disease genes. [ABSTRACT FROM AUTHOR]

ABCA4-associated Stargardt disease (STGD1) leads to bilateral central vision loss and is responsible for 12% of inherited retinal disease-related blindness. The lack of approved treatments highlights the urgent need for effective therapies. This review explores personalized treatments for STGD1, focusing on therapeutic alternative splicing, genome editing, and translational read-through technologies. Literature searches as of July 2023 were undertaken via PubMed. Significant progress has been made in sequencing technology, revealing the complexities of the ABCA4 locus. Comprehensive functional assays can now enable the determination of pathogenicity for ABCA4 variants of uncertain significance. These breakthroughs facilitate the application of gene expression modulation technologies, ushering in a new era of personalized therapeutics. By targeting the ABCA4 gene and manipulating its expression, tailored treatments can address ABCA4-associated STGD1, offering enhanced efficacy and precise interventions based on the individual's genetic profile. These advancements provide hope to those affected by STGD1, with improved treatment options and the potential to prevent vision loss. The convergence of genetic analysis breakthroughs and gene expression modulation technologies revolutionizes our understanding and treatment of inherited disorders, unlocking a promising frontier in personalized therapeutics. This transformative approach to STGD1 holds promise for similar breakthroughs in other inherited conditions. [ABSTRACT FROM AUTHOR]

Next-generation sequencing has revolutionized rare disease diagnostics, but many patients remain without a molecular diagnosis, particularly because many candidate variants usually survive despite strict filtering. Exomiser was launched in 2014 as a Java tool that performs an integrative analysis of patients' sequencing data and their phenotypes encoded with Human Phenotype Ontology (HPO) terms. It prioritizes variants by leveraging information on variant frequency, predicted pathogenicity, and gene-phenotype associations derived from human diseases, model organisms, and protein-protein interactions. Early published releases of Exomiser were able to prioritize disease-causative variants as top candidates in up to 97% of simulated whole-exomes. The size of the tested real patient datasets published so far are very limited. Here, we present the latest Exomiser version 12.0.1 with many new features. We assessed the performance using a set of 134 whole-exomes from patients with a range of rare retinal diseases and known molecular diagnosis. Using default settings, Exomiser ranked the correct diagnosed variants as the top candidate in 74% of the dataset and top 5 in 94%; not using the patients' HPO profiles (i.e., variant-only analysis) decreased the performance to 3% and 27%, respectively. In conclusion, Exomiser is an effective support tool for rare Mendelian phenotype-driven variant prioritization.

Abstract Background Treatment options for patients with inherited retinal disease are limited, although research into novel therapies is underway. To ensure the success of future clinical trials, appropriate visual function outcome measures that can assess changes resulting from therapeutic interventions are urgently required. Rod-cone degenerations are the most common type of inherited retinal disease. Visual acuity is a standard measure but is typically preserved until late disease stages, frequently making it an unsuitable visual function marker. Alternative measures are required. This study investigates the clinical utility of a range of carefully selected visual function tests and patient reported outcome measures. The aim is to identify suitable outcome measures for future clinical trials that could be considered for regulatory approval. Methods This cross-sectional study involves two participant groups, patients with inherited retinal disease (n = 40) and healthy controls (n = 40). The study has been designed to be flexible and run alongside NHS clinics. The study is split into two parts. Part one includes examining standard visual acuity, low luminance visual acuity, the Moorfields acuity chart visual acuity, mesopic microperimetry and three separate patient reported outcome measures. Part two involves 20 min of dark adaptation followed by two-colour scotopic microperimetry. Repeat testing will be undertaken where possible to enable repeatability analyses. A subset of patients with inherited retinal disease will be invited to participate in a semi-structured interview to gain awareness of participants’ thoughts and feelings around the study and different study tests. Discussion The study highlights a need for reliable and sensitive validated visual function measures that can be used in future clinical trials. This work will build on work from other studies and be used to inform an outcome measure framework for rod-cone degenerations. The study is in keeping with the United Kingdom Department of Health and Social Care research initiatives and strategies for increasing research opportunities for NHS patients as part of their NHS care. Trial registration ISRCTN registry, ISRCTN24016133, Visual Function in Retinal Degeneration, registered on 18th August 2022.

Abstract Background Inherited retinal diseases (IRD) are genetically heterogeneous disorders that cause the dysfunction or loss of photoreceptor cells and ultimately lead to blindness. To date, next-generation sequencing procedures fail to detect pathogenic sequence variants in coding regions of known IRD disease genes in about 30–40% of patients. One of the possible explanations for this missing heritability is the presence of yet unidentified transcripts of known IRD genes. Here, we aimed to define the transcript composition of IRD genes in the human retina by a meta-analysis of publicly available RNA-seq datasets using an ad-hoc designed pipeline. Results We analysed 218 IRD genes and identified 5,054 transcripts, 3,367 of which were not previously reported. We assessed their putative expression levels and focused our attention on 435 transcripts predicted to account for at least 5% of the expression of the corresponding gene. We looked at the possible impact of the newly identified transcripts at the protein level and experimentally validated a subset of them. Conclusions This study provides an unprecedented, detailed overview of the complexity of the human retinal transcriptome that can be instrumental in contributing to the resolution of some cases of missing heritability in IRD patients.

Abstract Introduction Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA) are rare inherited retinal degenerative disorders. The Visual Symptom and Impact Outcomes patient-reported outcome (ViSIO-PRO) and observer-reported outcome (ViSIO-ObsRO) instruments were developed in this population to assess visual function symptoms and impacts on vision-dependent activities of daily living (ADL) and distal health-related quality of life (HRQoL). This study aimed to explore the psychometric properties of the ViSIO-PRO and ViSIO-ObsRO in RP/LCA. Methods The 49-item ViSIO-PRO and 27-item ViSIO-ObsRO instruments were completed by 83 adult and adolescent patients and 22 caregivers of child patients aged 3–11 years with RP/LCA, respectively, at baseline and 12–16-day follow-up. Concurrent measures were also administered at baseline. Psychometric analyses assessed item (question) properties, dimensionality, scoring, reliability, validity, and score interpretation. Results Item responses were mainly evenly distributed across the response scale, and inter-item correlations were mostly moderate to strong (> 0.30) at baseline within hypothesized domains. Item deletion was informed by item properties, qualitative data, and clinical input and supported retention of 35 ViSIO-PRO items and 25 ViSIO-ObsRO items. Confirmatory factor analysis in line with pre-hypothesized domains supported a four-factor model assessing visual function symptoms, mobility, vision-dependent ADL, and distal HRQoL. A bifactor model supported calculation of total scores and four domain scores. Internal consistency was high for domain and total scores (Cronbach’s alpha > 0.70) and test–retest reliability for total scores was strong between baseline and 12–16-day follow-up (intraclass correlation coefficients 0.66–0.98). Convergent validity was supported by strong correlations in a logical pattern with concurrent measures. Mean baseline scores differed significantly between severity groups. Distribution-based methods provided initial insights to guide interpretation of scores. Conclusions Findings supported item reduction and established scoring of the instruments. Evidence of reliability and validity as outcome measures in RP/LCA was also reported. Further research is ongoing to explore responsiveness of the ViSIO-PRO and ViSIO-ObsRO instruments and interpretation of change scores.

Paul O’Brien,1 Ashley Enstone,2 Daisy Bridge,2 Robin Wyn,2 Judit Banhazi3 1Novartis Ireland, Dublin, Ireland; 2Adelphi Values PROVE, Bollington, UK; 3Novartis Pharma AG, Basel, SwitzerlandCorrespondence: Paul O’Brien, Email paul-2.obrien@novartis.comIntroduction: Retinitis pigmentosa (RP) is an inherited retinal pathology associated with “night blindness” and progressive loss of peripheral vision, in some cases leading to complete blindness. Health state utility values are required for activities such as modelling disease burden or the cost-effectiveness of new interventions. The current study aimed to generate utility values for health states of varying levels of functional vision in RP, with members of the general public in the UK.Methods: Five health states were defined according to standard clinical measures of visual ability. Health state descriptions were developed following interviews with patients with RP in the UK (n=5). Further interviews were conducted for confirmation with healthcare professionals with specific experience of managing patients with RP in the UK (n=2). Interviews with members of the general public in the UK were conducted to value health states. A time trade-off (TTO) process based on the established Measurement and Valuation of Health (MVH) protocol was used. Due to the ongoing COVID-19 pandemic, all interviews were web-enabled and conducted 1:1 by a trained moderator.Results: In total, n=110 TTO interviews were conducted with members of the UK general public. Mean TTO utility values followed the logical and expected order, with increasing visual impairment leading to decreased utility. Mean values varied between 0.78 ± 0.20 (“moderate impairment”), and 0.33 ± 0.26 (“hand motion” to “no light perception”). Supplementary visual analogue scale (VAS) scores also followed the logical and expected order: mean VAS values varied between 47.95 ± 15.38 (“moderate impairment”) and 17.22 ± 12.49 in (“hand motion” to “no light perception”).Discussion: These data suggest that individuals living with RP have substantially impaired quality of life. Utility values for RP have been elicited here using a method and sample that is suitable for economic modelling and health technology assessment purposes.Keywords: retinitis pigmentosa, inherited retinal disease, health state utility, health-related quality of life, time trade-off, vignette study

Purpose: Choroideremia is an X-linked choroidopathy caused by pathogenic variants in the CHM gene. It is characterized by the early appearance of multiple scotomas in the peripheral visual field that spread and coalesce, usually sparing central vision until late in the disease. These features make quantitative monitoring of visual decline particularly challenging. Here, we describe a novel computational approach to convert Goldmann visual field (GVF) data into quantitative volumetric measurements. With this approach, we analyzed visual field loss in a longitudinal, retrospective cohort of patients with choroideremia. Design: Single-center, retrospective, cohort study. Participants: We analyzed data from 238 clinic visits of 56 molecularly-confirmed male patients with choroideremia from 41 families (range, 1–27 visits per patient). Patients had a median follow up of 4 years (range, 0–56 years) with an age range of 5 to 76 years at the time of their visits. Methods: Clinical data from molecularly-confirmed patients with choroideremia, including GVF data, were included for analysis. Goldmann visual field records were traced using a tablet-based application, and the 3-dimensional hill of vision was interpolated for each trace. This procedure allowed quantification of visual field loss from data collected over decades with differing protocols, including different or incomplete isopters. Visual acuity (VA) data were collected and converted to logarithm of the minimum angle of resolution values. A delayed exponential mixed-effects model was used to evaluate the loss of visual field volume over time. Main Outcome Measures: Visual acuity and GVF volume. Results: The estimated mean age at disease onset was 12.6 years (standard deviation, 9.1 years; 95% quantile interval, 6.5–36.4 years). The mean field volume loss was 6.8% per year (standard deviation, 4.5%; 95% quantile interval, 1.9%–18.8%) based on exponential modeling. Field volume was more strongly correlated between eyes (r2 = 0.935) than best-corrected VA (r2 = 0.285). Conclusions: Volumetric analysis of GVF data enabled quantification of peripheral visual function in patients with choroideremia and evaluation of disease progression. The methods presented here may facilitate the analysis of historical GVF data from patients with inherited retinal disease and other diseases associated with visual field loss. This work informs the creation of appropriate outcome measures in choroideremia therapeutic trials, particularly in trial designs. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

AbstractPurpose Accurate diagnosis of macular atrophy is paramount to enable appropriate treatment when novel treatments for geographic atrophy and macular dystrophies become available. Genetic testing is useful in distinguishing between the two conditions but is not feasible for the majority of patients in real-world clinical practice. Therefore, we aimed to investigate the potential misdiagnosis of inherited macular dystrophy as age-related macular degeneration (AMD) in real-world ophthalmic practice to assist in the development of guidelines to improve diagnostic accuracy while minimizing genetic testing for targeted patients.Methods Retrospective review of the medical records of patients diagnosed with AMD, which included imaging, between 1995 and 2023 from a large multidisciplinary private ophthalmic practice in Australia. We will use a stepwise method to screen for probable cases of macular dystrophy, followed by a consensus review by an expert panel. The outcomes are (1) to determine the potential misdiagnosis rate of macular dystrophy as atrophic AMD by retinal specialists and general ophthalmologists; (2) to identify clinical imaging modalities that are most useful for differentiating macular dystrophy from atrophic AMD; and (3) to establish preliminary guidance for clinicians to improve the diagnosis of macular atrophy from AMD in practice, and thereby target cost-efficient genetic testing.Discussion Improving the diagnostic accuracy of both AMD and macular dystrophy, while ensuring cost-efficient genetic testing, will improve the targeted treatment of macular diseases when emerging treatments become available.

To date, almost 600 genes have been associated with ocular genetic diseases. As these discoveries are made, clinical genetic testing continues to grow and become a more common element in the diagnostic workup of children with blindness and reduced vision. However, few studies have explored the motivations of parents of pediatric patients for pursuing genetic testing or the topics they would like to discuss during their visit. This study explored these gaps in the existing knowledge of clinical care for children with vision loss. We distributed a REDCap survey to parents of pediatric patients in the Indiana University Ocular Genetics Clinic and through the Foundation Fighting Blindness MyRetinaTracker database to examine factors that motivate families to undergo genetic testing, topics they are interested in discussing, and satisfaction with their current care. Parents were primarily motivated by the opportunity to learn about their child's prognosis, formal diagnosis, and possible treatment options. Parents were most interested in discussing prognosis, adaptations for vision loss, and testing logistics. Parents reported satisfaction with the care received; however, less than half were very satisfied with their understanding of prognosis and the support resources provided. Parents seem to be generally satisfied by the care from their ocular genetics team. However, families' desires are not being fully met, especially with information about prognosis and support resources. As the field of ocular genetics continues to grow, it is important we improve these offerings and optimize care for this patient population. [ABSTRACT FROM AUTHOR]

To establish the proportion of patients with retinitis pigmentosa (RP) meeting the Australian fitness to drive (FTD) visual standards. A prospective consecutive case series of patients with a clinical or genetic diagnosis of RP. Data on age at symptom onset, current driving status, inheritance pattern, better eye visual acuity (BEVA), binocular Esterman visual field (BEVF) parameters, genotype and ability to meet the driving standards based on BEVA and BEVF were collected. Outcome measures included the proportion of RP patients overall meeting the standards and clinical predictors for passing. A sub-analysis was performed on those RP patients who reported to drive. Change in BEVA and BEVF parameters across age in specific genotype groups was assessed. Overall, 228 patients with RP had a BEVF assessment. Only 39% (89/228) met the driving standards. Younger age at the time of testing was the only significant predictor (p < 0.01) for passing. Of the 55% of RP patients who reported to drive, 52% (65/125) met the standards, decreasing to 14% in the 56- to 65-year-old age group. RP patients harbouring mutations in HK1 or RHO genes may have slower rates of decline in their VF parameters. Nearly 40% of RP patients met the driving standards. However, almost 50% of RP drivers were unaware of their failure to meet the current standards. BEVF testing is essential in the assessment of RP patients who are still driving. Phenotype and genotype predictors for passing the standards warrant further investigation. Abbreviation: FTD, fitness to drive; IRD, inherited retinal disease; RP, retinitis pigmentosa; RHO, rhodopsin; HK1, hexokinase 1; PRPF31 pre-mRNA processing factor 31; RPGR, retinitis pigmentosa GTPase regulator; VF, visual field; BEVA, better eye visual acuity; BEVF, binocular Esterman visual field. [ABSTRACT FROM AUTHOR]

The demand for induced pluripotent stem cells (iPSC)‐derived retinal organoid and retinal pigment epithelium (RPE) models for the modelling of inherited retinopathies has increased significantly in the last decade. These models are comparable with foetal retinas up until the later stages of retinogenesis, expressing all of the key neuronal markers necessary for retinal function. These models have proven to be invaluable in the understanding of retinogenesis, particular in the context of patient‐specific diseases. Inherited retinopathies are infamously described as clinically and phenotypically heterogeneous, such that developing gene/mutation‐specific animal models in each instance of retinal disease is not financially or ethically feasible. Further to this, many animal models are insufficient in the study of disease pathogenesis due to anatomical differences and failure to recapitulate human disease phenotypes. In contrast, iPSC‐derived retinal models provide a high throughput platform which is physiologically relevant for studying human health and disease. They also serve as a platform for drug screening, gene therapy approaches and in vitro toxicology of novel therapeutics in pre‐clinical studies. One unique characteristic of stem cell‐derived retinal models is the ability to mimic in vivo retinogenesis, providing unparalleled insights into the effects of pathogenic mutations in cells of the developing retina, in a highly accessible way. This review aims to give the reader an overview of iPSC‐derived retinal organoids and/or RPE in the context of disease modelling of several inherited retinopathies including Retinitis Pigmentosa, Stargardt disease and Retinoblastoma. We describe the ability of each model to recapitulate in vivo disease phenotypes, validate previous findings from animal models and identify novel pathomechanisms that underpin individual IRDs. [ABSTRACT FROM AUTHOR]

Adaptive optics (AO) retinal imaging enables individual photoreceptors to be visualized in the clinical setting. AO imaging can be a powerful clinical tool for detecting photoreceptor degeneration at a cellular level that might be overlooked through conventional structural assessments, such as spectral-domain optical coherence tomography (SD-OCT). Therefore, AO imaging has gained significant interest in the study of photoreceptor degeneration, one of the most common causes of inherited blindness. Growing evidence supports that AO imaging may be useful for diagnosing early-stage retinal dystrophy before it becomes apparent on fundus examination or conventional retinal imaging. In addition, serial AO imaging may detect structural disease progression in early-stage disease over a shorter period compared to SD-OCT. Although AO imaging is gaining popularity as a structural endpoint in clinical trials, the results should be interpreted with caution due to several pitfalls, including the lack of standardized imaging and image analysis protocols, frequent ocular comorbidities that affect image quality, and significant interindividual variation of normal values. Herein, we summarize the current state-of-the-art AO imaging and review its potential applications, limitations, and pitfalls in patients with inherited retinal diseases. [ABSTRACT FROM AUTHOR]

NR2E3 is a nuclear hormone receptor gene required for the correct development of the retinal rod photoreceptors. Expression of NR2E3 protein in rod cell precursors suppresses cone-specific gene expression and, in concert with other transcription factors including NRL, activates the expression of rod-specific genes. Pathogenic variants involving NR2E3 cause a spectrum of retinopathies, including enhanced S-cone syndrome, Goldmann–Favre syndrome, retinitis pigmentosa, and clumped pigmentary retinal degeneration, with limited evidence of genotype–phenotype correlations. A common feature of NR2E3-related disease is an abnormally high number of cone photoreceptors that are sensitive to short wavelength light, the S-cones. This characteristic has been supported by mouse studies, which have also revealed that loss of Nr2e3 function causes photoreceptors to develop as cells that are intermediate between rods and cones. While there is currently no available cure for NR2E3-related retinopathies, there are a number of emerging therapeutic strategies under investigation, including the use of viral gene therapy and gene editing, that have shown promise for the future treatment of patients with NR2E3 variants and other inherited retinal diseases. This review provides a detailed overview of the current understanding of the role of NR2E3 in normal development and disease, and the associated clinical phenotypes, animal models, and therapeutic studies. [ABSTRACT FROM AUTHOR]

Nonparaneoplastic autoimmune retinopathy is a rare, potentially blinding retinal disease which can present as pericentral retinal degeneration or may be secondary to retinal damage from retinal degeneration. Treatment with IV immunoglobulin can be effective in these patients. Purpose: To report a case of nonparaneoplastic autoimmune retinopathy with phenotypical features of pericentral retinal degeneration (PRD) who responded to IV immunoglobulin therapy. Methods: A case report. A 27-year-old man presented with recent subacute progressive nyctalopia and photopsia. Results: Dilated fundoscopy demonstrated confluent yellow–white patches along the main temporal vascular arcades with sparing of the central island in the posterior pole. Color vision, fundus autofluorescence, fluorescein angiography, static visual field, and electroretinographic studies were inconclusive for retinal degeneration. Subsequent genetic testing for known mutations was negative. Workup for paraneoplastic autoimmune retinopathy was negative. Antiretinal antibodies were positive. The patient was diagnosed with nonparaneoplastic autoimmune retinopathy and was treated with IV immunoglobulin, which resulted in objective and subjective improvement on electroretinography, visual field, and optical coherence tomography of the retina. Conclusion: Nonparaneoplastic autoimmune retinopathy may present in a patient with the clinical phenotype of PRD. It is essential to rule out nonparaneoplastic autoimmune retinopathy in patients with subacute changes in the natural course of pericentral retinal degeneration because treatment with IV immunoglobulin may be helpful. [ABSTRACT FROM AUTHOR]

Abstract Inherited Retinal Diseases (IRDs) are considered one of the leading causes of blindness worldwide. However, the majority of them still lack a safe and effective treatment due to their complexity and genetic heterogeneity. Recently, gene therapy is gaining importance as an efficient strategy to address IRDs which were previously considered incurable. The development of the clustered regularly-interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) system has strongly empowered the field of gene therapy. However, successful gene modifications rely on the efficient delivery of CRISPR-Cas9 components into the complex three-dimensional (3D) architecture of the human retinal tissue. Intriguing findings in the field of nanoparticles (NPs) meet all the criteria required for CRISPR-Cas9 delivery and have made a great contribution toward its therapeutic applications. In addition, exploiting induced pluripotent stem cell (iPSC) technology and in vitro 3D retinal organoids paved the way for prospective clinical trials of the CRISPR-Cas9 system in treating IRDs. This review highlights important advances in NP-based gene therapy, the CRISPR-Cas9 system, and iPSC-derived retinal organoids with a focus on IRDs. Collectively, these studies establish a multidisciplinary approach by integrating nanomedicine and stem cell technologies and demonstrate the utility of retina organoids in developing effective therapies for IRDs.

Elucidation of the cellular changes that occur in degenerating photoreceptors of people with inherited retinal diseases (IRDs) has been a focus for many research teams, leading to numerous theories on how these changes affect the cell death process. What is clearly emerging from these studies is that there are common denominators across multiple models of IRD, regardless of the underlying genetic mutation. These common markers could open avenues for broad neuroprotective therapeutics to prevent photoreceptor loss and preserve functional vision. In recent years, the role of epigenetic modifications contributing to the pathology of IRDs has been a particular point of interest, due to many studies noting changes in these epigenetic modifications, which coincide with photoreceptor cell death. This review will discuss the two broad categories of epigenetic changes, DNA methylation and histone modifications, that have received particular attention in IRD models. We will review the altered epigenetic regulatory events that are believed to contribute to cell death in IRDs and discuss the therapeutic potential of targeting these alterations.

Background: The widespread adoption of exome sequencing has greatly increased the rate of genetic diagnosis for inherited conditions. However, the detection and validation of large deletions remains challenging. While numerous bioinformatics approaches have been developed to detect deletions from whole ‐ exome sequencing and targeted panels, further work is typically required to define the physical breakpoints or integration sites. Accurate characterisation requires either expensive follow ‐ up whole ‐ genome sequencing or the time ‐ consuming, laborious process of PCR walking, both of which are challenging when dealing with the repeat sequences which frequently intersect deletion breakpoints. The aim of this study was to develop a cost‐effective, long‐range sequencing method to characterise deletions. Methods: Genomic DNA was amplified with primers spanning the deletion using long‐range PCR and the products purified. Sequencing was performed on MinION flongle flowcells. The resulting fast5 files were basecalled using Guppy, trimmed using Porechop and aligned using Minimap2. Filtering was performed using NanoFilt. Nanopore sequencing results were verified by Sanger sequencing. Results: Four cases with deletions detected following comparative read‐depth analysis of targeted short‐read sequencing were analysed. Nanopore sequencing defined breakpoints at the molecular level in all cases including homozygous breakpoints in EYS, CNGA1 and CNGB1 and a heterozygous deletion in PRPF31. All breakpoints were verified by Sanger sequencing. Conclusions: In this study, a quick, accurate and cost ‐ effective method is described to characterise deletions identified from exome, and similar data, using nanopore sequencing. [ABSTRACT FROM AUTHOR]

To determine the validity of the validate the adult patient-reported outcome measure tools, the Michigan Retinal Degeneration Questionnaire (MRDQ) and Michigan Vision-Related Anxiety Questionnaire (MVAQ), in adolescent patients with inherited retinal diseases (IRDs). Ninety-one adolescent patients diagnosed with IRDs were recruited at the Hospital for Sick Children (University of Toronto) and the Kellogg Eye Center (University of Michigan). The patients were administered the MRDQ, MVAQ, and Patient Health Questionnaire-4 (PHQ-4). Test-retest variability was assessed in eighteen patients within 14 days of the initial administration. Adolescent responses were analyzed for validity and reliability. As a further validation step, comparisons were made to adult data from the original MRDQ and MVAQ studies to ensure consistency in response ranges. The existing MRDQ and MVAQ content and format could accurately detect the impact of IRD on activities of daily living in adolescents with IRDs. No floor/ceiling effects were identified, test-retest reliability was established (r = 0.73–0.86), and no items were excluded after differential item functioning analysis. Domain and trait associations with visual acuity and IRD phenotypes were similar between adolescents and adults. The MRDQ and MVAQ are psychometrically validated questionnaires for which we have shown validity for use in adolescent patients with IRDs. [ABSTRACT FROM AUTHOR]

Background: Treatment options for patients with inherited retinal disease are limited, although research into novel therapies is underway. To ensure the success of future clinical trials, appropriate visual function outcome measures that can assess changes resulting from therapeutic interventions are urgently required. Rod-cone degenerations are the most common type of inherited retinal disease. Visual acuity is a standard measure but is typically preserved until late disease stages, frequently making it an unsuitable visual function marker. Alternative measures are required. This study investigates the clinical utility of a range of carefully selected visual function tests and patient reported outcome measures. The aim is to identify suitable outcome measures for future clinical trials that could be considered for regulatory approval. Methods: This cross-sectional study involves two participant groups, patients with inherited retinal disease (n = 40) and healthy controls (n = 40). The study has been designed to be flexible and run alongside NHS clinics. The study is split into two parts. Part one includes examining standard visual acuity, low luminance visual acuity, the Moorfields acuity chart visual acuity, mesopic microperimetry and three separate patient reported outcome measures. Part two involves 20 min of dark adaptation followed by two-colour scotopic microperimetry. Repeat testing will be undertaken where possible to enable repeatability analyses. A subset of patients with inherited retinal disease will be invited to participate in a semi-structured interview to gain awareness of participants' thoughts and feelings around the study and different study tests. Discussion: The study highlights a need for reliable and sensitive validated visual function measures that can be used in future clinical trials. This work will build on work from other studies and be used to inform an outcome measure framework for rod-cone degenerations. The study is in keeping with the United Kingdom Department of Health and Social Care research initiatives and strategies for increasing research opportunities for NHS patients as part of their NHS care. Trial registration: ISRCTN registry, ISRCTN24016133, Visual Function in Retinal Degeneration, registered on 18th August 2022. [ABSTRACT FROM AUTHOR]

Mutations in the RCBTB1 gene cause inherited retinal disease; however, the pathogenic mechanisms associated with RCBTB1 deficiency remain poorly understood. Here, we investigated the effect of RCBTB1 deficiency on mitochondria and oxidative stress responses in induced pluripotent stem cell (iPSC)-derived retinal pigment epithelial (RPE) cells from control subjects and a patient with RCBTB1-associated retinopathy. Oxidative stress was induced with tert-butyl hydroperoxide (tBHP). RPE cells were characterized by immunostaining, transmission electron microscopy (TEM), CellROX assay, MitoTracker assay, quantitative PCR and immunoprecipitation assay. Patient-derived RPE cells displayed abnormal mitochondrial ultrastructure and reduced MitoTracker fluorescence compared with controls. Patient RPE cells displayed increased levels of reactive oxygen species (ROS) and were more sensitive to tBHP-induced ROS generation than control RPE. Control RPE upregulated RCBTB1 and NFE2L2 expression in response to tBHP treatment; however, this response was highly attenuated in patient RPE. RCBTB1 was co-immunoprecipitated from control RPE protein lysates by antibodies for either UBE2E3 or CUL3. Together, these results demonstrate that RCBTB1 deficiency in patient-derived RPE cells is associated with mitochondrial damage, increased oxidative stress and an attenuated oxidative stress response. [ABSTRACT FROM AUTHOR]

Photoreceptor development of the vertebrate visual system is controlled by a complex transcription regulatory network. OTX2 is expressed in the mitotic retinal progenitor cells (RPCs) and controls photoreceptor genesis. CRX that is activated by OTX2 is expressed in photoreceptor precursors after cell cycle exit. NEUROD1 is also present in photoreceptor precursors that are ready to specify into rod and cone photoreceptor subtypes. NRL is required for the rod fate and regulates downstream rod-specific genes including the orphan nuclear receptor NR2E3 which further activates rod-specific genes and simultaneously represses cone-specific genes. Cone subtype specification is also regulated by the interplay of several transcription factors such as THRB and RXRG. Mutations in these key transcription factors are responsible for ocular defects at birth such as microphthalmia and inherited photoreceptor diseases such as Leber congenital amaurosis (LCA), retinitis pigmentosa (RP) and allied dystrophies. In particular, many mutations are inherited in an autosomal dominant fashion, including the majority of missense mutations in CRX and NRL. In this review, we describe the spectrum of photoreceptor defects that are associated with mutations in the above-mentioned transcription factors, and summarize the current knowledge of molecular mechanisms underlying the pathogenic mutations. At last, we deliberate the outstanding gaps in our understanding of the genotype--phenotype correlations and outline avenues for future research of the treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Inherited retinal diseases (IRD) are genetically heterogeneous disorders that cause the dysfunction or loss of photoreceptor cells and ultimately lead to blindness. To date, next-generation sequencing procedures fail to detect pathogenic sequence variants in coding regions of known IRD disease genes in about 30–40% of patients. One of the possible explanations for this missing heritability is the presence of yet unidentified transcripts of known IRD genes. Here, we aimed to define the transcript composition of IRD genes in the human retina by a meta-analysis of publicly available RNA-seq datasets using an ad-hoc designed pipeline. Results: We analysed 218 IRD genes and identified 5,054 transcripts, 3,367 of which were not previously reported. We assessed their putative expression levels and focused our attention on 435 transcripts predicted to account for at least 5% of the expression of the corresponding gene. We looked at the possible impact of the newly identified transcripts at the protein level and experimentally validated a subset of them. Conclusions: This study provides an unprecedented, detailed overview of the complexity of the human retinal transcriptome that can be instrumental in contributing to the resolution of some cases of missing heritability in IRD patients. [ABSTRACT FROM AUTHOR]

Ongoing trials for retinitis pigmentosa (RP) are genotype-specific, with most trials conducted on European cohorts. Due to genetic differences across diverse ancestries and populations, these therapies may not be efficacious in East Asians. A literature search was conducted from 1966 to September 2022 for cohort studies on East Asian populations reporting on non-syndromic RP genotypes and variants. Population-weighted prevalence was used to determine the genotypes and individual variants across the entire cohort. The carrier prevalence of common variants was compared against those in Europe. A total of 12 articles describing 2,932 clinically diagnosed East Asian RP probands were included. We identified 876 variants across 54 genes. The most common genotypes included USH2A, EYS, RPGR, ABCA4, PRPF31, RHO, RP1, RP2, PDE6B and SNRNP200, with USH2A as the most common (17.1%). Overall, 60.5% of probands with clinically relevant variants were found to have one of the genotypes above, with 543/876 (62.0%) of the variants occurring in these genes. The most frequently reported variant was USH2A missense variant c.2802T>G/p.C934W (4.9%). Carrier prevalence of these variants was significantly different (p < 0.0001) than in Europe. USH2A was the most commonly affected RP gene in this East Asian cohort, although sub-population analysis revealed distinct genotype prevalence patterns. While the genotypes are similar between East Asia and European cohorts, variants are specific to East Asia. The identification of several prevalent variants in USH2A and EYS provides an opportunity for the development of therapeutics that are relevant for East Asia patients. [ABSTRACT FROM AUTHOR]

CNGB1 gene mutations are a well-known cause of autosomal recessive retinitis pigmentosa (RP), which was recently associated with olfactory dysfunction. The purpose of this study was to report the molecular spectrum and the ocular and olfactory phenotypes of a multiethnic cohort with CNGB1-associated RP. A cross-sectional case series was conducted at two ophthalmic genetics referral centers. Consecutive patients with molecularly confirmed CNGB1-related RP were included. All patients underwent a complete ophthalmological examination complemented by psychophysical olfactory evaluation. Fifteen patients (10 families: 8 Portuguese, 1 French, and 1 Turkish), mean aged 57.13 ± 15.37 years old (yo), were enrolled. Seven disease-causing variants were identified, two of which are reported for the first time: c.2565_2566del and c.2285G > T. Although 11/15 patients reported onset of nyctalopia before age 10, diagnosis was only established after 30 yo in 9/15. Despite widespread retinal degeneration being present in 14/15 probands, a relatively preserved visual acuity was observed throughout follow-up. Olfactory function was preserved in only 4/15 patients, all of whom carried at least one missense variant. Our study supports previous reports of an autosomal recessive RP-olfactory dysfunction syndrome in association with certain disease-causing variants in the CNGB1 gene and expands the mutational spectrum of CNGB1-related disease by reporting two novel variants. [ABSTRACT FROM AUTHOR]

Introduction: Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA) are rare inherited retinal degenerative disorders. The Visual Symptom and Impact Outcomes patient-reported outcome (ViSIO-PRO) and observer-reported outcome (ViSIO-ObsRO) instruments were developed in this population to assess visual function symptoms and impacts on vision-dependent activities of daily living (ADL) and distal health-related quality of life (HRQoL). This study aimed to explore the psychometric properties of the ViSIO-PRO and ViSIO-ObsRO in RP/LCA. Methods: The 49-item ViSIO-PRO and 27-item ViSIO-ObsRO instruments were completed by 83 adult and adolescent patients and 22 caregivers of child patients aged 3–11 years with RP/LCA, respectively, at baseline and 12–16-day follow-up. Concurrent measures were also administered at baseline. Psychometric analyses assessed item (question) properties, dimensionality, scoring, reliability, validity, and score interpretation. Results: Item responses were mainly evenly distributed across the response scale, and inter-item correlations were mostly moderate to strong (> 0.30) at baseline within hypothesized domains. Item deletion was informed by item properties, qualitative data, and clinical input and supported retention of 35 ViSIO-PRO items and 25 ViSIO-ObsRO items. Confirmatory factor analysis in line with pre-hypothesized domains supported a four-factor model assessing visual function symptoms, mobility, vision-dependent ADL, and distal HRQoL. A bifactor model supported calculation of total scores and four domain scores. Internal consistency was high for domain and total scores (Cronbach's alpha > 0.70) and test–retest reliability for total scores was strong between baseline and 12–16-day follow-up (intraclass correlation coefficients 0.66–0.98). Convergent validity was supported by strong correlations in a logical pattern with concurrent measures. Mean baseline scores differed significantly between severity groups. Distribution-based methods provided initial insights to guide interpretation of scores. Conclusions: Findings supported item reduction and established scoring of the instruments. Evidence of reliability and validity as outcome measures in RP/LCA was also reported. Further research is ongoing to explore responsiveness of the ViSIO-PRO and ViSIO-ObsRO instruments and interpretation of change scores. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa is an inherited disease, in which mutations in different types of genes lead to the death of photoreceptors and the loss of visual function. Although retinitis pigmentosa is the most common type of inherited retinal dystrophy, a clear line of therapy has not yet been defined. In this review, we will focus on the therapeutic aspect and attempt to define the advantages and disadvantages of the protocols of different therapies. The role of some therapies, such as antioxidant agents or gene therapy, has been established for years now. Many clinical trials on different genes and mutations causing RP have been conducted, and the approval of voretigene nepavorec by the FDA has been an important step forward. Nonetheless, even if gene therapy is the most promising type of treatment for these patients, other innovative strategies, such as stem cell transplantation or hyperbaric oxygen therapy, have been shown to be safe and improve visual quality during clinical trials. The treatment of this disease remains a challenge, to which we hope to find a solution as soon as possible.

Abstract Objective We aimed to evaluate the cost-effectiveness of voretigene neparvovec (VN) compared with standard of care (SoC) for patients with inherited retinal disease (IRD) caused by a biallelic RPE65-mutation. VN is a live, non-replicating adeno-associated virus serotype 2 (AAV2). SoC is best supportive care provided to patients with visual impairment. Patients under SoC may experience progressive vision loss leading to complete blindness. Methods We adapted a previously published Markov cohort model for IRD. An annual cycle length, life-long time horizon, discount rate of 3% for cost and health outcomes, and Swiss health system perspective were used. Data from a randomised controlled phase III trial of VN versus SoC (ClinicalTrials.gov: NCT00999609) were used to estimate transitions between health states in the first year, after which VN patients were assumed to remain for 39 subsequent years in the health state they were in at the end of the first year. After the 40th year for VN patients and 1st year for SoC patients, visual decline was modelled based on observational data on the natural progression of the disease. Quality-adjusted life years (QALYs) were calculated based on an external study which elicited clinicians’ EQ-5D-5L-based utility estimates for IRD patients with a RPE65-mutation. Costs (Swiss Francs (CHF), year 2018-2019) included drug acquisition/ administration, adverse events, testing for sufficient viable retinal cells, and healthcare-related costs of blindness. Societal costs of blindness were added in a complementary analysis. Robustness of the model results were tested in sensitivity and scenario analyses. Results For the base-case, VN resulted in incremental costs per patient of CHF 764’402 (VN: CHF 901’654, SoC: CHF 137’252), incremental blindness-free years of 7.67 (VN: 28.32, SoC: 20.65) and incremental QALYs of 6.73 (VN: 18.35, SoC: 11.62), leading to an incremental cost-effectiveness ratio of CHF 113’526 per QALY gained. In probabilistic sensitivity analysis, the cost-effectiveness of VN was better than CHF 100,000 per QALY gained in 41% of iterations. For the scenario analysis in which a societal perspective was adopted and for which a 50% work-related productivity loss from blindness was assumed, incremental costs of CHF 423,837 and an ICER of CHF 62’947 per QALY gained were produced. The scenario assuming VN treatment effect lasts for 20 years produced an ICER of CHF 156’171 per QALY gained, whereas assuming a life-long VN treatment effect resulted in an ICER of CHF 96’384 per QALY gained. Conclusion The incremental cost-effectiveness ratio of VN compared to the SoC was estimated to be CHF 113’526 and CHF 62’947 per QALY gained, respectively, from a Swiss healthcare system, and societal perspective assuming a 50% productivity loss.

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

Purpose: To describe ocular findings in individuals with primary hyperoxaluria type 1 (PH1), focusing on the correlations between retinal anatomy and retinal function. To characterize the retinal alterations that occur at different disease stages by evaluating individuals with diverse degrees of renal impairment associated with PH1. Design: A cross-sectional study. Participants: Patients diagnosed with PH1 based on clinical criteria and genetic testing, treated in the Pediatric Nephrology Unit of the Ruth Children’s Hospital, Rambam Health Care Campus, Haifa, Israel between 2013 and 2021. Methods: The ophthalmological assessment included a slit-lamp biomicroscopy of the anterior and posterior segment or indirect ophthalmoscopy. Electroretinography was employed for assessment of the retinal function, and retinal imaging included spectral-domain OCT and fundus autofluorescence. A systematic evaluation of the disease stage was based on clinical criteria including physical examination, purposeful imaging (X-ray, echocardiography, and US abdomen), and laboratory tests as needed. Main Outcome Measures: Anatomical and functional assessment of the retina in patients with PH1, and the relationship between retinal dysfunction and kidney impairment. Results: A total of 16 eyes were examined in the study of 8 children ranging in age from 4 to 19 years. Four eyes (25%) showed normal structural and functional retinal findings, 8 eyes (50%) presented functional impairment in the absence of pathological structural findings, and 4 eyes (25%) had advanced retinal damage that manifested as significant morphological and functional impairment. There was no direct relationship between the severity of the renal disease and the severity of the retinal phenotype. Conclusions: Subjects with PH1 present varying severity levels of the retinal phenotype, with possible discrepancy between the clinical retinal morphology and the retinal function noted on electroretinography. These findings raise questions about the molecular basis of the retinal manifestations in PH1. The presence of functional impairment in the absence of evident crystal deposition in the retina suggests that, in addition to oxalate crystal accumulation, other biomolecular processes may play a role in the development of retinopathy. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.