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Purpose: The objective of this paper is to shed light on the current landscape of genotyping practices, phenotyping practices and availability of essential vision rehabilitation management for inherited retinal diseases (IRD) in the Asia-Pacific (APAC) Region., Methods: The 62-item questionnaire was distributed electronically via email. The questions covered five domains: (1) structure of the IRD service and registry/database; (2) genotyping practices; (3) genetic counselling; (4) deep phenotyping practices; (5) low-vision rehabilitation services., Results: The survey was completed by 36 of 45 centres in twelve countries and regions in APAC. Among these centres, 42 % reported managing more than 1000 patients. Notably, 39 % of centres lack an IRD database or registry, and 44 % of centres have tested less than one-quarter of their IRD patients. The majority of centres (67 %) do not have genetic counsellors. While there was consistency in the imaging-based investigations, there was marked heterogeneity for functional testing using electrophysiology and formal perimetry. Only 34 % of centres confirmed the availability of access to low-vision assistive devices., Conclusions: This study reveals several critical gaps in managing IRDs in the APAC region. These include the lack of IRD database/registry in one-third of centres, a substantial proportion of patients remaining genetically undiagnosed, and limited availability of genetic counsellors. The findings also underscore a need to harmonise investigations for evaluating retinal function and identify areas for improvement in the provision of low-vision rehabilitation services., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Inherited retinal diseases (IRDs) are a group of rare genetic eye conditions that cause blindness. Despite progress in identifying genes associated with IRDs, improvements are necessary for classifying rare autosomal dominant (AD) disorders. AD diseases are highly heterogenous, with causal variants being restricted to specific amino acid changes within certain protein domains, making AD conditions difficult to classify. Here, we aim to determine the top-performing in-silico tools for predicting the pathogenicity of AD IRD variants. We annotated variants from ClinVar and benchmarked 39 variant classifier tools on IRD genes, split by inheritance pattern. Using area-under-the-curve (AUC) analysis, we determined the top-performing tools and defined thresholds for variant pathogenicity. Top-performing tools were assessed using genome sequencing on a cohort of participants with IRDs of unknown etiology. MutScore achieved the highest accuracy within AD genes, yielding an AUC of 0.969. When filtering for AD gain-of-function and dominant negative variants, BayesDel had the highest accuracy with an AUC of 0.997. Five participants with variants in NR2E3, RHO, GUCA1A, and GUCY2D were confirmed to have dominantly inherited disease based on pedigree, phenotype, and segregation analysis. We identified two uncharacterized variants in GUCA1A (c.428T>A, p.Ile143Thr) and RHO (c.631C>G, p.His211Asp) in three participants. Our findings support using a multi-classifier approach comprised of new missense classifier tools to identify pathogenic variants in participants with AD IRDs. Our results provide a foundation for improved genetic diagnosis for people with IRDs., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: To delineate the natural history of visual function parameters over time in individuals with Bietti crystalline dystrophy., Methods: This was a single-center retrospective longitudinal cohort study. Participants (n = 29) with a clinical diagnosis of Bietti crystalline dystrophy who harbored two alleles of disease-causing variants of the cytochrome P450 family 4 subfamily V member 2 gene (CYP4V2) were enrolled. Best-corrected visual acuity (BCVA), visual field (VF), and full-field ERG (ffERG) at baseline and their changes during the follow-up period were evaluated. Annual progression rates were calculated using three methods., Results: The mean age at the initial visit was 34.2 ± 7.5 years, with 5.9 ± 3.1 years follow-up. The annual progression rate from the longitudinal analysis using averaged individual progression rates was 0.079 logMAR units for BCVA, 1.14 dB for mean defect (MD) value of VF, and -18.06 µV and -5.45 µV for the b-wave amplitudes of scotopic 3.0 ERG and photopic 3.0 ERG, respectively. Mixed-model linear regression revealed annual progression rates of 0.068 logMAR units, 0.86 dB, -13.29 µV, and -3.75 µV, respectively. Cross-sectional progression rates from visual function versus age at baseline were 0.011 logMAR units, 0.47 dB, -1.85 µV, and -1.07 µV, respectively, which were significantly slower than those from the longitudinal data. Interocular symmetries for the MD values of VF and ffERG were good., Conclusions: Annual BCVA, VF, and ffERG progression rates were rapid, emphasizing the need for regular follow-up and early intervention. The progression rate cannot be inferred accurately from cross-sectional data from patients of different ages.

Purpose: To investigate the clinical and genetic characteristics for a large cohort of Chinese patients with Bietti crystalline retinopathy (BCR)., Methods: A total of 208 Chinese BCR patients from 175 families were recruited. Comprehensive clinical evaluations and genetic analysis were performed. Genotype-phenotype correlations were evaluated through statistical analysis., Results: The patients' median age was 37 years (range, 20-76 years). The median best corrected visual acuity (BCVA) was 0.8 LogMAR unit (range, 2.8 to -0.12). A significant decline of BCVA was revealed in patients over 40 years old (P<0.001). Two clinical types were observed: peripheral type (type P) and central type (type C). Significantly more type C patients had a worse central visual acuity, but a more preserved retinal function (P<0.05). Molecular screening detected biallelic CYP4V2 pathogenic variants in 98.3% (172/175) of the families, including 19 novel ones. The most frequent pathogenic variant was c.802-8&#95;810del17insGC, with the allele frequency of 55.7% (195/350), followed by c.992A>C (28/350, 8%) and c.1091-2A>G (23/350, 6.6%). BCR patients with one c.802-8&#95;810del17insGC and one truncating variant (IVS6-8/Tru) had BCVA>1.3 LogMAR unit (Snellen equivalent<20/400) at a younger age than those with homozygous c.802-8&#95;810del17insGC variants (homo IVS6-8) (P=0.031)., Conclusions: BCR patients preserved relatively good vision before 40 years old. Two distinct clinical types of BCR were observed. BCR patients with IVS6-8/Tru had an earlier decline in visual acuity than those with homo IVS6-8. Our findings enhance the knowledge of BCR and will be helpful in patient selection for gene therapy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Despite increasing success in determining genetic diagnosis for patients with inherited retinal diseases (IRDs), mutations in about 30% of the IRD cases remain unclear or unsettled after targeted gene panel or whole exome sequencing. In this study, we aimed to investigate the contributions of structural variants (SVs) to settling the molecular diagnosis of IRD with whole-genome sequencing (WGS). A cohort of 755 IRD patients whose pathogenic mutations remain undefined were subjected to WGS. Four SV calling algorithms including include MANTA, DELLY, LUMPY and CNVnator were used to detect SVs throughout the genome. All SVs identified by any one of these four algorithms were included for further analysis. AnnotSV was used to annotate these SVs. SVs that overlap with known IRD-associated genes were examined with sequencing coverage, junction reads and discordant read pairs. Polymerase Chain Reaction (PCR) followed by Sanger sequencing was used to further confirm the SVs and identify the breakpoints. Segregation of the candidate pathogenic alleles with the disease was performed when possible. A total of 16 candidate pathogenic SVs were identified in 16 families, including deletions and inversions, representing 2.1% of patients with previously unsolved IRDs. Autosomal dominant, autosomal recessive and X-linked inheritance of disease-causing SVs were observed in 12 different genes. Among these, SVs in CLN3, EYS and PRPF31 were found in multiple families. Our study suggests that the contribution of SVs detected by short-read WGS is about 0.25% of our IRD patient cohort and is significantly lower than that of single nucleotide changes and small insertions and deletions., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Optical coherence tomography (OCT) is an emerging imaging technique for diagnosing ophthalmic diseases and the visual analysis of retinal structure changes, such as exudates, cysts, and fluid. In recent years, researchers have increasingly focused on applying machine learning algorithms, including classical machine learning and deep learning methods, to automate retinal cysts/fluid segmentation. These automated techniques can provide ophthalmologists with valuable tools for improved interpretation and quantification of retinal features, leading to more accurate diagnosis and informed treatment decisions for retinal diseases. This review summarized the state-of-the-art algorithms for the three essential steps of cyst/fluid segmentation: image denoising, layer segmentation, and cyst/fluid segmentation, while emphasizing the significance of machine learning techniques. Additionally, we provided a summary of the publicly available OCT datasets for cyst/fluid segmentation. Furthermore, the challenges, opportunities, and future directions of artificial intelligence (AI) in OCT cyst segmentation are discussed. This review is intended to summarize the key parameters for the development of a cyst/fluid segmentation system and the design of novel segmentation algorithms and has the potential to serve as a valuable resource for imaging researchers in the development of assessment systems related to ocular diseases exhibiting cyst/fluid in OCT imaging.

Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessively inherited progressive retinal disease. Here, we describe the generation and characterization of a human induced pluripotent stem cell (hiPSC) line of BCD patient with CYP4V2 mutations. The reprogramming of this iPSC line was performed from skin fibroblast by using the Sendai-virus based approach. The established hiPSC line retained the disease-associated mutations and showed normal karyotype, pluripotency and differentiation capacity., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Lipid metabolic deficiencies are associated with many genetic disorders. Bietti crystalline dystrophy (BCD), a blindness-causing inherited disorder with changed lipid profiles, is more common in Chinese and Japanese than other populations. Our results reveal that mouse models lacking Cyp4v3 have less physiological and functional changes than those of BCD patients with this gene defect. After the administration of a high-fat diet (HFD), the occurrence of retinal lesions were both accelerated and aggregated in the Cyp4v3 -/- mouse models, implying that changed lipid levels were not only associated factors but also risk factors to BCD patients. Facilitated by the results, we found that the reduced electroretinography waveforms and retinal thickness observed in the HFD-induced mouse models were effectively recovered after subretinal delivery of a human CYP4V2 gene carried by an adeno-associated virus vector, which demonstrates the potential curability of BCD by gene therapy.

Inherited retinal disease (IRD) is a category of genetic disorders affecting retina. Understanding the molecular basis of IRD is vital for clinical and genetic classification of patients. Uyghur people is an isolated ethnic group mainly residing in northwestern China with genetic admixture from Europeans and East Asians. The genetic etiology of IRD in this specific population still remains unknown. Here, by next-generation sequencing (NGS), we screened mutations in over 200 known retinal disease genes in a cohort of 12 unrelated Uyghur IRD probands. Out of the 12 probands, six are solved with high confidence, two with low confidence, while the remaining four are unsolved. We identified known disease-causing alleles in this cohort that suggest ancient Uyghur migration and also discovered eight novel disease-associated variants. Our results showed NGS-based mutation screening as a reliable approach for molecular diagnosis. In addition, this approach can also be applied to reveal the genetic history of a specific ethnic group.

Purpose: The aim of this study is to characterize the clinical features of four unrelated Chinese patients with retinal dehydrogenase 5 (RDH5) retinopathy (fundus albipunctatus) and to identify the genetic defects underlying this disorder., Methods: Complete ophthalmic examinations, including slit-lamp biomicroscopy, dilated indirect ophthalmoscopy, spectral domain optical coherence tomography, and full-field electroretinography were performed. Genomic DNA was prepared from peripheral venous leukocytes. Polymerase chain reaction and direct sequencing were used to screen the coding exons and exon/intron boundaries of the RDH5 gene (11-cis-retinol dehydrogenase)., Results: Four patients with RDH5 retinopathy, including two 6-year-old boys, from 4 unrelated Chinese families were recruited in this study. A novel c.832C>T (p.Arg278Ter) nonsense mutation of the RDH5 gene was identified in one 6-year-old boy, who has a compound heterozygous mutation with c.928delC/InsGAAG (p.Leu310GluVal). Homozygous Leu310GluVal mutations were identified in 2 male patients including the other 6-year-old boy. The other patient was a 29-year-old woman in whom compound heterozygous changes c.500G>A (p.Arg167His) and Leu310GluVal in RDH5 were identified. All patients manifested the fundus phenotype of fundus albipunctatus. Electroretinograms recorded in 1 boy (Case 3) showed scotopic waveforms within normal range under standard conditions and no change after prolonged dark adaptation. Scotopic waveforms were within the normal range for Case 4 while higher amplitudes (30% increase) were recorded after prolonged dark adaptation. The two adult patients had depressed scotopic electroretinogram responses under standard conditions. Optical coherence tomography showed discrete highly reflective lesions extending from the retinal pigment epithelium to the level of the external limiting membrane., Conclusion: A novel c.832C>T (p.Arg278Ter) nonsense mutation in RDH5 was identified. A specific mutation, Leu310GluVal, was seen in the homozygous state in one adult male and one boy and in the heterozygous state in one female adult and one boy with RDH5 retinopathy, suggesting a common mutation. Preserved rod function was observed in one young subject in this study.