We present the results of the first study of a large cohort of patients with inherited retinal dystrophies (IRD) performed for the Polish population using whole-exome sequencing (WES) in the years 2016-2019. Moreover, to facilitate such diagnostic analyses and enable future application of gene therapy and genome editing for IRD patients, a Polish genomic reference database (POLGENOM) was created based on whole-genome sequences of healthy Polish Caucasian nonagenarians and centenarians. The newly constructed database served as a control, providing a comparison for variant frequencies in the Polish population. The diagnostic yield for the selected group of IRD patients reached 64.9%. The study uncovered the most common pathogenic variants in ABCA4 and USH2A in the European population, along with several novel causative variants. A significant frequency of the ABCA4 complex haplotype p.(Leu541Pro; Ala1038Val) was observed, as well as that of the p.Gly1961Glu variant. The first VCAN causative variant NM_004385.5:c.4004-2A>G in Poland was found and described. Moreover, one of the first patients with the RPE65 causative variants was identified, and, in consequence, could receive the dedicated gene therapy. The availability of the reference POLGENOM database enabled comprehensive variant characterisation during the NGS data analysis, confirming the utility of a population-specific genomic database for enhancing diagnostic accuracy. Study findings suggest the significance of genetic testing in elder patients with unclear aetiology of eye diseases. The combined approach of NGS and the reference genomic database can improve the diagnosis, management, and future treatment of IRDs.

Background: Retinitis pigmentosa (RP) is a group of hereditary retinal dystrophies characterized by progressive degeneration of photoreceptor cells, which results in debilitating visual impairment. This systematic review aims to evaluate the efficacy and safety of emerging treatment modalities for RP, including gene therapy, mesenchymal-cell-based approaches, and supplementary interventions. Methods: A comprehensive search of electronic databases was conducted to identify relevant studies published up to February 2024. Studies reporting outcomes of treatment interventions for RP, including randomized controlled trials, non-randomized studies, and case series, were included. Data extraction and synthesis were performed according to predefined criteria, focusing on assessing the quality of evidence and summarizing key findings. Results: The search yielded 13 studies meeting inclusion criteria, encompassing diverse treatment modalities and study designs. Gene therapy emerged as a promising therapeutic approach, with several studies reporting favorable outcomes regarding visual function preservation and disease stabilization. Mesenchymal-cell-based therapies also demonstrated potential benefits, although evidence remains limited and heterogeneous. Supplementary interventions, including nutritional supplements and neuroprotective agents, exhibited variable efficacy, with conflicting findings across studies. Conclusions: Despite the lack of definitive curative treatments, emerging therapeutic modalities promise to slow disease progression and preserve visual function in individuals with RP. However, substantial gaps in evidence and heterogeneity in study methodologies underscore the need for further research to elucidate optimal treatment strategies, refine patient selection criteria, and enhance long-term outcomes. This systematic review provides a comprehensive synthesis of current evidence and highlights directions for future research to advance the care and management of individuals with RP.

Sequence variants in Eyes Shut Homolog (EYS) gene are one of the most frequent causes of autosomal recessive retinitis pigmentosa (RP). Herein, we describe an Italian RP family characterized by EYS-related pseudodominant inheritance. The female proband, her brother, and both her sons showed typical RP, with diminished or non-recordable full-field electroretinogram, narrowing of visual field, and variable losses of central vision. To investigate this apparently autosomal dominant pedigree, next generation sequencing (NGS) of a custom panel of RP-related genes was performed, further enhanced by bioinformatic detection of copy-number variations (CNVs). Unexpectedly, all patients had a compound heterozygosity involving two known pathogenic EYS variants i.e., the exon 33 frameshift mutation c.6714delT and the exon 29 deletion c.(5927þ1_5928-1)_(6078þ1_6079-1)del, with the exception of the youngest son who was homozygous for the above-detailed frameshift mutation. No pathologic eye conditions were instead observed in the proband\'s husband, who was a heterozygous healthy carrier of the same c.6714delT variant in exon 33 of EYS gene. These findings provide evidence that pseudodominant pattern of inheritance can hide an autosomal recessive RP partially or totally due to CNVs, recommending CNVs study in those pedigrees which remain genetically unsolved after the completion of NGS or whole exome sequencing analysis.

UNASSIGNED: Biallelic pathogenic variants in CDH23 can cause Usher syndrome type I (USH1), typically characterized by sensorineural hearing loss, variable vestibular areflexia, and a progressive form of rod-cone dystrophy. While missense variants in CDH23 can cause DFNB12 deafness, other variants can affect the cadherin 23 function, more severely causing Usher syndrome type I D. The main purpose of our study is to describe the genotypes and phenotypes of patients with mild retinitis pigmentosa (RP), including sector RP with two pathogenic variants in CDH23.
UNASSIGNED: Clinical examination included medical history, comprehensive ophthalmologic examination, and multimodal retinal imaging, and in case 1 and 2, full-field electroretinography (ERG). Genetic analysis was performed in all cases, and segregation testing of proband relatives was performed in case 1 and 3.
UNASSIGNED: Three unrelated cases presented with variable clinical phenotype for USH1 and were found to have two pathogenic variants in CDH23, with missense variant, c.5237 G > A: p.Arg1746Gln being common to all. All probands had mild to profound hearing loss. Case 1 and 3 had mild RP with mid peripheral and posterior pole sparing, while case 2 had sector RP. ERG results were consistent with the marked loss of retinal function in both eyes at the level of photoreceptor in case 1 and case 2, with normal peak time in the former.
UNASSIGNED: Patients harbouring c.5237 G > A: p.Arg1746Gln variants in CDH23 can present with a mild phenotype including sector RP. This can aid in better genetic counselling and in prognostication.

BACKGROUND: The purpose of this project was to explore the current standards of clinical care genetic testing and counseling for patients with inherited retinal diseases (IRDs) from the perspective of leading experts in selected European countries. Also, to gather opinions on current bottlenecks and future solutions to improve patient care.
METHODS: On the initiative of the European Vision Institute, a survey questionnaire with 41 questions was designed and sent to experts in the field from ten European countries. Each participant was asked to answer with reference to the situation in their own country.
RESULTS: Sixteen questionnaires were collected by November 2023. IRD genetic tests are performed in clinical care settings for 80% or more of tested patients in 9 countries, and the costs of genetic tests in clinical care are covered by the public health service to the extent of 90% or more in 8 countries. The median proportion of patients who are genetically tested, the median rate of genetically solved patients among those who are tested, and the median proportion of patients receiving counseling are 51-70%, 61-80%, and 61-80%, respectively. Improving the education of healthcare professionals who facilitate patient referrals to specialized centers, improving access of patients to more thorough genotyping, and increasing the number of available counselors were the most advocated solutions.
CONCLUSIONS: There is a significant proportion of IRD patients who are not genetically tested, whose genetic testing is inconclusive, or who do not receive counseling. Educational programs, greater availability of state-of-the-art genotyping and genetic counselors could improve healthcare for IRD patients.

Accurate interpretation of sequence variants in inherited retinal dystrophy (IRD) is vital given the significant genetic heterogeneity observed in this disorder. To achieve consistent and accurate diagnoses, establishment of standardized guidelines for variant interpretation is essential. The American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for variant interpretation serve as the global \"cross-disease\" standard for classifying variants in Mendelian hereditary disorders. These guidelines propose a systematic approach for categorizing variants into 5 classes based on various types of evidence, such as population data, computational data, functional data, and segregation data. However, for clinical genetic diagnosis and to ensure standardized diagnosis and treatment criteria, additional specifications based on features associated with each disorder are necessary. In this context, we present a comprehensive framework outlining the newly specified ACMG/AMP rules tailored explicitly to IRD in the Japanese population on behalf of the Research Group on Rare and Intractable Diseases (Ministry of Health, Labour and Welfare of Japan). These guidelines consider disease frequencies, allele frequencies, and both the phenotypic and the genotypic characteristics unique to IRD in the Japanese population. Adjustments and modifications have been incorporated to reflect the specific requirements of the population. By incorporating these IRD-specific factors and refining the existing ACMG/AMP guidelines, we aim to enhance the accuracy and consistency of variant interpretation in IRD cases, particularly in the Japanese population. These guidelines serve as a valuable resource for ophthalmologists and clinical geneticists involved in the diagnosis and treatment of IRD, providing them with a standardized framework to assess and classify genetic variants.

OBJECTIVE: The purpose of our study was to assess the phenotypic and genotypic spectrum in a large cohort of patients with PRPF31-associated retinal dystrophy.
METHODS: Retrospective cohort study.
METHODS: In this retrospective chart review study, we collected cross-sectional data on the phenotype and genotype of patients with PRPF31-associated retinal dystrophy from the clinics for inherited retinal dystrophies at the University of Tuebingen and the local RetDis database and biobank. Patients underwent thorough ophthalmological examinations and genetic testing.
RESULTS: Eighty-six patients from 61 families were available for clinical assessment, while genomic DNA was available for 111 individuals (index patients and family members). Fifty-three different disease-associated variants were observed in our cohort. Point mutations were the most common class. All but two patients exhibited features of a typical Retinitis pigmentosa (RP). One patient showed a cone-rod dystrophy pattern. One mutation carrier revealed no signs of a retinal dystrophy. There was a statistically significant better visual acuity for patients with large deletions in the 20-39 age group. Cystoid macular edema was common in those with preserved central retina and showed an association with female sex.
CONCLUSIONS: Our study confirms high phenotypic variability in disease onset and age at which legal blindness is reached in PRPF31-associated RP. Non-penetrance is commonly documented in family history, although poorly represented in our study, possibly indicating that true asymptomatic mutation carriers are rare if followed-up over lifetime with thorough ophthalmologic workup.

Inherited Retinal Dystrophies (IRD) are diverse rare diseases that affect the retina and lead to visual impairment or blindness. Research in this field is ongoing, with over 60 EU orphan medicinal products designated in this therapeutic area by the Committee for Orphan Medicinal Products (COMP) at the European Medicines Agency (EMA). Up to now, COMP has used traditional disease terms, like retinitis pigmentosa, for orphan designation regardless of the product\'s mechanism of action. The COMP reviewed the designation approach for IRDs taking into account all previous Orphan Designations (OD) experience in IRDs, the most relevant up to date scientific literature and input from patients and clinical experts. Following the review, the COMP decided that there should be three options available for orphan designation concerning the condition: i) an amended set of OD groups for therapies that might be used in a broad spectrum of conditions, ii) a gene-specific designation for targeted therapies, and iii) an occasional term for products that do not fit in the above two categories. The change in the approach to orphan designation in IRDs caters for different scenarios to allow an optimum approach for future OD applications including the option of a gene-specific designation. By applying this new approach, the COMP increases the regulatory clarity, efficiency, and predictability for sponsors, aligns EU regulatory tools with the latest scientific and medical developments in the field of IRDs, and ensures that all potentially treatable patients will be included in the scope of an OD.

Introduction: TULP1 exemplifies the remarkable clinical and genetic heterogeneity observed in inherited retinal dystrophies. Our research describes the clinical and molecular characteristics of a patient manifesting an atypical retinal dystrophy pattern, marked by the identification of both a previously unreported and a rarely encountered TULP1 variant. Methods: Whole-exome sequencing was performed to identify potential causative variants. The pathogenicity of the identified TULP1 variants was evaluated through in silico predictors and a minigene splice assay, specifically designed to assess the effect of the unreported TULP1 variant. Results: We identified two TULP1 gene variants in a patient exhibiting unusual and symmetrical alterations in both retinas, characterized by an increase in autofluorescence along the distribution of retinal vessels. These variants included a known rare missense variant, c.1376T>C, and a novel splice site variant, c.822G>T. For the latter variant (c.822G>T), we conducted a minigene splice assay that demonstrated the incorporation of a premature stop codon. This finding suggests a likely activation of the nonsense-mediated mRNA decay mechanism, ultimately resulting in the absence of protein production from this allele. Segregation analysis confirmed that these variants were in trans. Discussion: Our data support that individuals with biallelic TULP1 variants may present with a unique pattern of macular degeneration and periarteriolar vascular pigmentation. This study highlights the importance of further clinical and molecular characterization of TULP1 variants to elucidate genotype-phenotype correlations in the context of inherited retinal dystrophies.

UNASSIGNED: Optical coherence tomography (OCT) is a noninvasive, frequently used imaging technology that enables detailed viewing of retina anatomy. It is used to monitor disease progression in retinitis pigmentosa (RP) eyes, including detecting changes in retinal thickness.
UNASSIGNED: The purpose of the study is to determine the clinical presentation and macular morphology in RP eyes using OCT imaging.
UNASSIGNED: A retrospective review of case records and OCT scans in eyes diagnosed with RP in two ophthalmic clinics in Nigeria. Biodata, Snellen best-corrected visual acuity (BCVA), intraocular pressure (IOP), vertical cup-to-disc ratio (VCDR), and presence of maculopathy were determined. Data were analyzed using IBM SPSS version 22.0 (IBM Corp. Armonk, NY, USA).
UNASSIGNED: Fifty-five eyes of 28 patients (18 males and 10 females), with a mean age of 47.16 ± 15.56 years (22-77 years), were studied. 40-49 years was the most frequent age group, 28.6%. Severe visual impairment occurred in 22% of eyes and myopia in 32%. Twenty-nine percent had undergone cataract surgery or had a significant cataract. The mean IOP was 11 mmHg, and the mean VCDR was 0.46. On OCT examination, macular atrophy was the most common finding in 74.5% of eyes, epiretinal membrane in 16.3%, cystoid macular edema in 7.3%, vitreomacular adhesion in 5.4%, and vitreomacular traction in 1.8%. There was no association between macular morphology, macular thickness, and BCVA (P = 0.155, P = 0.424).
UNASSIGNED: OCT provides information on macula structure in RP eyes. About 14.5% of eyes had a normal macula, while 85.5% had a maculopathy, confirming that RP eyes have a higher rate of maculopathy than non RP eyes. OCT evaluation of an RP eye should be a standard workup for the early detection of such maculopathy and monitoring for disease progression.
Résumé Contexte: La tomographie par cohérence optique (OCT) est une technologie d\'imagerie non invasive fréquemment utilisée qui permet une visualisation détaillée de l\'anatomie de la rétine. Elle est utilisée pour surveiller la progression de la maladie dans les yeux de la rétinite pigmentaire (RP), y compris la détection des changements dans l\'épaisseur de la rétine. Objectif: Le but de l\'étude était de déterminer la présentation clinique et la morphologie maculaire des yeux présentant une RP à l\'aide de l\'imagerie OCT. Méthodes: Une revue rétrospective des dossiers de cas et des scans OCT dans les yeux diagnostiqués de RP a été réalisée dans deux cliniques ophtalmologiques au Nigeria. Les données biographiques, la meilleure acuité visuelle corrigée de Snellen (MAVC), la pression intraoculaire (PIO), le rapport cup-sur-disc vertical (RCDV) et la présence de maculopathie ont été déterminés. Les données ont été analysées à l\'aide d\'IBM SPSS version 22.0 (IBM Corp. Armonk, NY, USA). Résultats: Cinquante-cinq yeux de 28 patients (18 hommes et 10 femmes), âgés en moyenne de 47,16 ± 15,56 ans (22–77 ans) ont été étudiés. Les 40 à 49 ans étaient la tranche d\'âge la plus fréquente à 28,6 %. Une déficience visuelle sévère est survenue dans 22 % des yeux et une myopie dans 32 %. Vingt-neuf pour cent avaient subi une chirurgie de la cataracte ou avaient une cataracte importante. La PIO moyenne était de 11 mmHg et le RCDV moyen était de 0,46. À l\'examen OCT, on retrouvait l\'atrophie maculaire prédominante dans 74,5 % des yeux, la membrane épirétinienne (16,3 %), l\'œdème maculaire cystoïde (7,3 %), l\'adhérence vitréomaculaire (5,4 %) et la traction vitréomaculaire (1,8 %). Il n\'y avait aucune association entre la morphologie maculaire, l\'épaisseur maculaire et la MAVC (P = 0,155, P = 0,424). Conclusion: l\'OCT fournit des informations sur la structure de la macula dans la RP. Environ 14,5% des yeux avaient une macula normale contre 85,5% avec maculopathie, confirmant ainsi que les yeux avec RP ont un taux de maculopathie plus élevé que les yeux sans RP. L\'évaluation OCT d\'un œil avec RP devrait être un bilan standard pour la détection précoce de maculopathie et la surveillance de la progression de la maladie. Mots-clés: Membrane épirétinienne, dystrophie rétinienne héréditaire, atrophie maculaire, œdème maculaire, tomographie par cohérence optique, rétinite pigmentaire.