Search Results (412)

Congenital stationary night blindness (CSNB) is a rare, genetically and clinically heterogeneous group of non-progressive inherited retinal diseases characterized by night blindness, myopia, nystagmus, and decreased visual acuity, for which comprehensive genetic characterization remains essential to enable accurate diagnosis and future gene therapy development. In this study, we performed a clinical and genetic analysis of twenty-one Polish families diagnosed with CSNB using next-generation sequencing (NGS)-based targeted gene panels and, in one case, whole-exome sequencing (WES), complemented by Sanger sequencing for variant validation and segregation analysis. Pathogenic variants were identified in six genes: GPR179 and NYX were the most frequently affected (six families each), followed by CACNA1F (three families), GRM6, TRPM1, and SLC24A1 (two families each). The complete Schubert–Bornschein form predominated in our cohort, in contrast to previous reports indicating higher prevalence of the incomplete form. Notably, ten previously unreported variants were identified in CACNA1F, GRM6, and NYX, expanding the known mutational spectrum of CSNB. Certain variants appear enriched in the Polish population. These findings underscore the value of NGS-based approaches for precise molecular diagnosis of CSNB and contribute to the broader understanding of its genetic architecture. Full article

Background/Objectives: Inherited retinal diseases (IRDs) represent a group of rare conditions characterized by significant clinical and genetic heterogeneity. Historically, the diagnosis of these conditions relied primarily on clinical presentation and imaging techniques. This literature review aims to discuss the current state of progress and ongoing challenges in applying precision medicine approaches to IRDs and to examine how advances in genetic testing have transformed diagnostics and opened new therapeutic avenues. Methods: This review examines the application of genetic testing methods to IRDs, with particular focus on next-generation sequencing (NGS) technologies. The review also evaluates current patient selection protocols that combine genetic confirmation, retinal structural evaluation, and detailed genetic counselling to achieve optimal therapeutic outcomes. Results: The implementation of NGS has significantly enhanced diagnostic capabilities for IRDs by enabling precise identification of specific genetic mutations. This advancement has paved the way for targeted therapeutic strategies, exemplified by Luxturna for RPE65-related IRDs. However, several barriers to broader adoption of precision medicine persist, including high costs, varied access to services, and complexities in interpreting genetic variants. Conclusions: While the continued development of innovative therapeutic modalities offers promise for expanding treatment options for IRDs, fully harnessing the potential of current and emerging therapeutic technologies requires addressing existing economic, technological, educational, and infrastructural challenges. Full article

Inherited retinal diseases (IRDs) are a major cause of visual impairment worldwide, marked by extensive genetic and phenotypic heterogeneity. Recent estimates from the U.S. suggest a prevalence of nearly 1 in 1000 individuals, reflecting both disease burden and improved diagnostic recognition. This review traces the shift from linkage analysis and Sanger sequencing to high-throughput next-generation sequencing, including panel-based, whole-exome, and whole-genome sequencing. Phenotype-driven testing strategies and standardized variant interpretation frameworks, such as the American College of Medical Genetics and Genomics guidelines, have substantially increased diagnostic yield. Copy number and structural variant detection, transcriptomics, and functional assays further help address unresolved cases. Nonetheless, barriers remain regarding cost, access, and the interpretation of variants of uncertain significance. Molecular confirmation has become essential for access to novel gene-directed therapies, exemplified by voretigene neparvovec for biallelic RPE65 variants, and is often a prerequisite for clinical trial participation. The growing role of genetic testing highlights the need for multidisciplinary evaluation and standardized outcome measures. Emerging tools, including artificial intelligence-assisted variant prioritization, image-to-genotype modeling, and multi-omics analyses, bridge molecular diagnoses with clinical phenotypes, accelerating the transition to targeted therapies. Continued progress will depend on increased access, standardized analytical regulations, and the integration of emerging technologies into routine clinical care. Full article

Inherited retinal dystrophies (IRDs) comprise a diverse group of genetic disorders that frequently result in irreversible vision loss due to photoreceptor dysfunction or degeneration. Among them, retinitis pigmentosa (RP) and achromatopsia (ACHM) are, in some cases, associated with pathogenic variants in PDE6A and PDE6C, respectively, which are key components of the phototransduction cascade. As most of IRDs still lack effective therapies, retinal organoids (ROs) provide a valuable in vitro model for the investigation of disease-associated mechanisms. Here, we generated induced pluripotent stem cell (iPSC)-derived ROs from an RP patient carrying compound heterozygous PDE6A mutations and from a patient with ACHM harboring a homozygous PDE6C mutation, along with their corresponding CRISPR/Cas9-corrected isogenic controls, which, to our knowledge, represent the first patient-derived RO models reported for the PDE6A and PDE6C genes. The mutant PDE6A line exhibited impaired neuroretinal vesicle formation and RO differentiation; however, a subset of RP-derived ROs matured appropriately and retained photoreceptor features. Moreover, the specific isoform expression pattern detected in retinal tissues reflected differences across developmental maturation stages that could influence disease severity. In contrast, the PDE6C_mutant ROs displayed normal structure and maturation, although cGMP hydrolysis within photoreceptors was likely compromised. In both models, CRISPR/Cas9-mediated correction restored the disease-associated phenotype resembling wild-type ROs. Collectively, these findings provide new insights into PDE6-associated pathogenesis, underscore the utility of patient-specific and gene-corrected ROs for elucidating IRD mechanisms, and support gene editing as a promising therapeutic strategy. Full article

Background/Objectives: The current study was designed to identify the underlying genetic causes of congenital stationary night blindness (CSNB) in the indigenous consanguineous families from the Southern Punjab region of Pakistan, a population where the inherited retinal disorders are relatively common. Methods: A detailed questionnaire and medical examination were done to check the presence of CSNB in the affected individuals of the enrolled families. Whole-exome sequencing (WES) was performed to identify the pathogenic variants, followed by segregation analyses to confirm the segregation of the identified variants with the disease phenotype in the available affected individuals of the families. Results: We identified two novel and three known pathogenic variants in SAG, GRK1, TRPM1, SLC24A1, and GPR179, having established roles in CSNB. Two novel variants, NM_001252020.1 (p.Gly1020Arg) and NM_001004334.3 (p.Trp508Ter), were identified, and their segregation was confirmed in two families, PKIURP102 and PKIURP564, respectively. NM_002929.3 (p.Arg19Ter) and NM_001301032.1 (p.Phe538CysfsTer23) were the reported variants identified in PKIURP17 and PKIURP528 families, respectively. NM_000541.5 (p.Glu306Ter) was identified in two independent families, PKIURP552 and PKIURP565. Conclusions: Identification of five pathogenic variants in five different genes shows the genetic heterogeneity of CSNB in Pakistani patients. Our findings also expand the mutational spectrum of CSNB in the Pakistani population and may help in the identification of mutational hotspots and may help in the genetic diagnosis of CSNB in consanguineous populations. Full article

Background: Non-syndromic retinitis pigmentosa (RP) is characterized by rod–cone degeneration, resulting in night blindness, visual field constriction, and eventual blindness. Recessively inherited RP is predominantly exacerbated in consanguineous populations, such as Pakistan. This study aimed to perform the genetic analysis of sixteen non-syndromic RP segregating Pakistani families, and to summarize the mutation spectrum of non-syndromic RP in our population by reviewing related literature. Methods: We screened 16 non-syndromic RP families using targeted capture panel sequencing of 344 genes related to inherited retinal dystrophies. Variants were prioritized based on rarity (minor allele frequency (MAF) < 0.001 in the gnomAD South Asian subset), pathogenicity assessments using ACMG/AMP criteria, and REVEL scores (>0.5). Candidate variants were validated for familial segregation through Sanger sequencing. Results: We identified 15 distinct variants across 14 genes associated with non-syndromic retinitis pigmentosa, comprising 6 missense, 7 nonsense, 1 frameshift, and 2 splice-site variants, including 4 novel variants, i.e., p.(Val220Met) and p.(Pro1282SerfsTer2) in RP1, 1 each in PDE6B (c.2021+5G>A), and PRCD p.(Ser38Ter). Homozygosity predominated, underscoring the impact of consanguinity on the burden of autosomal recessive disease in the present cohort, while the CERKL disease-causing mutation, i.e., p.(Arg257Ter), recurred in two families. Conclusions: This study expands Pakistan’s non-syndromic RP mutational spectrum by identifying novel variants in RP1, PDE6B, and PRCD, alongside recurrent CERKL and RHO mutations of the local population. The literature review suggests that RP1, TULP1, and PDE6B are among the most mutated genes in our population, supporting the value of population-specific genetic panels to enhance diagnostics and carrier screening. Full article

Prominin-1 (Prom1/CD133) has long been recognized as a structural determinant of photoreceptor outer segment (OS) morphogenesis, yet rapidly accumulating evidence extends its role to retinal pigment epithelium (RPE) homeostasis, encompassing autophagy–lysosomal flux, outer segment phagocytosis, mitochondrial function, and regulation of inflammatory stress. This review synthesizes mechanistic and transcriptomic insights that position PROM1 as a central regulator of photoreceptor and RPE integrity, reframing Prom1 disease as a multi-compartment retinal disorder relevant to both inherited retinal dystrophies (IRDs) and atrophic age-related macular degeneration (aAMD). We develop a dual-axis conceptual model in which Prom1 dysfunction can initiate pathology in either the photoreceptors (OS morphogenesis failure) or the RPE, including impaired autophagic flux, lysosomal activity, defective phagocytosis, and Epithelial-Mesenchymal Transition (EMT)-like de-differentiation, with secondary cross-compartmental degeneration. Clinically, autosomal-dominant missense variants associate with macular or cone-rod dystrophy, whereas biallelic truncating/splice-site mutations drive early-onset rod–cone disease and panretinal/RPE atrophy, illustrating genotype–phenotype diversity. By integrating recent high-resolution transcriptomic data from Prom1-deficient RPE cells with long-standing insights into photoreceptor biology, we highlight converging pathways of degeneration that challenge a photoreceptor-centric view and unify disparate phenotypes within a single molecular framework. These insights broaden the therapeutic landscape, advancing gene augmentation and pathway-targeted strategies to preserve RPE integrity, sustain photoreceptor function, and modify disease course in PROM1-associated IRDs and atrophic AMD. Full article

Background: Retinal and optic nerve disorders are a leading cause of irreversible visual impairment worldwide. Advances in molecular genetics—including next-generation sequencing, genome-wide association studies, and gene-based therapeutic technologies—have reshaped understanding of both inherited and complex retinal diseases. However, translating genetic discovery into sustained clinical benefit remains biologically and practically constrained. Methods: A structured literature search was conducted using PubMed and Scopus to identify relevant studies published between 2015 and 2025. The search focused on molecular genetics, epigenetic modulation, mitochondrial biology, and translational applications in inherited retinal dystrophies and selected complex retinal diseases, prioritizing high-impact original research and systematic reviews addressing diagnostic innovation and therapeutic development. Results: Inherited retinal dystrophies represent the most advanced model of precision ophthalmology, with diagnostic yields approaching 70–80% in well-characterized cohorts. Gene augmentation and genome-editing strategies have demonstrated proof-of-concept efficacy, yet clinical benefit depends on residual cellular viability, delivery efficiency, and durability of expression. Emerging platforms include AAV-mediated gene transfer, in vivo CRISPR-based editing, RNA-directed splice modulation, and mitochondrial-targeted approaches. Persistent barriers include unresolved non-coding and structural variants, variant interpretation uncertainty, and endpoint selection in clinical trials. In contrast, complex retinal diseases such as glaucoma, age-related macular degeneration, and pathological myopia reflect polygenic susceptibility interacting with environmental and aging-related factors. Although polygenic risk scores refine probabilistic prediction, their utility is limited by ancestry bias and incomplete predictive performance. Epigenetic and mitochondrial mechanisms further modulate disease expression but remain largely non-actionable in routine practice. Conclusions: Retinal genetics has progressed from gene discovery to early therapeutic implementation. Future advances will depend on improved variant detection, functional validation, biomarker-guided staging, and integration of genomics with imaging and longitudinal modeling to achieve durable and equitable precision ophthalmology. Full article

Background/Objectives: Inherited retinal diseases (IRDs) represent a genetically heterogeneous group of disorders caused by mutations in over 280 genes with more than 3100 identified variants. While gene-specific replacement therapies have achieved landmark success with voretigene neparvovec (Luxturna) for biallelic RPE65-associated retinal dystrophy, developing individual therapies for each genetic subtype remains impractical. This review examines gene-agnostic therapeutic approaches utilizing neuroprotection and immunomodulation that target common pathophysiological mechanisms shared across multiple IRD genotypes. Methods: We reviewed the literature on neuroprotective and immunomodulatory gene therapy strategies for IRDs, focusing on neurotrophic factors and complement system modulation. Results: Neuroprotective approaches delivering neurotrophic factors—including pigment epithelium-derived factor (PEDF), ciliary neurotrophic factor (CNTF), rod-derived cone viability factor (RdCVF), brain-derived neurotrophic factor (BDNF), fibroblast growth factors (FGFs), glial cell line-derived neurotrophic factor (GDNF), and proinsulin—have demonstrated photoreceptor preservation across multiple preclinical IRD models regardless of the underlying genetic mutation. The recent FDA approval of CNTF cell-based gene therapy (Encelto) for macular telangiectasia type 2 validates this therapeutic paradigm. Complement system inhibition represents another gene-agnostic strategy, with intravitreal complement inhibitors approved for geographic atrophy secondary to age-related macular degeneration and gene therapy approaches targeting C3, C5, or delivering soluble complement regulators under investigation for IRDs. Combination strategies simultaneously addressing multiple pathogenic pathways may offer synergistic benefits. Conclusions: Gene-agnostic approaches targeting neuroprotection and immunomodulation offer a therapeutic paradigm capable of benefiting patients across the spectrum of IRD genotypes, potentially transforming treatment for conditions where mutation-specific therapies remain unavailable. Full article

Background: Heimler syndrome (HS) is a rare autosomal recessive disorder representing the mildest end of the peroxisome biogenesis disorder spectrum. It is caused by hypomorphic mutations in peroxisomal assembly genes, most commonly PEX1 and PEX6, and is characterized by sensorineural hearing loss, amelogenesis imperfecta, and retinal dystrophy. Due to phenotypic overlap with other inherited sensory disorders, particularly Usher syndrome, diagnosis of this condition is frequently delayed. Methods: We investigated two unrelated Saudi families presenting with congenital hearing loss and retinal dystrophy who were initially diagnosed with Usher syndrome. Detailed clinical evaluation, including comprehensive ophthalmologic and audiologic assessments, was performed. Whole-exome sequencing (WES) was conducted to identify the underlying genetic cause, followed by variant filtering and in silico pathogenicity prediction. Results: We identified a novel homozygous missense variant, p.Val97Gly (V97G), in the PEX6 gene that co-segregated with the disease phenotype in both families. This variant was absent from major population databases, including dbSNP, the 1000 Genomes Project, ExAC, and gnomAD, and was predicted to be deleterious by multiple in silico prediction tools. Clinically, affected individuals presented with congenital sensorineural hearing loss, pigmentary retinal dystrophy with electrophysiological evidence of cone–rod dysfunction, enamel abnormalities consistent with amelogenesis imperfecta, and mild dysmorphic facial features, supporting a diagnosis within the Heimler syndrome spectrum. Conclusions: Our findings expand the mutational spectrum of PEX6 and highlight Heimler syndrome as an important differential diagnosis in patients presenting with Usher-like phenotypes. To the best of our knowledge, this study represents the first report of the PEX6 p.Val97Gly variant associated with Heimler syndrome in a Saudi population, underscoring the value of whole-exome sequencing for accurate diagnosis and genetic counseling in individuals with inherited sensory disorders. Full article

Mitochondrial reactive oxygen species (mtROS) play a dual role in retinal physiology, acting as essential redox signalling mediators under homeostatic conditions but driving oxidative damage and neurodegeneration once regulatory thresholds are exceeded. Owing to the exceptionally high energetic demands of retinal neurons and supporting cells, even subtle perturbations in mitochondrial redox balance can precipitate progressive retinal dysfunction. Increasing evidence indicates that retinal neurodegenerative diseases, including glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), and inherited optic neuropathies, are characterised not by uniform oxidative stress, but by disease- and stage-specific mtROS signatures shaped by mitochondrial quality control capacity. This review synthesises current insights into the sources, regulation, and signalling functions of mtROS in the retina, with particular emphasis on threshold-dependent redox transitions, reverse electron transport, and the progressive failure of mitochondrial quality control mechanisms, including mitophagy, mitochondrial dynamics, and redox-responsive transcriptional networks. The limitations of non-selective antioxidant strategies are critically examined, highlighting why indiscriminate ROS suppression has yielded limited clinical benefit. In contrast, emerging therapeutic approaches aimed at recalibrating mitochondrial redox homeostasis, rather than abolishing physiological signalling, are discussed in the context of disease stage, metabolic state, and mitochondrial competence. By integrating redox biology with mitochondrial quality control and precision medicine concepts, this review proposes a unifying framework in which retinal neurodegeneration is governed by regulated mtROS signalling and the progressive exhaustion of mitochondrial resilience. This model defines critical therapeutic windows for mitochondria-targeted intervention and provides a framework for biomarker-guided patient stratification. Full article

Genome editing has emerged as a transformative approach for understanding and treating retinal degenerative diseases. Combining this technology with pluripotent stem cells provides an ideal platform for modeling human development and disease, and investigating emerging therapeutic strategies ultimately aimed towards in vivo correction. This approach enables both functional studies to understand retinal degeneration and the early development of targeted therapies for inherited disease. This review offers a comprehensive overview of genome-editing techniques and the ability to create new clinically relevant models to understand human disease in retinal research, focusing on the use of the CRISPR-Cas9 system in induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), as well as highlighting recent advancements in base and prime editing. Gene editing in various retinal diseases is discussed in context of studies focusing on disease modeling or developing therapeutic strategies. Continued refinement of these techniques will be essential for advancing translational applications in retinal disease treatment. Full article

Background: Senior–Loken syndrome (SLS) is a rare autosomal recessive ciliopathy classically defined by the concurrence of nephronophthisis, frequently progressing to end-stage renal disease (ESRD), and retinal dystrophy, most commonly presenting as retinitis pigmentosa (RP). Given its phenotypic overlap with other renal–retinal syndromes, establishing a definitive diagnosis necessitates integrated clinical evaluation and molecular confirmation. Case Presentation: A 28-year-old Chinese female presented with a two-month history of binocular floaters. Her medical history was significant for ESRD of five years’ duration, managed with maintenance hemodialysis. Ophthalmic assessment revealed retinal pigment mottling along the inferior temporal arcades and generalized arterial attenuation. Spectral-domain optical coherence tomography demonstrated outer retinal thinning with loss of the ellipsoid zone at corresponding locations. Perimetry confirmed visual field constriction, and full-field electroretinography showed severely reduced rod- and cone-mediated responses. Genetic testing was performed and a pathogenic variant in the NPHP1 gene was identified. Segregation studies confirmed both parents as heterozygous carriers, consistent with autosomal recessive inheritance. Collectively, these findings established a diagnosis of SLS. Conclusions: This case reinforces that SLS should be considered in the differential diagnosis of any young patient exhibiting RP alongside chronic kidney disease, particularly in the setting of early-onset ESRD. It also illustrates the essential role of a coordinated, multidisciplinary approach—encompassing nephrology, ophthalmology, and genetics—in diagnosing complex ciliopathies. Genetic confirmation not only validates the clinical diagnosis but also provides a foundation for family counseling, prognostic stratification, and future eligibility for gene-specific therapeutic trials. Full article

Gene editing, particularly CRISPR/Cas technology, represents a promising approach for the treatment of rare genetic diseases, including inherited retinal dystrophies, for which effective therapies are largely unavailable. Despite extensive research investigating gene editing across a wide range of cell types, transient delivery of CRISPR/Cas components and efficient homology-directed repair (HDR) in differentiated cells remain challenging. In this study, we employed hiPSCs derived from patients with Stargardt disease or Best disease, carrying pathogenic variants in ABCA4 or BEST1, respectively, to explore gene editing in human models. CRISPR/Cas9 and Cas12 nucleases were delivered into hiPS-derived retinal pigment epithelium (RPE) and retinal organoids using lipoplexes and compared with electroporation. We evaluated transfection efficiency, sgRNA-mediated DNA cleavage, and HDR-based correction. Precise repair of the pathogenic BEST1 variant was successfully achieved in hiPS-derived RPE cells using both nucleases, with Cas12 yielding the highest efficiency, exceeding 10% of HDR correction. Edited RPE cells preserved normal morphology and expressed specific maturity markers. In contrast, retinal organoids exhibited moderate transfection efficiency but showed no detectable CRISPR/Cas-induced DNA cleavage, highlighting the need for further optimization of gene editing in more complex cellular tissues. This study demonstrates, for the first time, precise correction of a single-nucleotide mutation in patient-derived RPE using CRISPR/Cas9 and Cas12 delivered using lipoplexes. These findings underscore the therapeutic potential of CRISPR/Cas-based strategies for inherited retinal dystrophies and provide a proof of concept for future clinical approximations. Full article

This study compared real-world overall survival and the risk of physical comorbidities and mental health conditions among patients aged <65 years with versus without inherited retinal diseases (IRDs) in the United States (US). Optum^® Electronic Health Record data (January 2014–January 2023) were evaluated for IRD (patients with ≥2 medical visits with an IRD diagnosis; index date: second such medical visit) and non-IRD (patients without an IRD diagnosis; index date: random medical visit) cohorts. Baseline demographics were balanced between cohorts using propensity score matching (2:1). Outcome measures were overall survival (date of death due to any cause) and presence of physical comorbidities and mental health conditions (medical visit with a corresponding diagnosis code). In total, 4594 patients with IRD were matched to 9188 patients without IRD (mean age: 38.7 vs. 38.2 years, 53.9% vs. 55.1% female, mean follow-up: 53.1 vs. 52.8 months). Over 84 months, patients with versus without IRD had a 24% higher risk of death (overall survival: 95.8% vs. 96.7%; hazard ratio: 1.24; 95% confidence interval: 1.00–1.53; p = 0.046) and were at significantly higher risk for each evaluated physical comorbidity and mental health condition (all p < 0.05). The development of novel therapies is thus needed to address the clinical burden of IRD. Full article