Search Results (33)

Rare genetic disorders of the central nervous system (CNS) remain some of the most complex and challenging diseases to treat for several reasons. Targeting the CNS, especially the brain, presents one of the greatest obstacles in gene therapy using adeno-associated virus (AAV) vectors. Although various AAVs have been identified for their ability to transduce different cells in the CNS, their effectiveness and efficiency are significantly limited by the presence of neutralising antibodies (NAbs) and restricted cargo capacity. Despite these challenges, our understanding of AAV structure and technological advances continue to enable researchers to develop innovative strategies that have resulted in groundbreaking, FDA-approved therapeutic products now available for Leber congenital amaurosis (LCA) (Luxturna^®), spinal muscular atrophy (SMA) (Zolgensma^®), and the two recent gene therapy products for aromatic L-amino acid decarboxylase (AADC) deficiency, Kebilidi^® and Upstaza^®, which currently hold FDA and EMA approval, respectively. This review aims to highlight recent advances in the field of AAV gene therapy for neurological disorders, identify research gaps, and suggest areas for future investigation to enable potential breakthroughs particularly in neurodegenerative, neurodevelopmental, and neuromuscular disorders. We foresee that more tissue- and cell-specific AAV vectors designed using AI-powered platforms will emerge to precisely and efficiently target specific brain regions, transforming how CNS disorders are treated. Full article

RPE65, an isomerohydrolase expressed in retinal pigment epithelium (RPE), is critical for the visual cycle. More than 115 missense variants of the RPE65 gene have been associated with Leber’s congenital amaurosis (LCA), a severe childhood retinal dystrophy. Due to high genetic heterogeneity, the variant-specific pathogenic mechanisms remain largely uncharacterized. In this study we focus on an LCA patient carrying compound heterozygous RPE65 variants (c.200T > G, c.430T > C), aiming to dissect the mechanistic/functional basis of mutated protein-driven retinal degeneration and evaluate gene therapy-mediated restoration using patient-specific hiPSCs-RPE (iRPE). Transient overexpression of wild-type/mutant RPE65 in HEK293T cells showed both variants markedly destabilize the RPE65 protein through the autophagosome–lysosome degradation pathway and its isomerohydrolase activity required for the retinoid visual cycle. We further established a patient-specific iRPE platform suitable for enzymatic activity analysis. Characterization of patient-specific iRPE cells revealed those compound heterozygous variants did not compromise iRPE morphology, most gene expression, or core canonical physiological features of iRPE. However, they significantly downregulate endogenous RPE65 protein abundance and dampen enzymatic function. Subsequently, we delivered RPE65 via adeno-associated viral (AAV) vectors driven by either the ubiquitous CMV promoter or RPE-specific VMD2 promoter into patient iRPE to validate therapeutic potency, and verified that exogenous RPE65 supplementation effectively restores deficient isomerohydrolase activity in this disease model. Collectively, this work elucidates the variant-specific pathogenesis of RPE65-associated LCA and preliminarily assesses the efficacy of gene augmentation, providing preclinical experimental evidence to support the referral of this patient for clinical RPE65 gene replacement therapy. Full article

Gene replacement therapy can be used for the treatment of hereditary retinopathies, such as retinol dehydrogenase 12 (RDH12)-associated Leber congenital amaurosis 13 (LCA13); however, the lack of animal models accurately mimicking the human disease phenotype requires the initial in vitro confirmation of therapy efficacy. Two synthetic serotypes (2.7m8 and PHP.S) of adeno-associated virus (AAV) were tested against the natural serotypes (5 and 9) with the aim of increasing the transduction efficiency and delivery of the green fluorescent protein (GFP) in HEK293 and ARPE-19 cells. The three most efficient serotypes were then used for the delivery of RDH12, followed by the assessment of its functional activity in the transduced cells. In the in vitro test system, a cassette encoding GFP and the wild-type (wt) RDH12 was delivered into ARPE-19 and HEK293 cells by rAAV 5, PHP.S, and 7m8 at 30K and 60K VG/cell. RDH12 mutants pThr155Ile (RDH12mut) and Met1* (RDH12sc) were used to mimic the RDH12-associated pathology. Transduction efficiency and protein expression were assessed by flow cytometry, fluorescence microscopy, and Western blotting. Percentages of AAV7m8-transduced GFP+ cells 1.5- and 6.4-times higher were observed as compared to AAV5 and AAV.PHP.S, respectively. 4-hydroxynonenal (4-HNE), more toxic to the cells with dysfunctional RDH12, was used on cells expressing the three RDH12wt versions. Following treatment with 100 μM 4-HNE, 2.6 (AAV5) and 8.8 (AAV7m8) times more cells co-expressing RDH12wt and GFP were alive as compared to the cells expressing only GFP. The number of live RDH12wt-expressing cells was also 32 and 9.6 times higher than that of RDH12sc-expressing cells and the negative control (NC), respectively. The developed approach enables the functional assessment of RDH12 replacement therapy only in rAAV-transduced cells and demonstrates that rAAV7m8 is the most efficient serotype for this purpose. Full article

Background/Objectives: Genetic variants in the cone–rod homeobox (CRX) gene, a transcription factor critical for the differentiation, function, and survival of photoreceptors, are a rare cause of inherited retinal diseases (IRDs). CRX-associated retinopathies can produce variable phenotypes, including Leber congenital amaurosis (LCA), maculopathy (M), cone-rod dystrophy (CRD), and rod-cone dystrophy (RCD), such as retinitis pigmentosa (RP). Based on clinical observations at our eye institute, we hypothesized that nasal retinal degeneration is a feature of CRX-associated maculopathy and M/CRD. Methods: We performed an IRB-approved, retrospective review of patients at our eye institute with CRX-associated retinopathy to assess the frequency of nasal degeneration and potential genotype–phenotype correlations. Results: A total of 15 patients with a CRX-associated retinopathy and meeting the inclusion criteria were identified (LCA 3, RCD/RP 2, M/CRD 10). Overall, nasal degeneration occurred in 8 of 15 patients (53.3%) in the cohort. Nasal retinal degeneration was seen in the M/CRD (6 of 10; 60.0%) as well as LCA groups (2 of 3; 66.6%). No significant differences in age, gender, or presenting visual acuity were observed between patients with and without nasal degeneration. Genetic variants associated with nasal degeneration are localized to both the homeobox motif and activation domain. Intronic variants were relatively more common in patients with nasal degeneration, while missense variants predominated in those without, although these differences were not statistically significant. Conclusions: We conclude that nasal degeneration is a feature of a subset of CRX-associated phenotypes, affects both genders, and can be caused by genetic variants in multiple locations and of various subtypes. Full article

Leber congenital amaurosis (LCA) is a severe inherited retinal disorder manifesting at birth or in early infancy, with a subset of cases linked to mutations in the aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) gene. Initially identified as the disease locus for LCA4, AIPL1 exhibits a retina-specific expression pattern. Its protein product is a unique member of the FKBP family, distinguished by its specific structural features and specialized functions. A wide spectrum of mutations in AIPL1 is associated with varying severities of retinal degeneration, implicating diverse pathogenic mechanisms. While the early onset and rapid progression of AIPL1-related disorders pose a therapeutic challenge, significant progress in gene therapy has unlocked promising avenues for effective treatment. This comprehensive review summarizes current findings to spark interest and pave the way for further studies in the therapy of AIPL1-caused retinal diseases. Full article

Non-syndromic Inherited Retinal Dystrophies (IRDs) are a set of degenerative retinal diseases that vary clinically and genetically, including Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). IRDs are a significant cause of vision loss in young adults globally. To date, more than 280 genes have been associated with IRD pathogenesis. This study aims to investigate the genetic basis of non-syndromic IRD in the Qatari population and to assess the diagnostic yield of various genetic tests through a retrospective cohort study. Our study identified 49 eligible patients with IRD, 61.2% of whom were Qatari. Rod-dominated phenotypes accounted for 51% of the hereditary retinal diseases in this cohort. Whole-exome sequencing with mitochondrial genome testing (WES Plus) was the most frequently utilized genetic test. A total of 55 variants were identified across 32 IRD-associated genes. Of the 49 cases, 34 (69.4%) were initially classified as solved, and an additional five were likely to be solved based on familial segregation analysis. Variants in the ABCA4 gene were the most commonly observed, present in eight patients, with the c.5882G>A variant being the most recurrent, identified in three of these cases. Specific genes exhibited recurrent variations, including pan-ethnic variants that are common across multiple populations. These variants merit prioritization in testing due to their global prevalence. WES is recommended as a first-tier test for non-syndromic IRD cases, as it accelerates diagnosis, facilitates earlier interventions, and provides a comprehensive genetic picture by incorporating information from family members. Moreover, our study highlighted the significance of performing family segregation analyses in identifying possible causative variants. This is the first genetic study of IRD in Qatar, laying the groundwork for further research on the epidemiology and genetics of non-syndromic IRD in this understudied region. Full article

Biallelic pathogenic variants in the CRB1 gene are associated with severe retinal dystrophies, including early onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA), retinitis pigmentosa (RP), cone–rod dystrophy (CORD), and macular dystrophy (MD). Despite growing research, scant genotype–phenotype correlations have been established. Here, we present two cases involving individuals that presented with cystoid macular oedema and high intraocular pressure, which were later diagnosed as CRB1-MD, demonstrating a mild and stable phenotype. Two unrelated patients of African heritage were included, a 7-year-old female (case 1) and a 25-year-old female (case 2), both presenting with ocular hypertension and cystoid macular oedema. Case 2 had a history of bilateral plateau iris, treated with laser iridotomy. Baseline visual acuity for case 1 was 0.66 logMAR in the right eye and 0.54 logMAR in the left eye. For case 2, visual acuity was recorded as 0.30 logMAR in both eyes. Genetic testing confirmed a homozygous c.2506C>A p.(Pro836Thr) variant in the CRB1 gene in both cases. Longitudinal follow-up over seven years revealed stable visual acuity, improvement of cystoid macular oedema, and effective intraocular pressure control with topical ocular hypotensive therapy. This study establishes a novel genotype–phenotype correlation between the c.2506C>A p.(Pro836Thr) variant and MD, suggesting a mild, stable disease course in homozygous cases. The findings also highlight a potential association of this variant with elevated IOP, expanding the clinical spectrum of CRB1-related ocular conditions. Early genetic diagnosis and regular ophthalmic monitoring are essential to optimise management and identify therapeutic opportunities in patients with mild CRB1-related phenotypes. Full article

Background: Leber congenital amaurosis (LCA) is a congenital onset severe form of inherited retinal dystrophy (IRD) and a common cause of pediatric blindness. Disease-causing variants in at least 14 genes are reported to predispose LCA phenotype. LCA is inherited as an autosomal recessive disease. It can be an isolated eye disorder or as part of a syndrome, such as Senior Loken or Joubert syndrome. Sequencing studies from consanguineous populations have proven useful for novel variants identification; thus, the present study aimed to explore the genetic heterogeneity of 15 consanguineous Pakistani families, each segregating a severe IRD phenotype using targeted next generation sequencing. Methods: This study enrolled 15 consanguineous families, each with multiple affected cases of retinal dystrophy phenotype. DNA was extracted from blood samples. Targeted panel sequencing of 344 known genes for IRDs was performed, followed by Sanger sequencing for segregation analysis. Results: Data analysis revealed a total of eight reported (c.316C>T and c.506G>A in RDH12; c.864dup and c.1012C>T in SPATA7, as well as c.1459T>C, c.1062_1068del, c.1495+1G>A, c.998G>A in the CRB1, LCA5, TULP1, and IFT140 genes, respectively) and four novel homozygous (c.720+1G>T in LCA5, c.196G>C in LRAT, c.620_625del in PRPH2, and c.3411_3414del in CRB1) variants segregating with disease phenotype in each respective family. Furthermore, a novel heterozygous variant of CRB1 gene, i.e., c.1935delC in compound heterozygous condition was found segregating with disease phenotype in one large family with multiple consanguinity loops. Conclusion: Comprehensive molecular diagnosis of 15 consanguineous Pakistani families led to the identification of a total of 5 novel variants contributing to genetic heterogeneity of LCA-associated genes and helped to provide genetic counseling to the affected families. Full article

Inherited retinal diseases (IRDs) are a clinically and genetically diverse group of progressive degenerative disorders that can result in severe visual impairment or complete blindness. Despite their predominantly monogenic inheritance patterns, the genetic complexity of over 300 identified disease-causing genes presents a significant challenge in correlating clinical phenotypes with genotypes. Achieving a molecular diagnosis is crucial for providing patients with definitive diagnostic clarity and facilitating access to emerging gene-based therapies and ongoing clinical trials. Recent advances in next-generation sequencing technologies have markedly enhanced our ability to identify genes and genetic defects leading to IRDs, thereby propelling the development of gene-based therapies. The clinical success of voretigene neparvovec (Luxturna), the first approved retinal gene therapy for RPE65-associated Leber congenital amaurosis (LCA), has spurred considerable research and development in gene-based therapies, highlighting the importance of reviewing the current status of gene therapy for IRDs, particularly those utilizing adeno-associated virus (AAV)-based therapies. As novel disease-causing mutations continue to be discovered and more targeted gene therapies are developed, integrating these treatment opportunities into the standard care for IRD patients becomes increasingly critical. This review provides an update on the diverse phenotypic–genotypic landscape of IRDs, with a specific focus on recent advances in the understanding of IRDs in children with infantile nystagmus syndrome (INS). We highlight the complexities of the genotypic–phenotypic landscape of INS-associated IRDs, including conditions such as achromatopsia, LCA, congenital stationary night blindness, and subtypes of retinitis pigmentosa. Additionally, we provide an updated overview of AAV-based gene therapies for these diseases and discuss the potential of gene-based therapies for underlying IRDs that lead to INS, offering a valuable resource for pediatric patients potentially eligible for ongoing clinical trials. Full article

Inherited retinal disorders (IRD) have become a primary focus of gene therapy research since the success of adeno-associated virus-based therapeutics (voretigene neparvovec-rzyl) for Leber congenital amaurosis type 2 (LCA2). Dozens of monogenic IRDs could be potentially treated with a similar approach using an adeno-associated virus (AAV) to transfer a functional gene into the retina. Here, we present the results of the design, production, and in vitro testing of the AAV serotype 9 (AAV9) vector carrying the codon-optimized (co) copy of aryl hydrocarbon receptor-interacting protein like-1 (AIPL1) as a possible treatment for LCA4. The pAAV-AIPL1co was able to successfully transduce retinal pigment epithelium cells (ARPE-19) and initiate the expression of human AIPL1. Intriguingly, cells transduced with AAV9-AIPL1co showed much less antiviral response than AAV9-AIPL1wt (wild-type AIPL1) transduced. RNA-sequencing (RNA-seq) analysis of trans-differentiated ARPE-19 cells transduced with AAV9-AIPL1co demonstrated significant differences in the expression of genes involved in the innate immune response. In contrast, AAV9-AIPL1wt induced the prominent activation of multiple interferon-stimulated genes. The key part of the possible regulatory molecular mechanism is the activation of dsRNA-responsive antiviral oligoadenylate synthetases, and a significant increase in the level of histone coding genes’ transcripts overrepresented in RNA-seq data (i.e., H1, H2A, H2B, H3, and H4). The RNA-seq data suggests that AAV9-AIPL1co exhibiting less immunogenicity than AAV9-AIPL1wt can be used for potency testing, using relevant animal models to develop future therapeutics for LCA4. Full article

The CRB1 gene plays a role in retinal development and its maintenance. When disrupted, it gives a range of phenotypes such as early-onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA), retinitis pigmentosa (RP), cone-rod dystrophy (CORD) and macular dystrophy (MD). Studies in CRB1 retinopathies have shown thickening and coarse lamination of retinal layers resembling an immature retina. Its role in foveal development has not yet been described; however, this retrospective study is the first to report foveal hypoplasia (FH) presence in a CRB1-related retinopathy cohort. Patients with pathogenic biallelic CRB1 variants from Moorfields Eye Hospital, London, UK, were collected. Demographic, clinical data and SD-OCT analyses with FH structural grading were performed. A total of 15 (48%) patients had EOSRD/LCA, 11 (35%) MD, 3 (9%) CORD and 2 (6%) RP. FH was observed in 20 (65%; CI: 0.47–0.79) patients, all of whom were grade 1. A significant difference in BCVA between patients with FH and without was found (p = 0.014). BCVA continued to worsen over time in both groups (p < 0.001), irrespective of FH. This study reports FH in a CRB1 cohort, supporting the role of CRB1 in foveal development. FH was associated with poorer BCVA and abnormal retinal morphology. Nonetheless, its presence did not alter the disease progression. Full article

Purpose: Gene therapy actually seems to have promising results in the treatment of Leber Congenital Amaurosis and some different inherited retinal diseases (IRDs); the primary goal of this strategy is to change gene defects with a wild-type gene without defects in a DNA sequence to achieve partial recovery of the photoreceptor function and, consequently, partially restore lost retinal functions. This approach led to the introduction of a new drug (voretigene neparvovec-rzyl) for replacement of the RPE65 gene in patients affected by Leber Congenital Amaurosis (LCA); however, the treatment results are inconstant and with variable long-lasting effects due to a lack of correctly evaluating the anatomical and functional conditions of residual photoreceptors. These variabilities may also be related to host immunoreactive reactions towards the Adenovirus-associated vector. A broad spectrum of retinal dystrophies frequently generates doubt as to whether the disease or the patient is a good candidate for a successful gene treatment, because, very often, different diseases share similar genetic characteristics, causing an inconstant genotype/phenotype correlation between clinical characteristics also within the same family. For example, mutations on the RPE65 gene cause Leber Congenital Amaurosis (LCA) but also some forms of Retinitis Pigmentosa (RP), Bardet Biedl Syndrome (BBS), Congenital Stationary Night Blindness (CSNB) and Usher syndrome (USH), with a very wide spectrum of clinical manifestations. These confusing elements are due to the different pathways in which the product protein (retinoid isomer-hydrolase) is involved and, consequently, the overlapping metabolism in retinal function. Considering this point and the cost of the drug (over USD one hundred thousand), it would be mandatory to follow guidelines or algorithms to assess the best-fitting disease and candidate patients to maximize the output. Unfortunately, at the moment, there are no suggestions regarding who to treat with gene therapy. Moreover, gene therapy might be helpful in other forms of inherited retinal dystrophies, with more frequent incidence of the disease and better functional conditions (actually, gene therapy is proposed only for patients with poor vision, considering possible side effects due to the treatment procedures), in which this approach leads to better function and, hopefully, visual restoration. But, in this view, who might be a disease candidate or patient to undergo gene therapy, in relationship to the onset of clinical trials for several different forms of IRD? Further, what is the gold standard for tests able to correctly select the patient? Our work aims to evaluate clinical considerations on instrumental morphofunctional tests to assess candidate subjects for treatment and correlate them with clinical and genetic defect analysis that, often, is not correspondent. We try to define which parameters are an essential and indispensable part of the clinical rationale to select patients with IRDs for gene therapy. This review will describe a series of models used to characterize retinal morphology and function from tests, such as optical coherence tomography (OCT) and electrophysiological evaluation (ERG), and its evaluation as a primary outcome in clinical trials. A secondary aim is to propose an ancillary clinical classification of IRDs and their accessibility based on gene therapy’s current state of the art. Material and Methods: OCT, ERG, and visual field examinations were performed in different forms of IRDs, classified based on clinical and retinal conditions; compared to the gene defect classification, we utilized a diagnostic algorithm for the clinical classification based on morphofunctional information of the retina of patients, which could significantly improve diagnostic accuracy and, consequently, help the ophthalmologist to make a correct diagnosis to achieve optimal clinical results. These considerations are very helpful in selecting IRD patients who might respond to gene therapy with possible therapeutic success and filter out those in which treatment has a lower chance or no chance of positive results due to bad retinal conditions, avoiding time-consuming patient management with unsatisfactory results. Full article

The photoreceptor outer segment is a highly specialized primary cilium that is essential for phototransduction and vision. Biallelic pathogenic variants in the cilia-associated gene CEP290 cause non-syndromic Leber congenital amaurosis 10 (LCA10) and syndromic diseases, where the retina is also affected. While RNA antisense oligonucleotides and gene editing are potential treatment options for the common deep intronic variant c.2991+1655A>G in CEP290, there is a need for variant-independent approaches that could be applied to a broader spectrum of ciliopathies. Here, we generated several distinct human models of CEP290-related retinal disease and investigated the effects of the flavonoid eupatilin as a potential treatment. Eupatilin improved cilium formation and length in CEP290 LCA10 patient-derived fibroblasts, in gene-edited CEP290 knockout (CEP290 KO) RPE1 cells, and in both CEP290 LCA10 and CEP290 KO iPSCs-derived retinal organoids. Furthermore, eupatilin reduced rhodopsin retention in the outer nuclear layer of CEP290 LCA10 retinal organoids. Eupatilin altered gene transcription in retinal organoids by modulating the expression of rhodopsin and by targeting cilia and synaptic plasticity pathways. This work sheds light on the mechanism of action of eupatilin and supports its potential as a variant-independent approach for CEP290-associated ciliopathies. Full article

To report the spectrum of Leber congenital amaurosis (LCA) associated genes in a large German cohort and to delineate their associated phenotype. Local databases were screened for patients with a clinical diagnosis of LCA and for patients with disease-causing variants in known LCA-associated genes independent of their clinical diagnosis. Patients with a mere clinical diagnosis were invited for genetic testing. Genomic DNA was either analyzed in a diagnostic-genetic or research setup using various capture panels for syndromic and non-syndromic IRD (inherited retinal dystrophy) genes. Clinical data was obtained mainly retrospectively. Patients with genetic and phenotypic information were eventually included. Descriptive statistical data analysis was performed. A total of 105 patients (53 female, 52 male, age 3–76 years at the time of data collection) with disease-causing variants in 16 LCA-associated genes were included. The genetic spectrum displayed variants in the following genes: CEP290 (21%), CRB1 (21%), RPE65 (14%), RDH12 (13%), AIPL1 (6%), TULP1 (6%), and IQCB1 (5%), and few cases harbored pathogenic variants in LRAT, CABP4, NMNAT1, RPGRIP1, SPATA7, CRX, IFT140, LCA5, and RD3 (altogether accounting for 14%). The most common clinical diagnosis was LCA (53%, 56/105) followed by retinitis pigmentosa (RP, 40%, 42/105), but also other IRDs were seen (cone-rod dystrophy, 5%; congenital stationary night blindness, 2%). Among LCA patients, 50% were caused by variants in CEP290 (29%) and RPE65 (21%), whereas variants in other genes were much less frequent (CRB1 11%, AIPL1 11%, IQCB1 9%, and RDH12 7%, and sporadically LRAT, NMNAT1, CRX, RD3, and RPGRIP1). In general, the patients showed a severe phenotype hallmarked by severely reduced visual acuity, concentric narrowing of the visual field, and extinguished electroretinograms. However, there were also exceptional cases with best corrected visual acuity as high as 0.8 (Snellen), well-preserved visual fields, and preserved photoreceptors in spectral domain optical coherence tomography. Phenotypic variability was seen between and within genetic subgroups. The study we are presenting pertains to a considerable LCA group, furnishing valuable comprehension of the genetic and phenotypic spectrum. This knowledge holds significance for impending gene therapeutic trials. In this German cohort, CEP290 and CRB1 are the most frequently mutated genes. However, LCA is genetically highly heterogeneous and exhibits clinical variability, showing overlap with other IRDs. For any therapeutic gene intervention, the disease-causing genotype is the primary criterion for treatment access, but the clinical diagnosis, state of the retina, number of to be treated target cells, and the time point of treatment will be crucial. Full article

This study aimed to investigate the clinical characteristics of Korean patients with retinal dystrophy associated with pathogenic variants of cone rod homeobox-containing gene (CRX). We retrospectively enrolled Korean patients with CRX-associated retinal dystrophy (CRX-RD) who visited two tertiary referral hospitals. Pathogenic variants were identified using targeted panel sequencing or whole-exome sequencing. We analyzed clinical features and phenotypic spectra according to genotype. Eleven patients with CRX-RD were included in this study. Six patients with cone-rod dystrophy (CORD), two with macular dystrophy (MD), two with Leber congenital amaurosis (LCA), and one with retinitis pigmentosa (RP) were included. One patient (9.1%) had autosomal recessive inheritance, and the other ten patients (90.9%) had autosomal dominant inheritance. Six patients (54.5%) were male, and the mean age of symptom onset was 27.0 ± 17.9 years. At the first presentation, the mean age was 39.4 ± 20.6 years, and best-corrected visual acuity (BCVA) (logMAR) was 0.76 ± 0.90 in the better eye. Negative electroretinography (ERG) was observed in seven (63.6%) patients. Nine pathogenic variants were identified, including two novel variants, c.101-1G>A and c.898T>C:p.(*300Glnext*118). Taken together with the variants reported in prior studies, all variants within the homeodomain are missense variants, whereas most variants downstream of the homeodomain are truncating variants (88%). The clinical features of pathogenic variants within the homeodomain are either CORD or MD with bull’s eye maculopathy, whereas variants downstream of the homeodomain cause more diverse phenotypes, with CORD and MD in 36%, LCA in 40%, and RP in 24%. This is the first case series in Korea to investigate the CRX-RD genotype–phenotype correlation. Pathogenic variants downstream of the homeodomain of the CRX gene are present as RP, LCA, and CORD, whereas pathogenic variants within the homeodomain are mainly present as CORD or MD with bull’s eye maculopathy. This trend was similar to previous genotype–phenotype analyses of CRX-RD. Further molecular biologic research on this correlation is required. Full article