ABSTRACT Introduction Achromatopsia (ACHM) is a rare, inherited disorder in which patients cannot distinguish colors. The clinical phenotypes include light sensitivity, impaired color vision, partial or complete loss of photoreceptor function, reduced visual acuity and nystagmus. To date, six genes (CNGA3, CNGB3, GNAT2, PDE6H, PDE6C, and ATF6) are known to be the primary causes of ACHM, affecting the normal function of the cone photoreceptors. Methodology Whole-exome sequencing was performed in five families with 15 affected individuals. Candidate variants, prioritized using VARDIGS, were confirmed by Sanger sequencing and evaluated according to ACMG (2015) criteria. In-silico protein modeling and molecular dynamics simulations were employed to predict structural consequences of the variants. Results All affected individuals exhibited hallmark clinical features of congenital achromatopsia, including vision loss, photophobia, night blindness, color blindness, refractive errors (myopia/hyperopia), and nystagmus. Notably, progressive vision loss was observed in three families. Four homozygous pathogenic variants were identified: CNGA3:c.1641C > A p.(Phe547Leu), CNGB3:c.199_200delAC p.(Thr67GlnfsTer20), CNGB3:c.1214T > C p.(Leu405Ser), and PDE6C: c.1336 G > T p.(Glu446Ter), all consistent with cone dystrophies phenotypes. Conclusion Our findings expand the mutational spectrum of achromatopsia and other inherited retinal diseases. To the best of our knowledge, these variants have been reported for the first time in Pakhtun ethnic group of Pakistani population. The identification of pathogenic variants provides valuable insight for future research on gene therapy eligibility and personalized medicine.

ABSTRACT Purpose To report a genetically confirmed case of autosomal recessive bestrophinopathy (ARB) associated with angle-closure glaucoma (ACG) and complicated by central retinal vein occlusion (CRVO). Methods A 28-year-old man with a history of glaucoma and irregular follow-up presented with decreased vision and underwent comprehensive ophthalmic examination, multimodal imaging, and genetic testing. Results Best-corrected visual acuity was 0.1 in the right eye and counting fingers at 1 meter in the left eye. Both eyes demonstrated shallow anterior chambers, closed angles on gonioscopy, and short axial lengths. Fundus examination disclosed multifocal yellowish subretinal deposits in the right eye and dilated tortuous veins, extensive intraretinal hemorrhages, and macular edema in the left eye, consistent with CRVO. Optical coherence tomography showed mild cystoid change in the right eye and marked cystoid macular edema with subretinal fluid in the left eye. Fluorescein angiography revealed peripheral retinal ischemia. The left eye was treated with intravitreal anti-VEGF therapy, panretinal photocoagulation, and subsequently trabeculectomy for uncontrolled intraocular pressure; the right eye later underwent trabeculectomy. Genetic testing identified a homozygous likely pathogenic variant in BEST1. At 1-year follow-up, intraocular pressure was ≤12 mmHg in both eyes without medication. Conclusions This case highlights a rare coexistence of genetically confirmed ARB, ACG, and CRVO and underscores the importance of careful anterior and posterior segment evaluation in BEST1-related disease.

ABSTRACT Introduction: Cystic maculopathy (CM) occurs in 10–50% of inherited rod-cone retinal degenerations (RCD), with carbonic anhydrase inhibitors reported to show improvement, but rebound may occur. Alternate day treatment with topical Brinzolamide may alleviate this effect. We assessed treatment response in alternate day vs continuous day dosing.Methods: A retrospective chart review of patients with RCD undertaken, identifying those with CM, recording treatment regimen, vision, and OCT parameters. Outcomes were visual acuity (VA) improvement ≥3 letters significant, OCT reduction of mean cyst size (CMT) ≥11% significant, and macular volume (MV).Results: Of 260 patients identified, 66 (25.3%) had CM; complete data were available for 22 patients (41 eyes) in Group 1 (alternate day) and 12 patients (22 eyes) in Group 2 (continuous). In group 1, VA improved in 29% patients, with significant CMT mean reduction of 16 μm (80% eyes). Group 2 VA improved in 13.6% patients, with significant CMT mean reduction of 34 μm (77% eyes). No statistical difference between groups was found with VA or MV. Mean CMT reduction was significant in Group 2, 21 μm (p-value 0.034) and VA improvement was better with alternate day treat- ment.Discussion: This study suggests both treatment regimens have similar functional outcomes, enabling a tailored and patient-centric approach to dosing.

ABSTRACT Purpose: While diagnostic disparities by race and age of onset are reported in inherited retinal diseases, their impact on Stargardt disease (STGD)—a clinically and genetically heterogeneous macular dystrophy—remains unclear. Methods: We analyzed 246 STGD patients at a U.S. referral center (2003–2024) who completed genetic testing, comparing laboratory-reported results (lab-GT) with manual, phenotype-integrated reinterpretation (m-GT) of ABCA4 sequencing incorporating updated variant databases and genotype-phenotype correlation. Diagnostic yield and variant burden were assessed by race and age of onset. Results: Positive/likely positive (P/LP) lab-GT was identified in 79% (195), with 78% (191) attributable to ABCA4 (ABCA4-positive lab-GT: 57% [141]). M-GT increased ABCA4-P/LP yield to 91% (224). Black participants had lower ABCA4-positive lab-GT than White participants (55% vs. 73%) and fewer pathogenic variants; on multivariable analysis, Black race (OR 0.34) and later age of onset (OR 0.95/year) independently predicted reduced molecular diagnosis. The disparity by race resolved with P/LP m-GT (89% vs. 90%); by age of onset, yield remained lower in late-onset cases (ABCA4-P/LP lab-GT: 86% early- [≤10 yrs], 83% intermediate- [11–44 yrs], 54% late-onset [≥45 yrs], improving to 97%, 94%, and 77% after m-GT). Conclusion: Posttest reinterpretation improves diagnostic yield, particularly for Black and late-onset STGD patients, underscoring the value of ancestry-informed interpretation, historical reanalysis, and genotype-phenotype correlation.

ABSTRACT Purpose The study aimed to identify pathogenic variants in the CHST6 gene in a cohort of Egyptian patients diagnosed with macular corneal dystrophy (MCD). Methods Sanger sequencing of the CHST6 gene was performed in 16 individuals affected by MCD from nine unrelated Egyptian families, as well as in their available first-degree relatives. Surgical management data for affected individuals were also collected. Results Nine different pathogenic or likely pathogenic variants were identified, three of which were novel. All affected individuals carried homozygous mutations, consistent with autosomal recessive inheritance. Parental consanguinity was documented in eight of the nine families. All patients required surgery to restore vision. The mean age at corneal grafting in the first eye was 32.7 ± 8.9 years (range 17–44 years). Conclusions This study broadens the genetic landscape of MCD by identifying novel CHST6 variants in an Egyptian cohort. The high rate of homozygosity highlights the significant role of consanguinity in shaping the genetic burden of rare diseases in Egypt and the wider Middle East and North Africa region.

ABSTRACT Purpose This study aimed to report the clinical, electrophysiological, and genetic findings in two siblings of an Egyptian family with type 2 Oguchi disease, with multimodal imaging performed for proper evaluation. Methods Two siblings of consanguineous parents presented with poor night vision underwent full ophthalmological examination, ultra-widefield fundus photography, fundus autofluorescence (FAF) and spectral-domain optical coherence tomography (SD-OCT) of the macula, repeated fundus photography following dark adaptation for 3 hours and electroretinogram (ERG). Exome sequencing (ES) was performed for one patient and Sanger sequencing was then used for segregation analysis. Results The clinical findings and investigations were suggestive of the Oguchi disease phenotype. The ES revealed a homozygous stop gain variant, first time to be detected in Ouchi II patient, in exon 6 of the G-protein receptor kinase 1 (GRK1) gene, c.1338c>A: p.Cys446Ter. Conclusions These are the first molecularly confirmed patients from Egypt with Oguchi disease type 2. In addition, we identified a pathogenic GRK1 variant first time to be detected in Oguchi II patients expanding both the phenotypic and mutational spectrum of Oguchi disease.

ABSTRACT Introduction This study reports the ocular and systemic manifestations, genetic findings, and management approaches in 10 patients diagnosed with ligneous conjunctivitis (LC) and followed at a university hospital. Methods In this retrospective case series, medical records were retrospectively reviewed to collect demographic characteristics, age at diagnosis, family history, serum plasminogen (PLG) activity levels, ocular/systemic findings, and treatment modalities. Results Ten patients (7 females, 3 males; age range: 2–40 years) were followed for a mean duration of 9.4 ± 5.5 years. PLG activity was markedly reduced (18–25%) in six individuals. Systemic comorbidities included hydrocephalus (n = 3), gingivitis (n = 3), cervicitis/vaginitis (n = 4), menstrual irregularities (n = 2), infertility (n = 2), dacryocystitis (n = 2), epilepsy (n = 1), growth retardation (n = 1), deafness (n = 1), and brain tumor (n = 1). Whole-exome sequencing identified four distinct PLG variants, including homozygous pathogenic variants in five patients and a heterozygous variant in one. Treatment strategies involved pseudomembrane excision, topical heparin, corticosteroids, cyclosporine, and fresh frozen plasma (FFP). Systemic FFP was administered in selected cases. Additional procedures included amniotic membrane transplantation (n = 4) and cataract surgery (n = 3). Conclusion The diagnosis of LC is based on the integration of clinical and genetic findings, characterized by recurrent, firm pseudomembranes on the tarsal conjunctiva and often supported by a positive family history or parental consanguinity. Reduced PLG activity, histopathological confirmation of fibrin-rich membranes, and supportive genetic findings further substantiate the diagnosis.

ABSTRACT Purpose Case report describing electroretinography findings in a child with a pathogenic mutation in ATP1A3 Methods Details of this case were retrospectively reviewed. History was significant for progressive high myopia and alternating hemiplegia of childhood with a confirmed genetic diagnosis. Results Electroretinography findings demonstrated evidence of both rod and cone dystrophy in a child with a pathogenic mutation in ATP1A3 causing alternating hemiplegia of childhood Conclusions This report details a previously under-reported associated between mutations in ATP1A3 and retinal dystrophy. We believe that wider dissemination of these findings will help counsel patients and family members about vision loss that may be attributed to retinal rather than optic nerve findings.

ABSTRACT Background The 2p duplication syndrome is a rare clinically heterogeneous disorder that arises from non-recurrent chromosomal rearrangements involving ~6 Mb up to ~90 Mb. The patients are characterized by a wide range of symptoms, including developmental delay, intellectual disability, distinctive facial features, congenital heart defects, and various ophthalmic manifestations. Case presentation We report a male newborn with maternally inherited unbalanced translocations resulting in partial trisomy of chromosome 2p (33.9 Mb) - 46,XY,der(10)t(2;10)(p22.3;p1?5)dmat. Fluorescence in situ hybridization and chromosomal microarray analyses confirmed three copies of 2p25.3-p22.3 region, encompassing 51 known disease-causing genes. The patient presented with low birth weight, ventricular septal defect, camptodactyly of the 3rd digit of the left hand and mild early feeding problems. Ophthalmological assessment revealed macular and optic nerve hypoplasia. MRI demonstrated hypoplasia of the optic chiasm and optic nerves, and partial agenesis of falx cerebri. Conclusion We describe macular and optic nerve hypoplasia in a patient with a novel chromosomal rearrangement resulting in 2p partial trisomy and provide an overview of 17 previously reported cases presenting ocular abnormalities. A broad variability of ophthalmological phenotypes has been observed, further expanded by the current report.

ABSTRACT Introduction Variants in the RCBTB1 gene have recently been described in patients with inherited retinal disease; so far, there is limited knowledge about this entity, differential diagnoses, and disease progression. Here, we report a novel splice variant in RCBTB1 and describe the associated retinopathy. Methods Clinical assessment included multimodal imaging with optical coherence tomography, blue-light fundus autofluorescence, and near-infrared fundus autofluorescence. Atrophy progression was evaluated over time. Genetic testing was conducted by next-generation sequencing, pathogenicity was assessed by in silico analysis. Results A 54-year-old woman presented with a best-corrected visual acuity of 20/50 in the right and 20/63 in the left eye, respectively. Fundus examination showed macular and peripapillary atrophy with foveal sparing, as well as granular alterations extending to the mid-peripheral retina. Genetic testing revealed a novel splice variant (c.1325-2A>G) in intron 11 of RCBTB1. Discussion We confirm that RCBTB1-associated retinal dystrophy shares phenotypic similarities with mitochondrial retinopathy. Multimodal retinal imaging is vital to assess disease progression and may facilitate a better understanding of this pathology.