ABSTRACT Background One of the conditions that might harm your eyesight is diabetic retinopathy (DR), DR may set in slowly but surely for those with long-term diabetes and poor glucose control. ‎ Objective To establish a connection between the various genotypes of the rs1800624 SNP and the rs80096349 SNP located in the AGER gene and DR patients. ‎ Methods The current case-control research examined one hundred thirty-four individuals diagnosed with type 2 diabetes and thirty-six healthy individuals who did not have DM. These samples were obtained from Amir Al-Muminin, a private hospital in Najaf, Iraq. The tetra primers ARMS-PCR method was utilized to determine the genotype of rs1800624 SNP of the AGER gene. Results A significant association was found between genotypes (AA, AG, and GG) and DR subgroups (NPDR & PDR) in patients (p = 0.001). The AG genotype of rs1800624 SNP is associated with a lowering the risk of developing NPDR (OR = 0.30; 95% CI = 0.12-0.74; p = 0.009 between controls and NPDR, OR = 0.36; 95% CI = 0.14-0.90; p = 0.029 between NDR and NPDR). HRM analysis verified the presence of only two genotypes in the samples: wild type (GG) and a heterozygous mutant (GA). However, a significant association between genotypes was observed when comparing DR status with controls and NDR (p = 0.031). Conclusion The rs1800624 SNP of the AGER gene is associated with the risk of NPDR and PDR in T2DM, and the polymorphism of the rs80096349 may be associated with retinopathy in the Iraqi population.

ABSTRACT Background Neurofibromatosis type-2-related schwannomatosis (NF2-SWN, formerly neurofibromatosis type 2) is a rare genetic disorder marked by the development of multiple nervous system tumors. Case Presentation We report a 21-month-old female patient who presented for left eye deviation. Upon examination, intermittent exotropia and a fundus mass were detected. Wide field fundus examination revealed the presence of a combined hamartoma involving the optic nerve and retina. This finding was supported by MRI highlighting the lesion’s characteristics. The patient’s father and other relatives on the paternal side displayed symptoms of NF2-SWN, evident through the presence of acoustic neuroma, although they did not exhibit any ocular symptoms. DNA analysis revealed a novel loss-of-function mutation in exon 15 of the NF2 gene (NM_000268.3: c.1627_1628del, p.Lys543Aspfs *21) in both the patient and her father at a heterozygous state. By the age of three, her vision worsened, and optical coherence tomography showed vitreomacular traction and intraretinal fluid surrounding the lesion. Conclusion This case underscores the need to consider NF2- SWN in peripapillary hamartoma diagnoses and highlights the importance of genetic testing for early detection and management.

ABSTRACT Background Danon disease is a rare, multisystemic X-linked dominant disorder caused by variants in the LAMP2 gene. It can be associated with retinal degeneration, but this is not well characterized. Here we describe a late presentation of a mild retinal phenotype, initially diagnosed as choroideremia carrier, associated with a novel variant in the LAMP2 gene. Methods Retrospective analysis of the case included medical history, ophthalmic examination, multimodal retinal imaging, and microperimetry. Genetic testing was conducted to establish the molecular diagnosis. Results A 54-year-old female presented with worsening night vision, without any family history. BCVA was 6/6 bilaterally and fundus examination showed light peripheral pigmentary changes bilaterally. FAF demonstrated a widespread speckled pattern and OCT revealed hyper-reflective spots in the outer nuclear layer. Differentials included non-genetic and genetic causes, suspected of being a manifesting choroideremia carrier. However, initial genetic testing by targeted analysis of retinal disorders did not detect a pathogenic variant. Further systems review revealed that the patient had previously been diagnosed with dilated cardiomyopathy, mini-stroke and partial deafness. Subsequent whole mitochondrial genome sequencing analysis did not detect any pathogenic variants too. Finally, whole exome sequencing with targeted analysis of a panel of hypertrophic cardiomyopathy genes identified a novel pathogenic heterozygous variant (c.925del, p.(Ser309fs)) in the LAMP2 gene, confirming the diagnosis of X-linked Danon disease. Conclusion Recording previous medical history and extraocular symptoms is crucial. The similarity in choroideremia carrier and Danon disease retinal phenotypes suggests a possible common pathway in these two genes where pathogenic variants lead to retinal pigment epithelium degeneration.

ABSTRACT Importance Alström syndrome is a rare genetic disorder characterized by retinopathy and has life-threatening complications. Alström syndrome is frequently misdiagnosed or confused with other early childhood disorders with retinopathy. Understanding the spectrum of ocular manifestations of Alström syndrome is essential for ophthalmologists to recognize the cause and institute-appropriate care for this disorder that requires multidisciplinary attention. Objective To quantify and summarize the common ocular findings of Alström syndrome Design Case series, clinical exam data obtained from 2015 to 2023 Setting Semiannual multidisciplinary Alström syndrome clinics (2015–2023) at the Greater Baltimore Medical Center (GBMC), organized by Alström Syndrome International (ASI) Participants Forty-eight patients (38 children, 10 adults) with a known diagnosis of Alström syndrome participated in the semiannual multidisciplinary Alström syndrome clinics. Patients apply to be seen and are accepted based on need and capacity. Intervention(s) or Exposure(s) Not applicable Main Outcome(s) and Measure(s) Clinical ocular findings Results Participants in this study had a median age of 8 years (15 months to 42 years). Visual acuity and progression of vision loss varied. The youngest patient who was legally blind was 2 years old. The oldest patient who maintained useful vision was 7 years old. All patients 8 years old or older were legally blind. Nystagmus (94%, 45 of 48) and photophobia (73%, 35 of 48) were the most common first presenting ocular symptoms in childhood. Retinal vascular attenuation (91%, 40 of 44) and retinal internal limiting membrane changes (68%, 30 of 44) were the most commonly documented retinal findings in both children and adults followed by optic nerve (ON) pallor and retinal pigment epithelium (RPE) mottling. Less than half of the children had ON pallor (38%, 14 of 37) and RPEmottling (38%, 14 of 37), while all adults had these two findings (100%, 7 of 7). Retinal pigment clumps were not common in children (11%, 4 of 37), while common in adults (86%, 6 of 7). Conclusions and Relevance Knowledge of these ocular findings is key to promptly recognize Alström syndrome. The ocular phenotype of Alström syndrome is largely dependent on age, suggesting that low vision interventions and potential gene-based therapeutics should target children with this disorder.

ABSTRACT Purpose The biallelic variant of MAB21L1 has previously been documented in conjunction with the autosomal recessive cerebellar, ocular, craniofacial, and genital syndrome (COFG). The purpose of this study was to investigate the gene-disease association of MAB21L1 and the newly discovered autosomal dominant (AD) microphthalmia. Methods We report the presence of an exceptionally rare missense variant in a single allele of the Arg51 codon of MAB21L1 among four individuals from a single family diagnosed with microphthalmia, which suggesting an autosomal dominant inheritance pattern. Subsequently, based on comprehensive literature review, we identified another 13 families that have reported cases of autosomal dominant microphthalmos. Results Genotype-phenotype analysis revealed that patients with a single allele missense variant in MAB21L1 exhibited solely eye abnormalities. This starkly diverged from the clinical presentation of COFG, typified by the concurrent occurrence of ocular and extraocular symptoms stemming from the biallelic variant in MAB21L1. Our findings revealed that the heterozygous pathogenic variant in MAB21L1 resulted in the emergence of autosomal dominant microphthalmia. By combining these genetic and experimental evidence, the clinical validity of MAB21L1 and the emerging autosomal dominant microphthalmia can be regarded as moderate. Conclusion In summary, there is sufficient convincing evidence to prove that MAB21L1 is a novel pathogenic gene responsible for autosomal dominant microphthalmia, thus offering valuable insights for precise diagnosis and targeted therapeutic interventions in cases of microphthalmia.

ABSTRACT Background Fleck corneal dystrophy (FCD) is a rare autosomal dominant disease that affects exclusively the corneal stroma. The disease is caused by heterozygous variants in PIKFYVE, a gene encoding a lipid kinase involved in multiple cellular pathways, primarily participating in membrane dynamics and signaling. This report describes a familial case of FCD caused by a complete deletion of the PIKFYVE gene. Material and methods A clinical ophthalmic examination was performed on the proband and family members. Genetic testing included next-generation sequencing (multigene panel), and chromosomal microarray analysis. A quantitative PCR assay was designed in order to segregate the deletion. Results A 19-year-old male, with no family or personal history of ocular disease, presented for evaluation due to an acute illness consisting of burning, foreign body sensation, and red eye. Slit lamp biomicroscopy revealed bilateral small pterygia and scattered bilateral white opacities in the corneal stroma, a very similar corneal phenotype was found in the 47-year-old father, who was asymptomatic. NGS detected a heterozygous deletion of the entire PIKFYVE coding sequence. CMA in DNA from the propositus indicated a 543 kb deletion in 2q33.3q34 spanning the entire PIKFYVE gene. The deletion was confirmed in the father. Conclusions We add to the molecular spectrum of FCD by describing a familial case of a whole PIKFYVE gene deletion in affected subjects. Our findings support that normal expression of PIKFYVE is necessary for corneal keratocytes homeostasis and normal corneal appearance. We conclude that PIKFYVE haploinsufficiency is the molecular mechanism underlying this familial case of FCD.

ABSTRACT Introduction Choroideremia (CHM) is an X-linked inherited retinal disease mostly affecting males. However, women with phenotypic and/or genotypic evidence of CHM may develop degenerative visual disability with advancing age. Our objective was to determine the visual impacts of phenotypic and/or genotypic evidence of CHM in women and its associated psychosocial burden and influence on activities of daily living (ADLs). Methods We conducted an international cross-sectional survey from April to December 2022 using an e-questionnaire distributed through not-for-profit stakeholder organizations and social media plat-forms. Results With a total of 55 respondents (n = 55), most women with phenotypic and/or genotypic evidence of CHM (76%) reported a change in their visual acuity. When assessing its impact on ADLs, Pearson’s correlation coefficient showed a negative correlation between driving (p = 0.046) and mobility capabil-ities (0.046) with the respondent’s age. More than half of women reported being afraid, anxious, and stressed, with women below the age of 50 years old reporting a significantly higher level of distress and hopelessness (p = 0.003), anxiety (p = 0.00007), issues with relaxing (p = 0.025), and negative personal thoughts (p = 0.042). Conclusion Overall, this survey outlines both physical and psychological burden of being a woman with phenotypic and/or genotypic evidence of CHM. Given the limited clinical research in females affected by CHM, this patient-centered survey is a crucial advocacy tool for these individuals.

ABSTRACT Background Congenital cataract is a common cause of blindness. Genetic factors always play important role. Material and Methods This study identified a novel missense variant (c.1412C>T (p.P471L)) in the EZR gene in a four-generation Chinese family with nuclear cataract by linkage analysis and whole-exome sequencing. A knockout study in zebrafish using transcription activator-like effector nucleases was carried out to gain insight into candidate gene function. Results Conservative and functional prediction suggests that the P-to-L substitution may impair the function of the human ezrin protein. Histology showed developmental delays in the ezrin-mutated zebrafish, manifesting as multilayered lens epithelial cells. Immunohistochemistry revealed abnormal proliferation patterns in mutant fish. Conclusions The study suggests that ezrin may be involved in the enucleation and differentiation of lens epithelial cells.

ABSTRACT Purpose This study aims to evaluate the ABCA4 variants in patients diagnosed with Stargardt disease. Methods This is a retrospective study designed to investigate variants in the ABCA4 in Stargardt disease and the clinical findings of the cases. Sex, age, age of onset of symptoms, best-corrected visual acuity, color fundus photography, optical coherence tomography, and visual field test of the patients were recorded. Genetic analyses were screened, and patients with at least two variants in the ABCA4 were included in this study. Results Twenty-seven patients diagnosed with Stargardt disease with the ABCA4 variants were included in this study. Twelve of them (44.4%) were female and fifteen (55.5%) were male. The mean age of the cases was 27.44 years (ranging from 8 to 56 years). Thirty different variants were detected in 54 ABCA4 alleles of 27 patients. The two most common pathogenic variants were c.5882 G>A p.(Gly1961Glu) and c.52C>T p.(Arg18Trp) in this cohort. Two novel variants were identified (c.3855_3856dup, c.1554 + 3_1554 + 4del) and the patient with the c.1554 + 3_1554 + 4del variant additionally had a different ABCA4 variant in trans. The other novel variant was homozygous. Conclusions In this study, two novel variants were described in a Turkish cohort with Stargardt disease. The variant c.52C>T p.(Arg18Trp) was the most common disease-causing variant besides the c.5882 G>A p.(Gly1961Glu) which was identified frequently in the previous studies. A larger sample size is necessary for describing different pathogenic variants and understanding the phenotype-genotype correlations.