Ophthalmic Genetics最新文献

This report presents the clinical and genetic findings of a patient with a de novo splice-site variant in the retinitis pigmentosa 2 (RP2) gene.A 32-year-old Japanese woman was experiencing night blindness and reduced visual acuity since her twenties. Her parents were not consanguineous, and she had no family history of ocular disease. Fundus examination revealed irregular-shaped degeneration and fundus autofluorescence imaging showed abnormal hypofluorescence in the area of the retinal degeneration. As whole exome sequencing on her and her parents revealed unremarkable in RetNet^TM genes, she was diagnosed as a sporadic case of retinitis pigmentosa (RP). However, subsequent whole genome sequencing revealed a heterozygous variant (c.102 + 2_102 + 5del) in the RP2 gene, but her parents did not carry the variant. Based on these clinical and genetic findings, we concluded that the patient was a symptomatic female carrier of RP2-associated RP.This report underscores the importance of comprehensive genomic analysis and family-based evaluation in uncovering hidden inheritance patterns, specifically in symptomatic female carriers of X-linked retinal dystrophies that initially appear sporadic. This study represents the first report to characterize the clinical phenotype associated with the splice-site variant c.102 + 2_102 + 5del in RP2.

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.

Objective: This study aims to describe the diagnosis and management of a case with bilateral anterior lenticonus.

Methods: A comprehensive ophthalmological assessment was performed on the proband, including: ultrasound biomicroscopy (UBM), optical biometric measurement, fundus photography, optical coherence tomography (OCT), visual field testing, and pure-tone audiometry. The patient subsequently underwent phacoemulsification with intraocular lens (IOL) implantation. Immunofluorescence analysis was utilized to assess the expression of the α5 chain of type IV collagen in the lens capsule. Whole exome sequencing (WES) of the proband complemented by Sanger sequencing validation of the parents was conducted to identify potential pathogenic variants.

Results: The proband exhibited binocular high myopia, with no significant improvement in visual acuity despite correction. UBM demonstrated anterior protrusion of the central lens area in both eyes. OCT revealed temporal retinal thinning in both eyes compared to the nasal retina. The corresponding protein was absent in the lens capsule of the proband. WES identified a novel variant (c.4821+2T>C: p.?) in the COL4A5 gene, and Sanger sequencing confirmed that the proband's mother was a carrier of this variant. The proband exhibited an absence of expression of the alpha 5 chain of type IV collagen (α5(IV)) in the lens capsule of the proband. Among various refractive calculation formulas, the aphakic formula demonstrated the smallest error.

Conclusion: A novel pathogenic COL4A5 splicing variant (c.4821+2T>C) was identified, which was associated with Alport syndrome. Furthermore, the aphakic formula may reduce refractive prediction error in cases of anterior lenticonus.

Aim: We describe the ophthalmologic findings in a patient with a disorder of sex development (DSD) and chromosome 2q22 duplication.

Methods: The patient underwent a comprehensive ophthalmologic examination including visual acuity testing, refraction, slit-lamp biomicroscopy, fundus examination, spectral-domain optical coherence tomography (SD-OCT), and fundus autofluorescence.

Results: Other than a large-angle left exotropia, the patient's corrected-distance visual acuity (CDVA) was 20/25 in the right and 20/40 in the left eye. Fundoscopy revealed small optic nerves on both sides, and venous tortuosity in both eyes. SD-OCT displayed normal foveal contour and retinal nerve fiber layer thickness bilaterally.

Conclusion: This is, to the best of our knowledge, the first detailed ophthalmologic report of a patient with DSD with 2q22 duplication with a presentation of a novel phenotype.

Introduction: Inherited retinal diseases (IRDs) are a leading cause of vision loss. Lack of awareness and reimbursement may prevent timely genetic testing, leading to delays in diagnosis, genetic counseling, and impeding life planning. We assessed healthcare costs and resource utilization (HCRU) relative to the timing of the genetic test.

Methods: Patients with a clinical IRD diagnosis who underwent a genetic test from 2017-June 2023 were identified from Optum's de-identified Clinformatics® Data Mart Database. Early testing was a genetic test ≤12 months, and Delayed Testing >12 months, after the first (index) ocular/retinal disorder diagnosis. All-cause HCRU from index until first genetic test date was assessed.

Results: 310 patients were included; 52.6% in the Early Test (mean age 45 ± 21.9 years), 47.4% in the Delayed Test groups (54 ± 22.5 years). Median time from index to genetic test was 101 and 847 days, respectively, with corresponding mean all-cause healthcare costs of $9,073 (±$24,258) and $75,553 (±$128,716), and mean ocular/retinal disorder-related costs of $2,899 (±$6,383) and $10,946 (±$32,801). The mean cost of genetic testing was US$585/patient.

Conclusions: Patients undergoing delayed vs early genetic testing incurred substantially higher HCRU. The cost to payers of genetic testing was markedly lower than the costs incurred when testing was delayed.

Aim: This study aimed to investigate the association of the TGFB1 -509C>T polymorphism with the development of Primary Open-Angle Glaucoma (POAG) and Primary Angle-Closure Glaucoma (PACG) in the Turkish population.

Methods: This study included patients from the Ophthalmology Departments of İzmir Katip Çelebi University and Ege University, divided into three groups: POAG (n = 115), PACG (n = 53), and control (n = 96). Detailed eye examinations and peripheral blood sample collections for DNA isolation were performed. The TGFB1 -509C>T polymorphism was evaluated via PCR amplification and sequencing analysis on the Illumina Miniseq platform.

Results: No significant differences were found among the groups regarding demographic characteristics. The POAG and PACG groups had significantly different intraocular pressure and cup/disc ratio compared to the control group. However, no significant association was found between the TGFB1 -509C>T polymorphism and the development of POAG or PACG in terms of allele frequency, genotype, and dominant/recessive model analysis.

Conclusion: In this study involving a well-defined Turkish sample, the TGFB1 -509C>T polymorphism was not associated with the development of POAG or PACG. However, given the limited sample size, especially in the PACG subgroup, these findings should be interpreted with caution. Further large-scale studies in broader Turkish populations are warranted to validate these results.

In an era of expanding sequencing technologies, increased variant identification requires assignment of potential functional impact to prioritize those that may be disease-causing. In this data note, we demonstrate the importance of using a refined human genome reference assembly and more diverse and curated population-based databases in guiding functional annotation of variants identified in inherited retinal disease (IRD) genes. We compared variant characteristics extracted from Genome Aggregation Database (gnomAD) population data extracted for 372 IRD disease genes from versions 3.1.2 (v3) and 4.1.0 (v4), which are aligned to the most recent Genome Reference Consortium Human Build 38 (GRCh38) as well as version 2.1.1 (v2), aligned to the previous GRCh37 build. Transformation of the Variant Effector Prediction (VEP), Combined Annotation Dependent Depletion (CADD) scores, and ClinVar pathogenicity annotations were used to generate receiver-operating characteristic (ROC) curves to calculate area under the curve (AUC) and area under the precision-recall curve (AUPRC). Comparisons of variant prediction by ClinVar designation showed that with improved functional annotation, the AUC climbs to 0.99 and AUPRC is 0.98 in differentiating pathogenic variants from nonpathogenic when using the most recent genome build and population database. More diverse population data allow for identification of rare variants and the incorporation of variant annotation metrics provides greater insight into pathogenicity parameters of IRD variants. This data note provides empirical evidence to adopt the newest genomic builds and databases to better prioritize variants as potentially disease-causing for more complete molecular diagnosis in IRD patients.

Introduction: A congenital optic nerve head anomaly (CONHA) is an umbrella term for structurally abnormal optic nerve heads present at birth which may lead to vision loss. The potential roles of motile and non-motile ciliopathies in this process are not well understood. This report describes a pediatric case of CONHA and implicates a motile ciliopathy in a possible mechanism that affects embryogenesis of the optic nerve head.

Case presentation: A 21-month-old male with a normal prenatal and postnatal course, past medical history of recurrent upper and lower airway infections, and no known ocular history was referred by a community ophthalmologist for evaluation of a dysplastic optic disc. After the initial visit, fundus examination at a subsequent EUA revealed a hypoplastic macula and an anomalous nerve. Evaluation by a pulmonologist at 32 months due to multiple airway infections revealed atopic dermatitis and moderate persistent asthma. Primary ciliary dyskinesia was ruled out.

Discussion: We theorize that this patient's fundus and systemic findings have a similar etiology. Differentiation of primary cilia on airway epithelial cells is known to produce motile cilia. We hypothesize that insults to a common cell may lead to disruption of three downstream pathways in our patient. The first line resulted in an atopic profile due to a disruption of motile ciliogenesis and mucociliary clearance. Second, disruption of primary cilia within the Sonic hedgehog pathway, a key regulator of neuronal development, may have resulted in a CONHA. Finally, the presence of abnormal primary cilia may have led to retinal dysplasia.

Conclusion: Linking systemic and ophthalmic findings can provide more insight into the role of motile cilia in other fundus conditions, allowing for targeted interventions. Thus, future research and gene therapy can work to prevent, or slow down, severe vision loss.

Purpose: To report clinical and imaging features of a pediatric patient with ACTA2 R179H 50 pathogenic variant using multimodal imaging.

Case report: A pediatric patient with a pathogenic ACTA2 variant presented with multisystemic 52 symptoms and prominently tortuous retinal vessels as seen on fundus photography, fluorescein 53 angiography, and optical coherence tomography angiography.

Conclusion: Non-invasive retinal imaging, including OCTA, may serve as a biomarker of 55 disease severity in pediatric patients. This approach allows for close monitoring of any vascular 56 changes over time.

Purpose: To investigate the clinical, imaging, electrophysiological, and genetic characteristics of male patients with RPGR-associated retinopathy exhibiting tapetal-like reflex (TLR) versus those without (non-TLR).

Methods: This retrospective observational study included 9 Indian males from 7 unrelated families with genetically confirmed pathogenic RPGR variants. Patients were divided into TLR (n=6) and non-TLR (n=3) groups based on fundus appearance. Multimodal imaging (fundus photography, fundus autofluorescence [FAF], optical coherence tomography [OCT]) and full-field electroretinography (ERG) were analyzed. Molecular genetic testing was performed to identify RPGR variants.

Results: The TLR group showed a characteristic golden, scintillating sheen with radial streaks on fundus exam. Median age of onset was 35 years with worse best-corrected visual acuity (BCVA) (0.66 LogMAR) and higher myopia (median -5.50 D) compared to the non-TLR group (23 years, 0.26 LogMAR, -1.00 D). FAF in the TLR group revealed central confluent or patchy macular atrophy surrounded by hyper-autofluorescence, whereas the non-TLR group exhibited widespread mid-peripheral degeneration and bull's eye maculopathy. OCT showed complete outer retinal atrophy (cRORA) in most TLR eyes and incomplete atrophy (iRORA) with preserved ellipsoid zone in the youngest patient. Non-TLR eyes demonstrated milder retinal atrophy with limited ellipsoid zone preservation. Full-field ERG demonstrated preserved scotopic but extinguished photopic responses in TLR eyes, while non-TLR eyes had extinguished photopic and severely reduced scotopic responses. All variants were hemizygous RPGR mutations in exon 15, predominantly frameshift or stop-gain mutations.

Conclusions: Tapetal-like reflex in male RPGR-associated retinopathy correlates with a cone-rod dystrophy-like phenotype featuring later onset, severe central atrophy, and predominant photopic dysfunction. In contrast, absence of TLR associates with rod-cone dystrophy-like features. Recognition of TLR may aid clinical classification, early diagnosis, and prognosis in RPGR-related retinal disease.