Ophthalmic Genetics最新文献

Background: Current diagnostic methods in Retinoblastoma (RB) rely on clinical and radiological examinations, which remain suboptimal, as there are non-RB cases with clinical and radiological features mimicking RB, leading to enucleation, which significantly affects patients' lives. As direct tumor biopsy is contraindicated due to the risk of metastasis, cell-free DNA (cfDNA) genetic analysis using aqueous humor (AH) liquid biopsy emerged as a promising minimally invasive alternative.

Materials and methods: A systematic literature search was conducted by the PRISMA 2020 guidelines across PubMed/MEDLINE, Embase, Scopus, and Web of Science up to March 6, 2025. Studies comparing genetic and molecular findings in matched AH and RB tumor samples were included, and of 436 initial records identified, 14 studies met the inclusion criteria after screening and eligibility assessment and were included in the analysis.

Results: Concordance analysis from published evidence revealed generally high concordance between AH cfDNA and tumor tissue for RB1 gene variants, SCNAs, and DNA methylation patterns. However, low cfDNA yield post-treatment, tumor heterogeneity, and differing genetic testing modality may affect the rate of detection. AH liquid biopsy demonstrates high comparability with direct tumor tissue analysis in examining key RB genetic and epigenetic alterations.

Conclusion: This review highlights the potential of AH liquid biopsy as a reliable surrogate for RB tumor biopsy, offering a minimally invasive approach to obtain crucial molecular information for RB diagnosis, treatment monitoring, and prognostication.

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.

Background: Ocular anomalies reported in FGFR2-related craniosynostosis include refractive errors, exophthalmos, and strabismus. Anterior segment anomalies have occasionally been reported in cases of FGFR2-related craniosynostosis.

Methods: We report a three-year-old boy with unilateral Peters anomaly, short stature, facial dysmorphism, posterior plagiocephaly, heart defects, and developmental delay. His maternal half-sister had bilateral posterior embryotoxon, dysmorphism, brittle teeth, umbilical hernia, developmental delay, heart defects, and microcephaly. Their mother had a normal slit lamp exam.

Results: A novel variant was found in FGFR2 (NM_000141.4: c.1376T>G p.(Met459Arg)) in the proband and maternal half-sister. No other variants of interest were identified in anterior segment genes. Incidentally, we identified a hemizygous variant in FGD1 (NM_004463.3: c.1292dupT p.(His432Profs*8)) in the proband; heterozygous in the mother.

Conclusion: FGD1 is associated with Aarskog-Scott syndrome (AAS) while FGFR2 is linked with 14 different phenotypes. The proband's features suggest AAS except for Peters anomaly and heart defects, which have been reported with FGFR2 variants. The shared novel FGFR2 variant suggests a dual diagnosis for the proband. Our findings support a role for FGFR2 in anterior segment development and broaden the genotypic and phenotypic spectrum of FGFR2-related disorders.

Aim: To report a case of Adams-Oliver Syndrome (AOS) presenting with retinopathy of prematurity (ROP)-like retinal findings and a novel homozygous mutation in the DOCK6 gene.

Methods: Single patient case report.

Results: A 6-week-old female infant with a premature birth at 35 weeks and birth weight of 1580 grams was referred to our clinic for presumed ROP stage 5 in the right eye and stage 4 in the left eye. Fluorescein angiography revealed peripheral avascular retina, abnormal vascular sprouts, and tractional retinal folds. Lens-sparing vitrectomy was performed, with subsequent surgical stabilization and ambulatory vision achieved during 60-month follow-up period. Genetic testing identified a novel homozygous mutation in the DOCK6 gene (c.4198_4199insATGG). The patient had mild systemic findings, including brachydactyly and nail hypoplasia, without significant dermatological, cerebral or cardiovascular anomalies. Family screening did not reveal any pathological findings, even on wide-field FA.

Conclusion: This case highlights the importance of genetic testing in atypical retinal vasculopathies resembling ROP. The findings expand the genotypic spectrum of DOCK6-related AOS and emphasize the need for multidisciplinary evaluation in similar presentations to guide accurate diagnosis and management.

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.

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.