Ophthalmic Genetics最新文献

The gamma-tubulin ring complex (γ-TuRC) is a highly conserved and ubiquitously expressed complex necessary for proper microtubule nucleation and mitotic spindle function. While it is well established that the microtubule network plays a critical role in proper neurodevelopment, the clinical phenotypes associated with defects in the γ-TuRC have only been characterized recently. Generally, the neurologic features associated with γ-TuRC defects include microcephaly associated with chorioretinopathy (MCCRP), lissencephaly, cerebellar atrophy, motor and speech delay, and intellectual disability with variable severity. Prominent ocular features including microphthalmia, nystagmus, and abnormal retinal vasculature or vitreoretinopathy have been characterized in MCCRP related to defects specifically in two γ-TuRC proteins, TUBGCP4 and TUBGCP6. The purpose of this study is to provide a clinically oriented review of the γ-TuRC and the neuro-ophthalmic developmental disorders resulting from defects in this complex. At this time, it is unknown why affected patients only demonstrate neurologic and ophthalmic phenotypes despite the ubiquitous expression of this critical protein complex; this represents an important unmet clinical and basic research need. Ophthalmic genetics and pediatric ophthalmology specialists should be familiar with γ-TuRC-related disorders, particularly because of the need for multi-disciplinary care for these patients and the phenotypic similarities to other inherited retinal conditions.

In line with recent shifts to globe-saving and vision-preserving approaches in retinoblastoma (RB), evidence demonstrated that cell-free DNA (cfDNA) from aqueous humor (AH) has emerged as a method to gain RB tumor genetic information. This analysis enables comprehensive profiling of molecular markers that may be associated with RB progression, metastasis risk, and treatment response without the need for direct tissue biopsy, which carries significant metastasis risk. Thus, this systematic review was done to synthesize evidence on molecular markers associated with RB disease progression and treatment outcomes. From literature searches across MEDLINE, Embase, Web of Science, and Scopus, covering publications within the last 10 years, up to 15 February 2025, 23 studies were included in the analysis. Findings from studies showed that MYCN, chromosome 6p gain, survivin, TFF1, UBE2C, UBE2T, AURKA, and AURKB are correlated with RB tumor progression, invasiveness, metastasis risk, and/or chemotherapy resistance. The integration of AH liquid biopsy in RB management may aid prognosis prediction and optimize treatment strategies. However, further research is needed to validate the prognostic significance.

NR2E3 is a nuclear orphan receptor essential for photoreceptor development. Variants in the NR2E3 gene are associated with autosomal recessive retinitis pigmentosa 37 (RP37) and enhanced S-cone syndrome (ESCS). We report a novel NR2E3 variant in a family with RP37, aiming to clarify pathogenicity through clinical and genetic evaluation. The proband, a 26-year-old woman, experienced childhood-onset nyctalopia and progressive vision loss. Fundus exam revealed mid-peripheral pigment clumps and parafoveal depigmentation. Fundus autofluorescence showed widespread hypo-autofluorescent lesions; spectral-domain OCT identified outer nuclear layer thinning and ellipsoid zone loss. Full-field electroretinography confirmed severely diminished scotopic and photopic responses. Her 23-year-old sister had milder pigmentary changes and cystoid macular edema, while their 20-year-old brother's phenotype was less pronounced. All three siblings were homozygous for a novel missense variant in NR2E3 (NM_014249.4:c.352 G > C; p.Val118Leu), located within the DNA-binding domain. Both parents were heterozygous carriers. A previously reported variant affecting the same codon but resulting in a different amino acid change, along with its elevated allele frequency in East Asian populations, suggests a founder effect and supports its pathogenic potential. This report supports reclassifying NR2E3 c.352 G > C (NM_014249.4) as likely pathogenic. A comprehensive genotype-phenotype analysis remains essential for advancing our understanding of NR2E3-associated retinal dystrophies.

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.

We describe a novel missense variant in IMPG2 in a patient with early-onset rod-cone dystrophy with central macular atrophy and evaluate the potential of adenine base editing (ABE) as a therapeutic strategy. Ophthalmic evaluation included ultra-widefield fundus photography, fundus autofluorescence, and spectral-domain optical coherence tomography. Genetic testing was performed with a targeted next-generation sequencing panel and Sanger confirmation. Variant pathogenicity was assessed using in silico prediction tools, protein stability algorithms, and structural modeling. ABE feasibility was analyzed through PAM site identification and guide RNA design. Genetic testing revealed compound heterozygosity for a pathogenic nonsense variant (c.411G>A; p.Trp137*) and a novel missense variant (c.871C>A; p.Arg291Ser) within the SEA-1 domain. While in silico prediction tools classified p.Arg291Ser as benign or neutral, structural modeling and stability analyses supported a destabilizing effect. Base editing assessment indicated that c.411G>A is targetable with ABE. This case underscores the clinical relevance of domain-specific IMPG2 variants and the limitations of in silico predictions. ABE offers a promising therapeutic option for IMPG2-associated retinopathy.

Introduction: The aim was to uncover potential associations between the VEGF gene variants rs699947, rs833061, and rs3025039 and diabetic retinopathy (DR).

Methods: A total of 202 individuals with type 2 diabetes mellitus (T2DM) were divided into three groups: controls (T2DM without retinopathy), non-proliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR). Genotyping was performed using the PCR-RFLP assay.

Results: Allele and genotype frequencies did not show any significant difference among three groups (p > 0.05, all). Under recessive model in NPDR group CA genotype of rs699947 exhibited significantly lower HbA1c (%) and HbA1c (mmol) levels (p = 0.049, p = 0.048, respectively) compared to CC and AA genotypes. Under dominant model in NPDR group of rs699947, HbA1c (%) and HbA1c (mmol) levels were significantly higher in variant allele carriers compared to normal genotypes (p = 0.03, p = 0.031, respectively). Fasting plasma glucose (FPG) levels of normal rs699947 genotypes were significantly higher compared to variant genotypes in NPDR and PDR groups (p = 0.047, p = 0.023, respectively). Logistic regression analysis showed that the variations examined do not affect DR (p > 0.05, all).

Conclusion: In conclusion, as the first study in the studied ethnicity, we did not observe any association between DR an VEGF gene variations rs699947, rs833061, and rs3025039.

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.

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.