Ophthalmic Genetics最新文献

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.

Background: Among the genes implicated in inherited retinal degenerations (IRDs), disease-causing variants in IDH3A have recently been reported, although they remain exceedingly rare. In some cases, these variants are associated with macular pseudocoloboma. IDH3A encodes the alpha subunit of the mitochondrial NAD⁺-dependent isocitrate dehydrogenase 3 (IDH3) complex, a key enzyme in the tricarboxylic acid (TCA) cycle.

Methods: Ophthalmic examination and whole-exome sequencing.

Results: We report the case of a 2-month-old female infant presenting with bilateral macular pseudocoloboma. Clinical examination showed age-appropriate visual behavior. Fundoscopy revealed well-defined atrophic lesions in the macula, retinal pigment epithelium (RPE) changes and vascular narrowing in both eyes. Whole-exome sequencing revealed that the patient appears to be homozygous for the NM_005530.3(IDH3A):c.364G>A (p.Ala122Thr) variant.

Conclusion: To our knowledge, this is the youngest reported patient with IDH3A-associated retinal dystrophy presenting with macular pseudocoloboma and expands the phenotypic spectrum of this disease.

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.

Introduction: Oculo-facio-cardio-dental (OFCD) syndrome is a rare X-linked dominant disorder caused by pathogenic BCOR variants and characterized by congenital cataracts, microcornea, and secondary glaucoma. Multilocus pathogenic variation (MPV), in which independent variants contribute to disease burden, can further complicate syndromic presentations and alter surgical planning. This case highlights the importance of longitudinal genetic evaluation in complex ophthalmic disease.

Methods: Comprehensive ophthalmic evaluation, multimodal imaging, and systemic assessment were performed. Trio exome sequencing was used as part of the genetic diagnostic work-up. Standard preoperative cardiovascular imaging was completed before planned glaucoma surgery.

Results: A 15-year-old female with OFCD exhibited congenital cataracts, bilateral microcornea, and persistent secondary glaucoma requiring multiple interventions. Trio exome sequencing confirmed a de novo pathogenic BCOR mutation and identified a paternally inherited pathogenic MYLK variant associated with thoracic aortic aneurysm and dissection. Although initially cleared for glaucoma surgery, routine preoperative screening revealed progressive ascending aortic dilation linked to the MYLKM variant, leading to postponement of ocular surgery due to increased anesthetic risk.

Discussion: This case demonstrates how MPV can significantly influence ophthalmic surgical decision-making. Genetic findings initially considered secondary became critical as cardiovascular risk evolved. Multidisciplinary coordination between ophthalmology and genetics is essential to integrate evolving genomic insights into perioperative care and ensure optimal patient safety.

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.

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.

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.

Purpose: Birt-Hogg-Dubé (BHD) syndrome 1 is caused by pathogenic folliculin (FLCN) variants, resulting in classic hair follicle tumors, pulmonary cysts, pneumothorax, and renal cancer. FLCN is expressed in retinal tissues, and previous reports of BHD described flecked chorioretinopathy, choroidal melanoma, chorioretinal atrophy, and retinal pigment epithelium microdetachments. FLCN has been implicated in numerous cellular processes of metabolism, autophagy, differentiation, ciliary function, and cellular adhesion.

Methods and findings: We performed a retrospective chart review of clinical information and imaging of patients with BHD from three centers and describe three patients who were found to have diffuse, abnormal, pinpoint foci observed across multiple retinal imaging modalities in both eyes (n = 6 eyes). These lesions were hypo- and hyperautofluorescent on fundus autofluorescence (FAF) and hypo- and hyperfluorescent on fluorescein angiography. Optical coherence tomography (OCT) revealed loss of inner retinal laminations, and numerous pinpoint hyperreflective lesions throughout the inner, middle, and outer retina which were seen in foveal, perifoveal, and peripheral retinal sections.

Conclusions: Mild retinal disorganization across multiple imaging modalities expands the ocular phenotype of BHD and likely arises from defects in cellular adhesion mediated by FLCN. Larger cohorts of patients with BHD may be necessary to establish these ocular imaging abnormalities as part of the BHD phenotypic spectrum.

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.