Ophthalmic Genetics最新文献

Purpose: To assess the detectability of the pathogenic RP1 Alu insertion using the PrismGuide™ inherited retinal dystrophy (IRD) panel, which targets 82 IRD genes, and whole-exome sequencing (WES).

Methods: A girl diagnosed with early-onset retinitis pigmentosa at age 7 underwent IRD panel testing and WES at age 15. Sequencing data from both platforms were evaluated using standard automated pipelines and manually reviewed with the Integrative Genomics Viewer (IGV). PCR and Sanger sequencing were performed for confirmation.

Results: Automated pipelines for both the IRD panel and WES failed to detect any reportable pathogenic variants. However, IGV review revealed a markedly reduced read coverage within exon 4 of RP1 in both datasets, suggesting the homozygous Alu insertion. PCR and Sanger sequencing confirmed the presence of the insertion. Thus, both short-read sequencing approaches failed to identify the variant.

Conclusions: Short-read sequencing technologies, including the IRD panel and WES, have limitations in detecting short interspersed nuclear elements such as the RP1 Alu insertion. This case emphasizes the importance of manual IGV review and the necessity of confirmatory Sanger sequencing when such structural variants are suspected despite negative automated analyses.

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: 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.

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: Fish-eye disease (FED) is a rare, autosomal recessive genetic disorder that can present at any age, from as early as the second decade of life to late adulthood. The hallmark clinical manifestation of FED is dyslipidemia and slowly progressive bilateral corneal opacification, which can impair vision quality due to highly elevated straylight. Here, we report the ophthalmic findings observed in FED by presenting a case that had been misdiagnosed for years until genetic testing was performed.

Methods: Case report.

Results: A 50-year-old patient presented with a 30-year history of subnormalvision, which had progressively worsened over the past two years, accompanied by intermittent episodes of bilateral ocular dryness. Ophthalmic examination revealed diffuse corneal haze despiterelatively well-preserved visual acuity. Anterior segment-opticalcoherence tomography (AS-OCT) imaging showed multiple areas of hyperreflective opacities bilaterally throughout the corneal stroma. A lipid panel revealed very low plasma high-density lipoproteincholesterol (HDL-C) levels. Subsequent genetic testing provided an explanation, identifying two novel variants in the LCAT gene, c.840_862dup, p.(Val288Alafs *130) and c.115A > T, p(Lys39*).

Conclusion: Ultimately, FED should be considered in the differential diagnosis of corneal clouding combined with low plasma HDL-C, which can be investigated using AS-OCT and confirmed through genetic interrogation of the LCAT gene.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease caused by mutations in the NOTCH3 gene. While it predominantly affects cerebral arterioles, emerging evidence indicates systemic vascular involvement. Ocular manifestations, particularly venous abnormalities such as branch retinal vein occlusion (BRVO), are exceedingly rare and not well characterized in CADASIL.

Case presentation: We report a case of a 63-year-old male presenting with decreased vision and floaters in the left eye. Multimodal imaging revealed macular edema, intraretinal hemorrhages, and superior temporal BRVO. Systemic risk factors were excluded. Genetic testing confirmed heterozygous pathogenic NOTCH3 variant c.317G>A (p.Cys106Tyr) and a variant of uncertain significance c.1774C>A (p.Arg592Ser). Based on this diagnosis, family members were referred for genetic counseling. The patient received intravitreal bevacizumab followed by dexamethasone implants due to recurrent cerebrovascular events and concerns regarding anti-VEGF systemic safety.

Conclusion: This case underscores that CADASIL-related vasculopathy may extend to the retinal venous system. Detailed ocular imaging can support early recognition of systemic microvascular disease. BRVO in CADASIL patients may represent an underrecognized manifestation, supporting the need for regular ophthalmic evaluation and interdisciplinary management.

Background and objectives: Rod-cone dystrophy (RCD), also known as retinitis pigmentosa, is the most common group of retinal dystrophies, affecting around 1:4,000 individuals worldwide. In the present work, we performed a copy number variation (CNV) analysis on next-generation sequencing (NGS) data from two Lebanese families with RCD, since no disease-causing mutations were identified through the analysis of single nucleotide variants (SNVs) and insertions/deletions (Indels). NGS, real-time PCR (qPCR), and chromosomal microarray were performed to identify, validate, and delineate the causative CNVs identified in both families involved in this study. Additionally, expression analysis using qPCR and western blotting was conducted to assess the effect of the PRPF31 variant on gene and protein expression levels.

Results: A novel heterozygous deletion (701 bp) spanning exons 6 and 7 of PRPF31 was identified in the first family (F11), resulting in autosomal dominant RCD due to haploinsufficiency. This was confirmed by reduced mRNA levels and the complete absence of protein expression in the affected individuals (F11:III.2 and F11:II.2). In the second family (F26), we identified a previously documented homozygous deletion in the exons 3-19 of MERTK gene, which is responsible for causing severe autosomal recessive RCD.

Conclusion: The current study expands the mutational spectrum of PRPF31 and MERTK genes, underscoring the importance of CNVs and haploinsufficiency in RCD etiology. These findings serve as a foundation for future analyses concerning gene augmentation therapies.

Background: Retinoblastoma, the primary ocular tumor in childhood, arises from the photoreceptor cells of the retina caused by pathogenic loss-of-function variants in both alleles of the RB1 gene, which can be either germline or somatic. The predisposition to hereditary retinoblastoma is primarily linked to germline variants in the RB1 gene.

Material and methods: Here, we describe a two-year-old girl from a Mennonite community who presented at 6 months of age with unilateral Group E retinoblastoma and underwent enucleation. She had a strong family history of cancer: a third elder sister deceased at age 4 with concurrent Burkitt lymphoma and medulloblastoma, and father diagnosed with carcinoid tumor at age 27.

Results: RB1 gene testing detected two pathogenic variants in the RB1 gene (c.299dup, c.1959del) in the tumor tissue. These variants were not identified in blood, indicating somatic changes. Testing of 49 genes associated with cancer predisposition identified a germline homozygous likely pathogenic variant in PMS2 (c.2095 G>T, p.Asp699His) in the proband, consistent with the diagnosis of constitutional mismatch repair deficiency (CMMRD). The proband's fourth elder sister who also tested homozygous for the PMS2 variant, was diagnosed with low grade glioma identified during screening as a part of surveillance for CMMRD.

Conclusions: This case highlights the importance of considering CMMRD in retinoblastoma with normal germline RB1 sequence, particularly with additional factors like family cancer history, consanguinity, or multiple childhood malignancies. Given retinoblastoma's association with CMMRD, screening for it in children with CMMRD is recommended.

Purpose: To describe a family with a previously unreported maculopathy across three generations.

Methods: This retrospective chart study describes three patients from three generations of a non-consanguineous Dutch family, with a distinctive maculopathy. All three patients underwent extensive ophthalmic examinations and multimodal imaging including best-corrected visual acuity, fundus photography, spectral-domain optical coherence tomography, fundus autofluorescence imaging, and full-field electroretinography (ffERG). Genetic analyses included next-generation sequencing, whole-exome sequencing, and single nucleotide polymorphism arrays.

Results: Three affected family members had a history of low visual acuity and congenital nystagmus, in combination with sharply demarcated areas of chorioretinal atrophy in the macula, which developed from early childhood. The two adult patients who underwent ffERG had cone and rod responses within normal limits, suggesting a central condition with a normally functioning retina extending beyond the lesions. No (likely) pathogenic variants in the known disease associated genes were found through extensive genetic analysis.

Conclusion: Pseudocolobomatous autosomal dominant atrophic maculopathy (PADAM) is a striking hereditary maculopathy that leads to progressive central vision loss. Future studies may provide additional insights into the genetic basis and underlying mechanisms of this remarkable clinical picture.