Ophthalmic Genetics最新文献

Background: Poland Syndrome is primarily characterized by musculoskeletal anomalies, such as unilateral absence of the sternocostal head of the pectoralis major. Ocular associations with Poland syndrome are rare, and ADAMTSL4 mutations, typically linked to autosomal recessive ectopia lentis, have not been previously associated with this condition.

Case: We describe a 20-month-old female with left-sided Poland syndrome who presented with intermittent right eye pain and a history of progressive corneal clouding. Examination revealed bilateral ectopia lentis, buphthalmos, and elevated intraocular pressure. Genetic testing identified a homozygous ADAMTSL4 variant (c.767_786del20), a novel association with Poland syndrome. The patient underwent successful bilateral lensectomy and anterior vitrectomy, and management of glaucoma was initiated. Her monochorionic diamniotic (MCDA) twin, also harboring the same ADAMTSL4 mutation, exhibited bilateral ectopia lentis and underwent surgical intervention.

Discussion: This report is the first to document an association between Poland syndrome and an ADAMTSL4 mutation, potentially suggesting a shared underlying defect in microfibril assembly. These findings expand our understanding of the genetic and developmental complexities of Poland syndrome and underscore the importance of early ophthalmological evaluation in such patients.

Conclusion: This case highlights the significance of genetic and ocular investigations in Poland syndrome, contributing to knowledge on its broader phenotypic spectrum and potential genetic etiologies. Further research is warranted to elucidate the role of ADAMTSL4 in microfibril-related anomalies.

Background: Oguchi disease, a rare form of congenital stationary night blindness (CSNB), is an autosomal recessive inherited retinal disorder (IRD) caused by pathogenic variants in the SAG gene, which encodes arrestin-1, a key protein in the phototransduction cascade.

Materials and methods: We present a case of a 35-year-old male with nyctalopia, progressive central vision loss, and refractory CME.

Case presentation: A 35-year-old male presented with nyctalopia and progressive central vision loss. Evaluation revealed attenuated retinal vessels, peripheral pigmentary changes, and severe CME bilaterally. Despite treatment with carbonic anhydrase inhibitors and NSAIDS, CME persisted. Initial genetic testing identified a heterozygous pathogenic SAG variant (p.Arg193*), raising suspicion for autosomal dominant RP. However, advanced long-read sequencing revealed a second pathogenic intronic SAG variant (c.-29+3A>G) in trans with the initial variant, confirming a diagnosis of autosomal recessive Oguchi disease.

Introduction: Inherited retinal diseases (IRDs) are clinically and genetically diverse conditions whose heterogeneity makes molecular diagnosis challenging. These challenges can lead to interpretation discordance which has a particular impact on gene-targeted therapies for IRD.

Methods: Discordance was evaluated in a clinical testing cohort and in ClinVar. 140 sequence variants identified through genetic testing in a cohort of pediatric participations with IRD were reclassified using the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines for variant interpretation. ClinVar datasets from December 2, 2019 and January 3, 2022 for the gene RPE65 were analyzed for discordance.

Results: The discordance rate in the pediatric cohort was 22.2%. Discordance in ClinVar increased from 23.6% to 36.6%.

Discussion: Discordance in the pediatric cohort may have been impacted by subjective application of the ACMG/AMP guidelines and heterogeneity in IRD. Subjectivity in the guidelines, laboratory differences, and lack of interpretation review may have contributed to discordance in ClinVar. Work to improve interpretation for IRD should include better understanding of the genetic influences of IRD and optimization of the ACMG/AMP guidelines for this field.

Purpose: Familial exudative vitreoretinopathy (FEVR) is a category of vitreoretinal diseases with a broad phenotypic spectrum ranging from subclinical peripheral vascular changes to total retinal detachments. We report the clinical and molecular genetic findings in a 43-year-old patient whose ocular findings were consistent with retinitis pigmentosa but genetic testing indicative of FEVR.

Methods: The patient underwent serial examinations over a 12-year period that included fluorescein angiography, electroretinophysiologic testing, and molecular genetic testing using a retinal dystrophy panel.

Results: Repeated examinations demonstrated retinal pigmentary changes, arteriolar narrowing, and waxy disc pallor consistent with retinitis pigmentosa. Fluorescein angiography demonstrated peripheral non-perfusion, staining, and window defects, while electroretinogram and electro-oculogram were within normal limits. Genetic testing identified a novel heterozygous likely pathogenic nonsense variant in TSPAN12 gene, c.315T > A, p. (Cys105*).

Conclusions: This report highlights a novel TPSAN12 pathogenic variant causing atypical FEVR which manifests with a retinitis pigmentosa phenotype.

Purpose: Causal variants in the EYS gene are a major cause of retinitis pigmentosa (RP). However, treatment development for EYS-RP has been hindered due to the large size of the coding sequence and transcriptional complexity of the mRNA. Recently developed adenine base editors (ABEs), a form of CRISPR gene editing, offer another method to develop treatment for genetic diseases caused by G>A point mutations.

Materials and methods: This is a retrospective report describing a 73-year-old female with RP, who underwent clinical examination and retinal imaging. Genetic testing included sequencing of 111 known retinal genes and in silico prediction of pathogenicity of the identified variants. Availability and safety of ABE-mediated approaches to correct the patient variant were analyzed.

Results: Clinical evaluation revealed moderately advanced retinitis pigmentosa which had become symptomatic at 35 years of age. Genetic testing revealed a likely pathogenic homozygous EYS c.6192-1 G>A mutation, disrupting a canonical splice acceptor site. As a result, exon skipping with related frameshift deletion and introduction of a premature stop-codon in the forming mRNA is likely, leading to significantly truncated protein or total abolition of translated EYS. Multiple ABE approaches to correct the variant were detected.

Conclusions: In summary, we report a novel splice site variant in EYS in a patient with classical signs of RP. Further research is needed to develop safe and efficient treatment options for EYS-associated RP.

Purpose: The study aimed to identify pathogenic variants in the CHST6 gene in a cohort of Egyptian patients diagnosed with macular corneal dystrophy (MCD).

Methods: Sanger sequencing of the CHST6 gene was performed in 16 individuals affected by MCD from nine unrelated Egyptian families, as well as in their available first-degree relatives. Surgical management data for affected individuals were also collected.

Results: Nine different pathogenic or likely pathogenic variants were identified, three of which were novel. All affected individuals carried homozygous mutations, consistent with autosomal recessive inheritance. Parental consanguinity was documented in eight of the nine families. All patients required surgery to restore vision. The mean age at corneal grafting in the first eye was 32.7 ± 8.9 years (range 17-44 years).

Conclusions: This study broadens the genetic landscape of MCD by identifying novel CHST6 variants in an Egyptian cohort. The high rate of homozygosity highlights the significant role of consanguinity in shaping the genetic burden of rare diseases in Egypt and the wider Middle East and North Africa region.

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.