Ophthalmic Genetics最新文献

Purpose: To describe previously unreported ocular manifestations associated with a de novo PAX2 variant and emphasise their diagnostic significance in PAX2 related disorder.

Methods: A two month old boy underwent comprehensive ocular assessment (cycloplegic refraction, slit lamp biomicroscopy, axial length, and fundus imaging), full field and multifocal electroretinography, high resolution orbital MRI, and renal ultrasonography. Trio whole genome sequencing (WGS) was performed to identify pathogenic variants.

Results: Ophthalmic evaluation revealed asymmetric microcornea (9.5 mm OD, 10.8 mm OS), microphthalmos (axial length 17.1 mm OD, 18.4 mm OS), anterior segment dysgenesis with shallow anterior chambers, and high myopia (12.50 D OD, 10.75 D OS). Fundus photography demonstrated bilateral, steeply excavated optic discs bordered by circumferential peripapillary retinal pigment epithelium agenesis. Multifocal ERG showed markedly reduced central responses, consistent with bilateral macular pathway dysfunction; full field ERG was otherwise within age matched limits. Orbital MRI confirmed fusiform enlargement of the intra orbital optic nerves and colobomatous optic nerve head defects, with anomalous infra orbital optic nerve sheaths. Renal ultrasound was normal. Trio WGS identified a de novo heterozygous PAX2 frameshift variant, c.76dup p.(Val26GlyfsTer28), classified as pathogenic (ACMG criteria PVS1, PS2).

Conclusions: This case expands the phenotypic spectrum of PAX2 related disorder to include anterior segment dysgenesis, axial myopia, peripapillary RPE agenesis, and abnormal infra orbital optic nerve sheaths in the absence of renal hypodysplasia. Recognition of these atypical ocular findings should prompt targeted genetic testing for PAX2, facilitating accurate diagnosis, anticipatory renal surveillance, and informed genetic counselling.

EGF-containing fibulin extracellular matrix protein 1 (EFEMP1), or fibulin-3, is an extracellular matrix glycoprotein encoded by the EFEMP1 gene. The role of EFEMP1 in the human eye is incompletely understood, but there are well-reported associations between mutations in the gene and a variety of ophthalmic diseases, such as myopia, juvenile open-angle glaucoma (JOAG), primary open-angle glaucoma (POAG) and familial drusen formation in Malattia Leventinese (ML)/Doyne honeycomb retinal dystrophy (DHRD). Variants which interact with EFEMP1 have also been identified in genome-wide association studies (GWAS) for age-related macular degeneration (AMD). Many of these conditions form a large component of ophthalmology case-load and have incompletely characterized pathogenesis. In this review, we will describe the role of EFEMP1 in ophthalmic disease. We discuss the role of EFEMP1 in Mendelian eye disease, its polygenic contributions to common ophthalmic conditions, and the potential to target EFEMP1 for therapeutic purposes.

Purpose: Leber congenital amaurosis (LCA) and early-onset severe retinal degeneration (EOSRD) are inherited retinal diseases (IRDs) characterized by visual impairment beginning in infancy or childhood. This study aimed to describe the clinical and genetic characteristics of the first prospectively enrolled Singaporean patient cohort with disease-causing variants in genes associated with LCA, EOSRD, or related early-onset phenotypes.

Methods: Thirty-four patients from 30 families were prospectively recruited and underwent comprehensive clinical and genetic evaluation. Phenotypic classification and genotypic distribution were analyzed and compared with previously reported cohorts.

Results: Of the 34 patients, 24 presented with typical phenotypes of LCA (n = 12) or EOSRD (n = 11). Among the remaining cases carrying genotypes usually linked to LCA, 7 were diagnosed with retinitis pigmentosa, 3 with cone dystrophy, and 1 with macular dystrophy. The most frequently implicated gene was CRB1, detected in 8 families (26.7%), followed by RDH12 (16.7%), and CEP290 and NMNAT1 (10% each). This genetic distribution differs from those reported in Western populations. Clinical phenotypes were heterogeneous with respect to disease course, macular involvement, retinal structural alterations, and residual photoreceptor function.

Conclusions: This study represents the first report of a genetically confirmed cohort of LCA and EOSRD patients from Southeast Asia. The findings highlight a distinct genotypic spectrum compared with Western populations and underscore the extensive clinical heterogeneity of early-onset IRDs. These data provide a valuable foundation for patient stratification and planning of future gene therapy trials in the region.

Background: Optic nerve hypoplasia (ONH), the leading congenital cause of permanent blindness, is characterized by a retinal ganglion cell (RGC) deficit at birth and frequently associated neurologic and endocrine abnormalities. Multifactorial developmental events are hypothesized to underlie ONH; however, environmental influences are unclear, and genetic causes are under-investigated.

Methods: To identify monogenic, disease-causing variants among ONH patients, exomes from 34 ONH subjects and their parents were sequenced and rare variants identified. Inheritance-modelled variants were evaluated using population frequency, pathogenicity predictions, and mutational constraint metrics. Variants with the strongest genetic effect lacked evidence that they are monogenic and causal. All rare variants were filtered using mutational constraint metrics and pathogenicity predictions. The resultant variant-harboring genes were examined for recurrence within the cohort, gene ontology over-representation, RGC expression, and coincidence with neuro developmental disorder (NDD), autism, and previously proposed ONH genes.

Results: Mutationally constrained genes with potentially pathogenic mutations were enriched in gene ontologies related to neuro developmental processes, were expressed in RGCs at significantly higher levels than random exome variant genes, and were enriched in autism and NDD-associated genes. Including the genes with strong genetic effect variants, these analyses call attention to 161 genes with potentially pathogenic variants that may contribute polygenic risk for ONH.

Retinoblastoma is a pediatric ocular malignancy caused by biallelic inactivation of the RB1 gene, with genetic testing crucial for determining heritability. This retrospective observational study analyzed the genotypic and phenotypic profiles of 200 RB patients from North India who underwent genetic testing at a tertiary eye hospital between January 2022 and April 2024. Targeted RB1 gene analysis was performed using next-generation sequencing on blood samples, with methylation specific-multiplex ligation-dependent probe amplification detecting large deletions or duplications. Phenotypic features, including age of onset, laterality, disease severity, metastasis, and recurrence, were assessed. Among 200 patients, 113 had unilateral RB, 85 bilateral, and two trilateral, with mean onset ages of 33 months for unilateral and 14 months for bilateral cases. Intraocular tumors were present in 84%, extraocular extension in 16%, and metastasis in 16% of cases. Pathogenic RB1 variations were identified in 48% of patients, predominantly in bilateral cases (77.08%). A trend toward mutation clustering in exons 14-21 was observed in 57% of patients. While bilateral disease showed a statistically significant correlation with genotype for non-sense variations (p = 0.05); no other clinical features were linked to specific mutations. This study highlights unique regional genotypic patterns and emphasizes the potential for cost-effective testing strategies in resource-limited settings.

Purpose: Two patients with a suspected inherited retinal dystrophy (IRD) were referred to a specialist ophthalmology clinic for genetic testing to determine the cause of their disease.

Case report: A 50-year-old female patient (P1) presented with retinitis pigmentosa and poor vision since childhood. Molecular genetic testing in P1 revealed two novel pathogenic variants in PHYH (NM_006214.4): p.(Val93*) and p.(Asn71Ilefs*23). A 57-year-old male patient (P2) presented with pigmentary changes at the macula. Molecular genetic testing in P2 revealed two novel variants in PHYN: p.(Phe183Ser) and c.2461G>C (splice acceptor). Both patients were referred to the metabolic disease clinic and phytanic acid levels were found to be 256 µg/mL in P1 (normal is < 3 µg/mL) and 48.2 µmol/L in P2 (normal is < 2.2 µmol/L) confirming the diagnosis of Refsum disease. Both patients shared systemic features of the disease including bilaterally abnormal metatarsals and dry skin, while P1 also had characteristic anosmia, kidney disease, peripheral neuropathy and mild hearing impairment.

Conclusion: We document for the first time an association between macular dystrophy and Refsum disease. Early diagnosis is important so that diet can be modified to improve prognosis for the complications associated with Refsum disease, although improvements in vision, slowing the retinal degeneration and overcoming refractory miosis, are less achievable.

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.

Background: The 2p duplication syndrome is a rare clinically heterogeneous disorder that arises from non-recurrent chromosomal rearrangements involving ~6 Mb up to ~90 Mb. The patients are characterized by a wide range of symptoms, including developmental delay, intellectual disability, distinctive facial features, congenital heart defects, and various ophthalmic manifestations.

Case presentation: We report a male newborn with maternally inherited unbalanced translocations resulting in partial trisomy of chromosome 2p (33.9 Mb) - 46,XY,der(10)t(2;10)(p22.3;p1?5)dmat. Fluorescence in situ hybridization and chromosomal microarray analyses confirmed three copies of 2p25.3-p22.3 region, encompassing 51 known disease-causing genes. The patient presented with low birth weight, ventricular septal defect, camptodactyly of the 3rd digit of the left hand and mild early feeding problems. Ophthalmological assessment revealed macular and optic nerve hypoplasia. MRI demonstrated hypoplasia of the optic chiasm and optic nerves, and partial agenesis of falx cerebri.

Conclusion: We describe macular and optic nerve hypoplasia in a patient with a novel chromosomal rearrangement resulting in 2p partial trisomy and provide an overview of 17 previously reported cases presenting ocular abnormalities. A broad variability of ophthalmological phenotypes has been observed, further expanded by the current report.

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.