Ophthalmic Genetics最新文献

Background: Trisomy 8 mosaicism (T8M) also known as Warkany syndrome 2 is a rare chromosomal disorder characterized by a highly variable phenotypic presentation. Ranging from mild congenital anomalies to life and sight threatening associations. Currently, the most common ophthalmic manifestations are strabismus, hypertelorism, and corneal opacities. Other visually debilitating features include microphthalmia, retinal dystrophy, and optic disc coloboma.

Case presentation: We present a case of a 9-year-old male who was referred to our ophthalmology service as a case of strabismus and bilateral ptosis with syndromic facial features of a protruded jaw, low set ears, and wide nasal bridge, and was later confirmed with cytogenetic analysis of T8M. To the best of our knowledge, this is the first reported case of T8M in our region, and the first to present euryblepharon as an associated ophthalmic manifestation, in addition to providing an updated review of the most commonly and newly documented manifestations of T8M.

Conclusion: The phenotypic variation of T8M is diverse and often unpredictable, ranging from mild ocular findings to visually debilitating manifestations. Comprehensive awareness of its ophthalmic features can aid ophthalmologists in early recognition and appropriate genetic evaluation and counseling.

Introduction: To evaluate the changes in central corneal thickness and curvature parameters in pediatric patients with Triple A syndrome and alacrima.

Methods: This retrospective study included 52 eyes of 26 patients with Triple A syndrome. All patients had alacrima. Pentacam was used to analyze the keratometry in the flat (K1) and steep meridian (K2) and maximum keratometry (Kmax), mean keratometry (Kmean) readings, central corneal thickness at the vertex (CCT) and at the thinnest point (CCT-TP) were recorded. Patients were divided into three groups based on their age (Group 1: 3-6 years, group 2: 7-12 years, group 3: 13-18 years). Values were compared between pediatric patients with Triple A and normal controls.

Results: The K1 values of all patients were significantly higher than those observed in healthy data (p < 0.001). 15 Group 1 had significantly lower K2 and higher CCT values (p = 0.008, p = 0.015). In group 2, K1 and Kmax were significantly higher, while CCT and CCT-TP were lower (p = 0.016, p < 0.001, p < 0.001, p < 0.001, respectively). In group 3, K1 and CCT and CCT-TP were significantly higher than the normal data (p = 0.019, p < 0.001, p < 0.001, respectively).

Discussion: Since dry eye syndrome may cause corneal changes, in AAAS patients, corneal topographic variations may occur due to alacrima. Thus, these patients should be evaluated during follow-up visits.

Introduction: Loeys-Dietz syndrome (LDS) is a rare autosomal dominant connective tissue disorder most commonly due to pathogenic variants in the transforming growth factor beta receptor genes TGFBR1 and TGFBR2. There have been reports of a few sporadic cases of LDS patients exhibiting a vitreoretinopathy phenotype due to pathogenic variants in the TGFBR2 gene.

Case presentation: We report a 13-year-old female with LDS who harbored a de novo pathogenic missense variant (c.1582C>T, p.Arg528Cys) in TGFBR2. She presented with reduced visual acuity in the right eye due to a vitreous hemorrhage. Fluorescein angiography identified neovascularization in the right eye with peripheral avascular retina in both eyes. These phenotypic features were similar to those seen in familial exudative vitreoretinopathy (FEVR). Intravitreal anti-VEGF treatment in the right eye led to visual improvement, followed by laser photocoagulation of the peripheral retina of both eyes to mitigate future complications.

Discussion: This is the second reported case of a missense variant at the amino acid residue 528 (Arg528) of TGFBR2 that results in a FEVR-like phenotype in a LDS patient. In silico protein prediction and machine learning analyses of the affected region of the TGFBR2 protein suggest this missense variant disrupts the protein kinase domain. We hypothesize this change influences the Wnt/beta-catenin pathway, leading to abnormal retinal vasculogenesis.

Conclusions: This case highlights the importance of a genotype to phenotype relationship in LDS and suggests that certain variants in TGFBR2 may predispose to vitreoretinopathy. Recognition of this is important as timely anti-VEGF and laser intervention can limit visual threatening complications.

Purpose: To assess the ocular characteristics, retinal microvasculature, and long-term outcomes of patients with nanophthalmos associated with mutations in the membrane frizzled-related protein (MFRP) gene, and to compare these findings with those observed in nanophthalmos cases without MFRP gene mutations.

Methods: In this retrospective cohort study, patients with MFRP-associated nanophthalmos and those with nanophthalmos without MFRP gene mutations were included. Best-corrected visual acuity (BCVA), spherical equivalent (SE), axial length (AL), optical coherence tomography (OCT), and OCT angiography parameters-including vascular density (VD) and foveal avascular zone (FAZ) measurements in the superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris (CC)-were evaluated at presentation and at the 5th-year follow-up.

Results: At presentation and 5-year follow-up, patients with MFRP-associated nanophthalmos exhibited significantly shorter AL and higher SE compared to those without MFRP mutations (all p < 0.001). Central macular thickness (CMT), subfoveal choroidal thickness (SFCT), and retinal nerve fiber layer (RNFL) thickness were significantly greater in the MFRP-associated group at presentation and 5-year follow-up (all p < 0.05). OCT angiography revealed reduced parafoveal VD in the SCP and DCP, as well as decreased foveal and parafoveal VD in the CC in the MFRP group compared to the group without MFRP mutations (all p < 0.05). FAZ areas in the SCP and DCP were also significantly smaller in the MFRP group (p < 0.001 and p = 0.01, respectively).

Conclusions: Eyes with MFRP-associated nanophthalmos exhibit significantly higher SE, shorter AL, and more pronounced alterations in retinal structure and microvasculature compared with eyes without MFRP mutations.

Introduction: We report the case of a 42-year-old Venezuelan woman with childhood-onset autosomal recessive retinitis pigmentosa type 90 (RP90), presenting an unusual and distinctive clinical phenotype characterized by macular pseudocoloboma, very early-onset acquired color vision disorder progressing to severe functional dyschromatopsia, and early-onset severe posterior subcapsular cataracts. Her affected brother exhibited a similar phenotype, while her parents and the other two siblings remained unaffected.

Methods and results: Massive parallel sequencing identified two novel IDH3A variants: c.127G>T (chr15:78449926 G>T; no dbSNP entry) and c.419T>C (chr15:78454052T>C; no dbSNP entry), in compound heterozygosity and confirmed to be in trans location. Both missense variants, absent from population databases, were predicted to be deleterious by multiple in silico tools and are located in critical domains involved in enzymatic complex stability, catalytic activity and subunit interactions.

Conclusions: This case reinforces the association between IDH3A mutations and RP90, corroborates key phenotypic features described in limited published reports-the presence of macular pseudocoloboma-and expands the mutational spectrum of the gene. Moreover, it highlights the role of mitochondrial metabolism in photoreceptor degeneration and proposes a link between them. Our findings underscore the need for functional studies to elucidate the pathogenic mechanisms underlying IDH3A-related retinopathies.

Introduction: PROM1 inherited retinal diseases (IRDs) result in significant phenotypic heterogeneity ranging from macular dystrophy to severe rod-cone dystrophy. This study examined a cohort of patients with autosomal recessive (AR) PROM1-associated IRD to determine important potential biomarkers of disease progression on multimodal imaging.

Methods: Ophthalmic phenotyping included clinical examination, OCT, fundus autofluorescence and electrophysiology.

Results: The cohort included six patients with bi-allelic variants, including two novel variants, and a median of 11.8 years of follow-up. Best-corrected visual acuity (BCVA) was maintained until a steep decline around 15 years of age. This was preceded by contraction of the subfoveal ellipsoid zone length (EZL), measured on OCT. Review of the literature demonstrated that cone or cone-rod dystrophy was the most frequently identified clinical phenotype. Loss of function variants including nonsense, frameshift and splice variants were particularly common.

Discussion: This study provides detailed insights into the natural history of AR PROM1 IRD and current understanding in the published literature. Contraction of the subfoveal EZL appears to be a potential biomarker for disease progression and occurs earlier than reduction in BCVA.

Purpose: Structural variants such as large deletions or insertions are rarely observed in the RS1 gene. Here, we report a 20-year-old male patient with X-linked retinoschisis (XLRS) carrying a novel deletion-insertion variant of RS1.

Methods: In addition to ophthalmological examinations, molecular genetic analyses were performed using exome sequencing, polymerase chain reaction and Sanger sequencing.

Results: The patient was diagnosed with XLRS based on findings from funduscopy, optical coherence tomography, and full-field electroretinography. Exome sequencing identified a deletion of RS1 exon 4, located between exons 19 and 20 of the CDKL5 gene, which is oriented in the reverse direction relative to RS1. Ultimately, we confirmed a 453 bp deletion, including exon 4 of RS1, along with a 15 bp insertion at the deletion site, by verifying sufficient sequencing coverage for exons 19 and 20 of CDKL5.

Conclusions: Exome sequencing is valuable not only for detecting single nucleotide variants but also for identifying exon deletions. Determining the coverage of exon regions in the CDKL5 gene can assist in defining deletion-insertion variants in RS1.

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.