Ophthalmic Genetics最新文献

Introduction: A congenital optic nerve head anomaly (CONHA) is an umbrella term for structurally abnormal optic nerve heads present at birth which may lead to vision loss. The potential roles of motile and non-motile ciliopathies in this process are not well understood. This report describes a pediatric case of CONHA and implicates a motile ciliopathy in a possible mechanism that affects embryogenesis of the optic nerve head.

Case presentation: A 21-month-old male with a normal prenatal and postnatal course, past medical history of recurrent upper and lower airway infections, and no known ocular history was referred by a community ophthalmologist for evaluation of a dysplastic optic disc. After the initial visit, fundus examination at a subsequent EUA revealed a hypoplastic macula and an anomalous nerve. Evaluation by a pulmonologist at 32 months due to multiple airway infections revealed atopic dermatitis and moderate persistent asthma. Primary ciliary dyskinesia was ruled out.

Discussion: We theorize that this patient's fundus and systemic findings have a similar etiology. Differentiation of primary cilia on airway epithelial cells is known to produce motile cilia. We hypothesize that insults to a common cell may lead to disruption of three downstream pathways in our patient. The first line resulted in an atopic profile due to a disruption of motile ciliogenesis and mucociliary clearance. Second, disruption of primary cilia within the Sonic hedgehog pathway, a key regulator of neuronal development, may have resulted in a CONHA. Finally, the presence of abnormal primary cilia may have led to retinal dysplasia.

Conclusion: Linking systemic and ophthalmic findings can provide more insight into the role of motile cilia in other fundus conditions, allowing for targeted interventions. Thus, future research and gene therapy can work to prevent, or slow down, severe vision loss.

Purpose: To report clinical and imaging features of a pediatric patient with ACTA2 R179H 50 pathogenic variant using multimodal imaging.

Case report: A pediatric patient with a pathogenic ACTA2 variant presented with multisystemic 52 symptoms and prominently tortuous retinal vessels as seen on fundus photography, fluorescein 53 angiography, and optical coherence tomography angiography.

Conclusion: Non-invasive retinal imaging, including OCTA, may serve as a biomarker of 55 disease severity in pediatric patients. This approach allows for close monitoring of any vascular 56 changes over time.

Purpose: To investigate the clinical, imaging, electrophysiological, and genetic characteristics of male patients with RPGR-associated retinopathy exhibiting tapetal-like reflex (TLR) versus those without (non-TLR).

Methods: This retrospective observational study included 9 Indian males from 7 unrelated families with genetically confirmed pathogenic RPGR variants. Patients were divided into TLR (n=6) and non-TLR (n=3) groups based on fundus appearance. Multimodal imaging (fundus photography, fundus autofluorescence [FAF], optical coherence tomography [OCT]) and full-field electroretinography (ERG) were analyzed. Molecular genetic testing was performed to identify RPGR variants.

Results: The TLR group showed a characteristic golden, scintillating sheen with radial streaks on fundus exam. Median age of onset was 35 years with worse best-corrected visual acuity (BCVA) (0.66 LogMAR) and higher myopia (median -5.50 D) compared to the non-TLR group (23 years, 0.26 LogMAR, -1.00 D). FAF in the TLR group revealed central confluent or patchy macular atrophy surrounded by hyper-autofluorescence, whereas the non-TLR group exhibited widespread mid-peripheral degeneration and bull's eye maculopathy. OCT showed complete outer retinal atrophy (cRORA) in most TLR eyes and incomplete atrophy (iRORA) with preserved ellipsoid zone in the youngest patient. Non-TLR eyes demonstrated milder retinal atrophy with limited ellipsoid zone preservation. Full-field ERG demonstrated preserved scotopic but extinguished photopic responses in TLR eyes, while non-TLR eyes had extinguished photopic and severely reduced scotopic responses. All variants were hemizygous RPGR mutations in exon 15, predominantly frameshift or stop-gain mutations.

Conclusions: Tapetal-like reflex in male RPGR-associated retinopathy correlates with a cone-rod dystrophy-like phenotype featuring later onset, severe central atrophy, and predominant photopic dysfunction. In contrast, absence of TLR associates with rod-cone dystrophy-like features. Recognition of TLR may aid clinical classification, early diagnosis, and prognosis in RPGR-related retinal disease.

Background: Vascular endothelial growth factor (VEGF) is an angiogenic factor that contributes to the vascular permeability and neovascularization. This study aims to investigate whether the polymorphisms of the VEGF gene at the -2578C/A (rs699947) and -634 G/C (rs2010963) are risk factors for diabetic retinopathy (DR) in Thai patients with type 2 diabetes.

Methods: We conducted a case-control study. Thai patients with type 2 diabetes were enrolled in the study and assigned to a diabetic with retinopathy (DR) or a diabetic without retinopathy (DWR) group based on the grading of retina images. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine polymorphisms of the VEGF gene at the -2578C/A and -634 G/C loci.

Results: A total of 85 patients, including 37 with DR and 48 without DR, were enrolled in this study. We found that the genotype distributions and allele frequencies for the VEGF-2578C/A (rs699947) and VEGF-634 G/C (rs2010963) polymorphisms did not differ between the patients with DR and those without DR. Neither polymorphism was significantly associated with DR development.

Conclusions: Our data suggest that VEGF-2578C/A (rs699947) and VEGF-634 G/C (rs2010963) polymorphisms may not be the risk factors for DR in Thai patients with type 2 diabetes mellitus.

Background: Infantile nystagmus syndrome is often the presenting symptom of an underlying retinal disorder, such as Congenital Stationary Night Blindness (CSNB). CSNB, an inherited retinal disorder affecting rod mediated "night" vision, has several known genetic causes. Despite advances in genetic testing, structural variants can be difficult to detect using traditional methods like whole exome sequencing.

Case presentation: We present a case involving a novel structural variant in CACNA1F, detected through whole genome sequencing (WGS), in an 8-year-old boy who initially presented with infantile nystagmus and high myopia. The CACNA1F variant consists of a 380 bp inverted duplication involving exons 41 and 42. Bioinformatics analyses predicted a cryptic exon insertion instead of exon 41, leading to 11 amino acids and a stop codon, resulting in protein truncation. PCR confirmed the presence of the duplication that is hemizygous in the proband and heterozygous in his carrier mother. Although highly myopic, she reports no night vision difficulties.

Conclusion: This case illustrates WGS's superior capacity to detect complex genomic rearrangements that conventional exome-focused or gene panel strategies may overlook. Our findings both expand the catalog of known pathogenic variants and underscore the role of WGS in genetic diagnosis.

Introduction: To describe examination and findings in a case of isolated maculopathy with genetic testing revealing an USH2A genotype.

Methods/results: A 65-year-old man was found to have slowly worsening central vision in both eyes over several years. Fundus examination showed parafoveal pigmentary changes with an otherwise normal peripheral exam in both eyes. Fundus autofluorescence revealed parafoveal hypofluorescence with surrounding ring like area of hyperfluorescence, with optical coherence tomography (OCT) showing retinal thinning and parafoveal photoreceptor loss. Multifocal electroretinography (ERG) demonstrated diminished central responses, with full field ERG showing normal scotopic response and reduced photopic responses. Genetic testing for retinal dystrophies revealed a homozygous pathogenic variant in USH2A c.10342G>A, p. Glu3448Lys.

Discussion: USH2A-associated retinal dystrophy usually presents with a rod-cone phenotype. While reports of a cone-rod phenotype have been described, we present the first reported case of isolated maculopathy in USH2A-associated retinal dystrophy.

Introduction: There is few data that investigate the genetic underpinnings of idiopathic foveal hypoplasia and assess its potential overlap with albinism-related gene variants in a cohort devoid of familial albinism history.

Methods: This cross-sectional study included 19 participants diagnosed with idiopathic foveal hypoplasia, confirmed via optical coherence tomography (OCT). We detailed ophthalmic evaluations and genotyping using a panel of 33 genes related to foveal hypoplasia.

Results: Of the 19 participants, 2 (10%) exhibited heterozygous pathogenic variants in genes typically associated with albinism (TYR and OCA2). Eyes from participants with variants had statistically significant lower central macula thickness than those without.

Discussion: The study reveals some albinism-associated variants among participants with idiopathic foveal hypoplasia, suggesting a possible genetic basis for this condition in a subset of cases.

Background: Myhre syndrome is an autosomal dominant condition caused by pathogenic variants in the transcriptional co-regulator SMAD4. Myhre syndrome is characterized by distinctive facial features, short stature, musculoskeletal abnormalities, and intellectual disability. Reported ocular abnormalities include refractive errors, corectopia, cataract, strabismus, and pseudo) papilledema.

Case report: We describe an 8-year-old boy with Myhre syndrome due to a c.1498A > G; p.I500V pathogenic variant in SMAD4. Ocular examination revealed bilateral emmetropia, mild visual acuity reduction in the right eye (20/25), grade 1b foveal hypoplasia in both eyes and small optic discs with pseudopapilledema.

Conclusion: This report marks the first reported case of foveal hypoplasia in Myhre syndrome, a potentially underreported finding, given the relative lack of OCT assessment in patients with Myhre syndrome. We discuss pathophysiological link between foveal hypoplasia and gain-of-function variants in SMAD4.

Purpose: To describe the earliest characteristics of patients with retinitis pigmentosa GTPase regulator-related retinal degeneration (RPGR-RD).

Methods: A retrospective chart review was conducted for patients evaluated at the University of Michigan, Kellogg Eye Center. Patients were classified into 3 phenotypes: rod-cone (RC), cone/cone-rod (CR), and female carriers. Chart review data included clinical diagnosis, age at symptom onset, family history of inherited retinal disease (IRD), patient-reported symptoms, refractive error, and genetic testing information. The relationship between certain covariates and time between (a) symptoms and diagnoses and (b) diagnosis and genetic testing was investigated with proportional hazard modeling.

Results: The charts of 131 patients were included: 82 RC, 31 CR, and 18 females. The median (range) ages at symptom onset were: RC, 6 (1-42) years; CR, 28 (1-47) years; and females, 11 (5-34) years. Most (83%) had a family history of IRD. The most common first-documented symptoms were: RC, peripheral vision loss (85%); CR, decreased vision (50%); females, night blindness (57%) and peripheral vision loss (57%). Most patients (80%) were myopic; 24% had high myopia. Time from clinical to genetic diagnosis was shorter given IRD family history (P < 0.001).

Conclusion: This study identified characteristics to facilitate earlier diagnosis of RPGR-RD, potentially shortening time to treatment and preventing further vision loss.

Background: Retinoblastoma is the most common intraocular tumor of childhood. In Lebanon, its incidence is reported at 3.6 per million person-years. This study aimed to characterize the spectrum of RB1 variants in hereditary retinoblastoma and explore genotype-phenotype associations in a Lebanese cohort.

Methods: A retrospective chart review was conducted on retinoblastoma patients enrolled in the Children's Cancer Institute at the American University of Beirut Medical Center from 2012 to 2022. Genetic data (RB1 sequencing and karyotype), clinical characteristics, imaging, treatment, and outcomes were collected and compared between hereditary and sporadic cases, and across different variant types.

Results: A total of 47 patients underwent genetic testing; 63% had hereditary retinoblastoma with 23 patients carrying single nucleotide changes, including four novel mutations, 3 patients with submicroscopic deletions/duplications, and 3 with deletion 13q syndrome. Nonsense mutations were most frequent (52.2%), followed by frameshift and splice-site alterations. Bilaterality was significantly associated with hereditary disease (85.7% vs. 21.1%, p < 0.001), and more common among Syrian patients (p = 0.04). Median age at diagnosis was younger in the hereditary group, although not statistically significant. Enucleation rates (57.1% vs. 78.9%) and vision outcomes were similar across groups (p > 0.05). No significant differences in treatment outcomes were found among different variant types. Among the 3 patients with deletion 13q, two exhibited severe psychomotor and developmental delays.

Conclusion: Hereditary retinoblastoma accounted for 63% of cases, with 23 pathogenic variants including four novel ones. Bilaterality and Syrian nationality were significantly associated with RB1 positivity. This study underscores the importance of comprehensive RB1 genetic testing in improving diagnostic accuracy, guiding treatment decisions, and supporting genetic counselling, particularly in non-Western populations.