Ophthalmic Genetics最新文献

Background: Cone dystrophy is a heterogeneous hereditary retinal disorder with disease symptoms appearing in the late first or early second decades of life.

Methods: A consanguineous Pakistani family with three affected individuals underwent detailed clinical and genetic investigation.

Results: The proband, a 63-years old male, showed severely reduced day vision, a visual acuity of counting fingers (CF), color vision deficiency, high myopia and photophobia. Fundus images showed bilateral peripapillary atrophy, bilateral dull foveal reflex, tilted disc, tessellated fundus, and hyperfluorescence at the peripheral superior temporal arcade and leak at an early stage. OCT macula and angiography findings suggested traction near the disc in the right eye and sub-retinal fluid at the fovea in the left eye. Retinal layers were normal toward the periphery but disorganized near the disc. Full visual field tests showed bilateral central scotoma, while single visual field tests indicated bilateral generalized depression of the visual field. The proband showed normal bilateral intraocular pressure, normal choroidal vessels, and unremarkable anterior segment. Exome sequencing identified a novel homozygous missense variant (POC1B:NM_172240.3:c.1391T>C;p.L464P) in the proband. Existing evidence supported pathogenicity of the identified variant in the family.

Conclusion: In conclusion, we document a first-ever Pakistani family with POC1B-related cone dystrophy.

Background: Primary open-angle glaucoma (POAG) is a subtype of glaucoma that accounts for 60%~70% of all cases. Its pathogenic mechanism is intricate and its pathogenic process is concealed. Numerous significant biological processes associated with POAG continue to be elucidated.

Methods: In this study, by exploring the expression data of POAG tissues and normal tissues, we mined the regulatory lncRNAs and mRNAs closely associated with the pathogenesis and progression of POAG by exploring a regulatory network of competing endogenous RNA (ceRNA), established by integrating gene expression data with the known lncRNA-miRNA and miRNA-mRNA-regulatory interactions. The key regulatory pathways and regulatory elements of POAG were identified by topological analysis. Simultaneously, the exome data of 28 cases with POAG and healthy controls were analyzed to identify high-frequency mutations and genes.

Results: A total of 2712 differentially expressed genes were identified, including 1828 mRNAs and 884 lncRNAs. Network analysis suggested that lncRNAs such as HAGLR, HOTAIR and MIR29B2CHG, and mRNAs such as PPP6R3, BMPR2 and CFL2, may be involved in the onset and progression of POAG. In addition, 55 mutations with potential pathogenicity were identified.

Conclusion: These genes and mutations provide novel potential genetic heterogeneity and genetic susceptibility of POAG, as well as fresh suggestions for elucidating the molecular mechanism underlying the pathogenesis of POAG.

Introduction: Wolfram syndrome due to bi-allelic variants in WFS1 and mono-allelic Wolfram-like syndrome have variable ocular and syndromic associations. In this report, eight patients are described.

Methods: A retrospective observational case series with detailed ophthalmic and systemic phenotyping, optical coherence tomography (OCT), and neuroimaging. Molecular investigations included gene panel and targeted Sanger sequencing.

Results: Eight patients (six female, two male) from six families were diagnosed with optic atrophy at a mean age of 15.5 ± 6.2 years (range 8-23) with mean follow-up of 3.2 ± 3.4 years (range 1.5-12.1). Three were asymptomatic. Mean presenting visual acuity was 0.31 ± 0.26 logMAR (Snellen equivalent 20/40). Diabetes mellitus was present in five patients (detected after screening in one), sensorineural hearing loss in five and diabetes insipidus in one. Other systemic features included psychiatric disorders in four patients and bladder dysfunction in three patients. OCT demonstrated marked nerve fiber layer loss in all patients. In dominant disease, macular OCT demonstrated a linear splitting abnormality of the outer plexiform layer (OPL) not found in recessive disease. Three novel variants in WFS1 were identified. After identification of the p.Val606Gly variant in three Māori patients including one with cone-rod retinal dystrophy, a reference database of 80 Māori/Pasifika patients with retinal dystrophy/optic atrophy was interrogated. This identified the variant in 10 patients with disease attributed to other genes.

Conclusions: In Wolfram syndrome, systemic features are variable. Pathognomonic OPL lamination is associated with dominant disease. Early recognition of potentially syndromic optic atrophy allows prompt diagnosis of unrecognized diabetes mellitus.

Background: Keratoconus (KC) is an asymmetrical bilateral corneal ectasia, of which the pathogenesis is unknown. Moreover, genetic factors play an important role. We reported ophthalmic findings in a Chinese family with monozygotic twins with KC to describe the clinical features and identify genetic variants.

Methods: Comprehensive ophthalmic clinical assessments and examinations, including history, slit-lamp biomicroscopy, best-corrected visual acuity, corneal topography, anterior segment optical coherence tomography, and corneal biomechanics, were carried out on the twins and their parents. Whole-genome sequencing (WGS) was performed to identify variants in this family. SIFT, PolyPhen2, MutationTaster, and CADD were used to predict the effect of amino acid substitutions on the affected protein.

Results: The twins presented typical KC features. However, their mother did not meet the criteria for a KC diagnosis but exhibited KC subclinical manifestations. After screening, 12 potentially pathogenic variants in 10 genes were identified in both twins and emerged as candidate variants for this family. These genes included 1 previously reported KC-associated variant (ZNF469, c.4384 G>A); 8 variants in 6 KC-associated genes (GRHPR, c.337 G>A, c.862_863del; COL6A1, c.920 G>A; FLG, c.8753C>G; HSPG2, c.9503C>T; KRT82, c.1306 G>A; SCN9A, c.5702_5706del, c.641 G>A); and 3 variants in 3 non-KC-associated genes (PDE6G, c.6C>A; HAL, c.1724C>T; AGBL1, c.2381 G>A).

Conclusions: The accumulation of these potentially pathogenic variants in twins may have caused KC in these twins. These results expand the spectrum of KC candidate variants and provide a basis for further studies on KC.

Stem cell-based therapy has gained importance over the past decades due to huge advances in science and technology behind the generation and directed differentiation of pluripotent cells from embryos and adult cells. Preclinical proof-of-concept studies have been followed by clinical trials showing efficacy and safety of transplantation of stem cell-based therapy, which are beginning to establish this as a modality of treatment. Disease candidates of interest are primarily conditions that may benefit from replacing dead or dying cells, including advanced inherited retinal dystrophies and age-related macular degeneration, and predominantly seek to transplant either RPE or photoreceptors, although neurotrophic approaches have also been trialed. Whilst a consensus has yet to be reached about the best stage/type of cells for transplantation (stem cells, progenitor cells, differentiated RPE and photoreceptors) and the methods of implantation (sheet, suspension), several CTs have shown safety. There remain potential concerns regarding tumorigenicity and immune rejection; however, with ongoing improvements in cell generation, selection, and delivery, these can be minimized. Earlier studies showed efficacy with immunosuppressive drugs to prevent rejection, and recent donor-matched transplants have avoided the need for immunosuppression. Retinal regenerative medicine is a challenging field and is in a nascent stage but holds tremendous promise. This narrative review delves into the current understanding of stem cells and the latest clinical trials of retinal cell transplantation.

Background: One of the conditions that might harm your eyesight is diabetic retinopathy (DR), DR may set in slowly but surely for those with long-term diabetes and poor glucose control. ‎.

Objective: To establish a connection between the various genotypes of the rs1800624 SNP and the rs80096349 SNP located in the AGER gene and DR patients. ‎.

Methods: The current case-control research examined one hundred thirty-four individuals diagnosed with type 2 diabetes and thirty-six healthy individuals who did not have DM. These samples were obtained from Amir Al-Muminin, a private hospital in Najaf, Iraq. The tetra primers ARMS-PCR method was utilized to determine the genotype of rs1800624 SNP of the AGER gene.

Results: A significant association was found between genotypes (AA, AG, and GG) and DR subgroups (NPDR & PDR) in patients (p = 0.001). The AG genotype of rs1800624 SNP is associated with a lowering the risk of developing NPDR (OR = 0.30; 95% CI = 0.12-0.74; p = 0.009 between controls and NPDR, OR = 0.36; 95% CI = 0.14-0.90; p = 0.029 between NDR and NPDR). HRM analysis verified the presence of only two genotypes in the samples: wild type (GG) and a heterozygous mutant (GA). However, a significant association between genotypes was observed when comparing DR status with controls and NDR (p = 0.031).

Conclusion: The rs1800624 SNP of the AGER gene is associated with the risk of NPDR and PDR in T2DM, and the polymorphism of the rs80096349 may be associated with retinopathy in the Iraqi population.

Background: Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive autoinflammatory disorder associated with systemic vasculitis and bone marrow failure. Reported ophthalmic findings in DADA2 include optic neuritis, retinal artery occlusion, uveitis, and optic atrophy. We report the case of a child found to have bilateral cataracts.

Case report: A three-year-old recent immigrant from Mexico with a diagnosis of DADA2 and transfusion-dependent anemia was referred to ophthalmology to screen for deferasirox-associated retinopathy in the setting of hemochromatosis. He was incidentally found to have bilateral posterior subcapsular cataracts with no other ophthalmic abnormalities. The child's lab findings were significant for chronic hyperferritinemia, and his history was significant for over a year of oral prednisone use in Mexico.

Conclusions: This is the first reported case of cataracts in a child with DADA2. While DADA2 is an autoinflammatory disorder, this child's lack of uveitis suggests a non-inflammatory etiology. Hyperferritinemia is a known cause of cataracts and is common in DADA2, but the child's history of oral steroid use in Mexico could also explain his cataracts. As pediatric cataracts have not otherwise been reported in DADA2, ophthalmologists should be aware of this possibility, especially in children with hyperferritinemia or a history of steroid use.

Purpose: To investigate whether genetic and clinical characteristics differ depending on generations using 326 patients (male/female, 259/67; mean age, 55.4 ± 12.5 years) with simple CSC.

Methods: All patients were diagnosed with simple CSC, defined as a retinal pigment epithelium alteration area equal to or smaller than 2-disc areas based on multimodal imaging at the initial presentation. We cross-sectionally evaluated clinical characteristics at the initial visit and genotyped CFH rs800292 and rs1329428 for all patients using TaqMan technology.

Results: As generations decreased, the proportion of males, subfoveal choroidal thickness, and prevalence of fibrin significantly increased (p < 0.001, p < 0.001, and p = 0.012, respectively), and the best-corrected visual acuity improved (p < 0.001); in contrast, the prevalence of pachydrusen significantly decreased (p < 0.001). The younger presentation was significantly associated with male and risk variants (T allele) of CFH rs1329428 (p = 9.1 × 10^-7 and p = 0.042, respectively), and patients were estimated to present 2 years younger per one T allele of CFH rs1329428 (p = 0.042, β = -1.95, stepwise regression analysis).

Conclusion: Clinical and genetic characteristics differed significantly among patients with simple CSC, depending on their generation.

Purpose: This study aims to estimate the potential causal relationship between genetically predicted levels of inflammatory cytokine and retinitis pigmentosa (RP) by performing Mendelian randomization (MR).

Methods: Single nucleotide polymorphisms (SNPs) were identified as instrumental variables (IVs) from publicly available genome-wide association study datasets. Inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods were applied in this MR analysis. IVW and MR-Egger were used to confirm heterogeneity and pleiotropy of identified IVs. Leave-one-SNP-out analysis was used to identify SNPs with potential impact.

Results: IVW results revealed that elevated levels of Tumor Necrosis Factor Alpha (TNF-α), Macrophage Inflammatory Protein-1a (MIP1a), and Monokine Induced by Gamma Interferon (MIG) were associated with higher RP risk (OR = 2.358, p = 0.050; OR = 2.583, p = 0.013; OR = 1.851, p = 0.015), while elevated levels of Interleukin-16 (IL-16) were associated with reduced RP risk (OR = 0.723, p = 0.019). The results of heterogeneity and pleiotropy (p > 0.05) confirmed there was no pleiotropy and heterogeneity in our IVW analysis. The association of TNF-α, MIP1a, MIG and IL-16 with RP from sensitivity analyses using these two sets of restricted IVs remained stable.

Conclusion: Our study provides evidence of potential causal relationships between several circulating cytokine levels and RP. Elevated levels of TNF-α, MIP1a, and MIG are associated with a higher risk of RP, while elevated levels of IL-16 are associated with a lower risk of RP. These cytokines may be novel biomarkers and therapeutic targets for RP.

Purpose: To report the occurrence of unilateral, neonatal-onset congenital glaucoma in a child with Rubinstein-Taybi Syndrome (RTS).

Case report: A 15-day-old male with features of RTS was presented with an enlarged corneal diameter, corneal haze, and peripheral corneal vascularization of the left eye. Ultrasound biomicroscopy of his left eye revealed iris atrophy, iridocorneal adhesions, and iris adhesions to a partially absorbed cataractous lens. Genetic evaluation of the child and the parents revealed a novel de novo heterozygous pathogenic variant in exon 5 of the CREBBP gene (NM_004380.3:c.1390C>T). A diode laser cyclophotocoagulation was performed to control the IOP in the left eye.

Conclusion: Unilateral neonatal-onset congenital glaucoma due to iridocorneal adhesions can be a rare presentation of Rubinstein-Taybi Syndrome.