Genotype-phenotype Correlations of Ocular Posterior Segment Abnormalities in Marfan Syndrome.

Purpose: Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 ( (FBN1). In addition to typical phenotypes such as ectopia lentis (EL) and aortic dilation, patients with MFS are prone to ocular posterior segment abnormalities, including retinal detachment (RD), maculopathy, and posterior staphyloma (PS). This study aims to investigate the correlations between FBN1 genotype and posterior segment abnormalities within a Chinese cohort of MFS. Design: Retrospective study. Participants: One hundred twenty-one eyes of 121 patients with confirmed FBN1 mutations between January 2015 and May 2023 were included. Methods: Comprehensive ophthalmic examination findings were reviewed, and the incidence of RD, atrophic, tractional, and neovascular maculopathy (ATN classification system), and PS was analyzed between different genotype groups. Only the more severely affected eye from each patient was included. Main Outcome Measures: Clinical features and risk factors. Results: Of 121 patients, 60 eyes (49.59%) exhibited posterior segment abnormalities, including RD (4, 3.31%), maculopathy (47, 38.84%), and PS (54, 44.63%). The mean age was 11.53 ± 11.66 years, with 79.34% of patients <20 years old. The location and region of mutations were found to be associated with the incidence of maculopathy (P = 0.013, P = 0.033) and PS (P = 0.043, P = 0.036). Mutations in the middle region had a lower incidence of maculopathy and PS (P = 0.028 and P = 0.006, respectively) than those in C-terminal region. Mutations in the transforming growth factor-ß (TGF-ß) regulating sequence exhibited a higher incidence of maculopathy and PS (P = 0.020, P = 0.040). Importantly, the location and region of mutations were also associated with the incidence of atrophic maculopathy (P = 0.013 and P = 0.033, respectively). Mutations in the middle region had a significantly lower probability of atrophic maculopathy (P = 0.006), while mutations in the TGF-ß regulating region had a higher incidence of atrophic maculopathy (P = 0.020). Conclusions: Maculopathy and PS were associated with the location and region of FBN1 mutations. Patients with mutations in the TGF-ß regulating region faced an increased risk of developing retinopathy. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Mutations in TSPAN12 gene causing familial exudative vitreoretinopathy.

BACKGROUND: To report newly found TSPAN12 mutations with a unique form of familial exudative vitreoretinopathy (FEVR) and find out the possible mechanism of a repeated novel intronic variant in TSPAN12 led to FEVR. RESULTS: Nine TSPAN12 mutations with a unique form of FEVR were detected by panel-based NGS. MINI-Gene assay showed two splicing modes of mRNA that process two different bands A and B, and mutant-type shows replacement with the splicing mode of Exon11 hopping. Construction of wild-type and mutant TSPAN12 vector showed the appearance of premature termination codons (PTC). In vitro expression detection showed significant down-regulated expression level of TSPAN12 mRNAs and proteins in cells transfected with mutant vectors compared with in wild-type group. On the contrary, translation inhibitor CHX and small interfering RNA of UPF1 (si-UPF1) significantly increased mRNA or protein expression of TSPAN12 in cells transfected with the mutant vectors. CONCLUSIONS: Nine mutations in TSPAN12 gene are reported in 9 FEVR patients with a unique series of ocular abnormalities. The three novel TSPAN12 mutations trigger NMD would cause the decrease of TSPAN12 proteins that participate in biosynthesis and assembly of microfibers, which might lead to FEVR, and suggest that intronic sequence analysis might be a vital tool for genetic counseling and prenatal diagnoses.

Genetic Characteristics and Clinical Manifestations of Foveal Hypoplasia in Familial Exudative Vitreoretinopathy.

PURPOSE: This study aimed to ascertain the occurrence of foveal hypoplasia (FH) in individuals diagnosed with familial exudative vitreoretinopathy (FEVR). DESIGN: Retrospective cohort study. METHODS: In this study, FEVR families and sporadic cases were diagnosed at the Eye and ENT Hospital, Fudan University, between 2017 and 2023. All patients attended routine ophthalmologic examinations and genetic screenings. The classification of FH was determined using optical coherence tomography (OCT) scans. The FH condition was classified into 2 subgroups: group A (FH being limited to the inner layers) and group B (FH affecting the outer layers). A total of 102 eyes from 58 patients were suitable for analysis. RESULTS: Forty-nine mutations in LRP5, FZD4, NDP, TSPAN12, KIF11, CTNNB1, and ZNF408 were examined and detected, with 26 of them being novel. Forty-seven eyes (46.1%) revealed FH. The majority (53.2%) were due to the typical grade 1 FH. Patients with mutations in LRP5 and KIF11 were found to exhibit a higher prevalence of FH (P = .0088). Group B displayed the lowest visual acuity compared with group A (P = .048) and the group without FH (P < .001). The retinal arteriolar angle in group B was significantly smaller than in group A (P = .001) and those without FH (P < .001). CONCLUSIONS: This study offers a new diagnostic approach and expands the spectrum of FEVR mutations. LRP5 and KIF11 were found to be more susceptible to causing FH in patients with FEVR. FEVR eyes with FH exhibited both greater visual impairment and reduced retinal arteriolar angles. The assessment of foveal status in patients with FEVR should be valued.

Updating Understanding of Macular Microvascular Abnormalities and Their Correlations With the Characteristics and Progression of Macular Edema or Exudation in Coats' Disease.

Objective: To investigate the associations of macular microvascular abnormalities with the characteristics and progression of macular edema or exudation in Coats' disease, toward an updated understanding of possible risk factors for macular edema or exudation. Methods: Twenty-six eyes (26 patients) with Coats' disease and macular edema or exudation underwent multimodal imaging and were followed for 18 months. The eyes were classified according to their outcomes (refractory or improved). Macular capillary affections were assessed by optical coherence tomography angiography (OCTA) and fluorescein angiography (FA). Histopathological analysis of the macular region of an additional enucleated eye was performed. Results: OCTA revealed telangiectasia in the deep capillary plexus (DCP) in 76.9% and the superficial capillary plexus (SCP) in 34.6% of 26 eyes with macular edema or exudation of Coats' disease, exceeding the rate detected by FA (21.4%). Eyes with intraretinal cystoid spaces/exudates of the macula presented higher presence of telangiectasia in the SCP (57.1% with vs. 8.3% without, X2 = 6.801, P = 0.009) and DCP (92.9 with vs. 58.3% without, X2 = 4.338, P = 0.037). The parafoveal vessel densities (VDs) and fractal dimension in the SCP and DCP were lower in affected eyes than in contralateral eyes (all P < 0.001). The VD in SCP (P = 0.009) and DCP (P = 0.010) were lower in refractory group than in improved group. Dilated capillaries with incomplete vessel walls and adjacent inflammatory cells were detected in the neuroretina of the macula in histopathological specimen. Conclusions: Macular capillary abnormalities, including telangiectasia and VD loss, were positively detected in eyes with macular edema or exudation of Coats' disease. Intraretinal cystoid spaces/exudates of the macula, rather than subretinal exudates, may be related to macular telangiectasia. VD losses in the SCP and DCP may be risk factors for refractory macular edema or exudation.