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Background: Familial exudative vitreoretinopathy (FEVR) is a genetic eye disorder that leads to abnormal development of retinal blood vessels, resulting in vision impairment. This study aims to identify pathogenic variants by targeted exome sequencing in 9 independent pedigrees with FEVR and characterize the novel pathogenic variants by molecular dynamics simulation., Methods: Clinical data were collected from 9 families with FEVR. The causative genes were screened by targeted next-generation sequencing (TGS) and verified by Sanger sequencing. In silico analyses (SIFT, Polyphen2, Revel, MutationTaster, and GERP + +) were carried out to evaluate the pathogenicity of the variants. Molecular dynamics was simulated to predict protein conformation and flexibility transformation alterations on pathogenesis. Furthermore, molecular docking techniques were employed to explore the interactions and binding properties between LRP5 and DKK1 proteins relevant to the disease., Results: A 44% overall detection rate was achieved with four variants including c.4289delC: p.Pro1431Argfs*8, c.2073G > T: p.Trp691Cys, c.1801G > A: p.Gly601Arg in LRP5 and c.633 T > A: p.Tyr211* in TSPAN12 in 4 unrelated probands. Based on in silico analysis and ACMG standard, two of them, c.4289delC: p.Pro1431Argfs*8 and c.2073G > T: p.Trp691Cys of LRP5 were identified as novel pathogenic variants. Based on computational predictions using molecular dynamics simulations and molecular docking, there are indications that these two variants might lead to alterations in the secondary structure and spatial conformation of the protein, potentially impacting its rigidity and flexibility. Furthermore, these pathogenic variants are speculated to potentially influence hydrogen bonding interactions and could result in an increased binding affinity with the DKK1 protein., Conclusions: Two novel genetic variants of the LRP5 gene were identified, expanding the range of mutations associated with FEVR. Through molecular dynamics simulations and molecular docking, the potential impact of these variants on protein structure and their interactions with the DKK1 protein has been explored. These findings provide further support for the involvement of these variants in the pathogenesis of the disease., (© 2023. The Author(s).)

Background: Familial exudative vitreoretinopathy (FEVR) is a rare congenital disorder of retinal vascular development. We aimed to study the vascular characteristics around the optic disc in neonates with FEVR and the relationship with disease severity., Methods: A retrospective, case-control study including 43 (58 eyes) newborn patients with FEVR at stages 1 to 3 and 30 (53 eyes) age-matched normal full-term newborns was conducted. The peripapillary vessel tortuosity (VT), vessel width (VW) and vessel density (VD) were quantified by computer technology. The t-distributed stochastic neighbor embedding (t-SNE) algorithm was used to visualize the relationship between the severity of FEVR and the characteristics of perioptic disc vascular parameters., Results: The peripapillary VT, VW and VD were significantly increased in the FEVR group compared with the control group (P < 0.05). Subgroup analysis showed that VW and VD increased significantly with progressing FEVR stage (P < 0.05). And only VT in stage 3 FEVR was significantly increased compared with stage 1 and stage 2 (P < 0.05). After controlling the confounders, ordinal logistic regression analysis indicated that the VW (aOR: 1.75, P = 0.0002) and VD (aOR: 2.41, P = 0.0170) were significantly independent correlated with the FEVR stage, but VT (aOR: 1.07, P = 0.5454) was not correlated with FEVR staging. Visual analysis based on the t-SNE algorithm showed that peri-optic disc vascular parameters had a continuity along the direction of FEVR severity., Conclusions: In the neonatal population, there were significant differences in peripapillary vascular parameters between patients with FEVR and normal subjects. Quantitative measurement of vascular parameters around the optic disc can be used as one of the indicators to assess the severity of FEVR., (© 2023. The Author(s).)

Purpose: To describe and analyze the clinical prognosis of infants diagnosed of familial exudative vitreoretinopathy (FEVR) with single gene mutation in long-term follow-up., Methods: A retrospective case study was conducted on 355 FEVR infants with single positive gene., Result: Of the 335 single-gene positive infant FEVR cases (under 3 years old), 20% (n = 67) was diagnosed of strabismus at first visit. Staging of various genotypes was different (P < 0.001). Patients with NDP mutations presented the most severe clinical phenotypes and patients with ZNF408 mutations presented the mildest clinical phenotypes. Most infants underwent surgery under 1 year old (5 th stage 75 of 108 [69.44%]). The axial length of different genotypes showed no significant difference (P = 0.2891). The 1 st to 3 rd stage cases were given intravitreal injection and/or retina photocoagulation with the last follow-up vision above 20/67. The 4 th to 5 th stage cases received the transcorneal vitrectomy with lensectomy or lens sparing vitrectomy (LSV), whose lens maintained transparent after LSV (11/14[78.58%]). After 2 to 10 years of follow-up, 37.96% (41/108) of post-surgery cases showed retinal funnel-like unfold and posterior pole unfold, 69.57% (16/ 23) of which received second surgery for closure of pupil with good prognosis. At the last follow-up, 20% (60/300) were with vision above 20/200., Conclusion: LRP5 gene mutation was the most common mutation in FEVR patients. The severity of the clinical phenotype varied with different gene mutations. The main surgical methods for cases at Stage 4-5 were transcorneal vitrectomy with lensectomy or LSV. The earlier FEVR occurred, the worse prognosis would be. Active surgical intervention and lens sparing were necessary for cases at Stage 4-5., (© 2022. The Author(s).)

Purpose: This study aims to analyze the Norrie disease gene (NDP) variants in patients with familial exudative vitreoretinopathy (FEVR) and their clinical features., Methods: Thirty-three Chinese patients (22 familial and 11 simplex) who were diagnosed as FEVR underwent detailed ocular examinations in Beijing Tongren Hospital. Peripheral venous blood was drawn from the patients and their family members for the extraction of genomic DNA. All exons of NDP gene were analyzed by direct sequencing of PCR-amplified DNA fragments., Results: Four novel mutations in NDP gene were identified in four X-linked FEVR families: a C → T transversion, c. 625C → T, in exon 3, resulting in a serine-to-proline change in codon 73 (S73P); a C → G transition, c. 751C → G, in exon 3, resulting in an arginine-to-glycine change in codon 115 (R115G); a T → C transversion of nucleotide 331 at 5'UTR in exon 2 (c.331 T → C); and a C → T transversion of the nucleotide 5 in intron 1 (IVS1 + 5C → T). The mutations were not present in the control group (n = 100)., Conclusions: Our results extend the spectrum of NDP gene mutations. The mutations in the non-coding region of NDP may play a crucial role in the pathogenesis of FEVR.

Background: To delineate the characteristics of complicated familial exudative vitreoretinopathy (FEVR) patients diagnosed before surgery or intra-/post-operatively and to analyze the risk factors for the diagnostic timing., Methods: Forty-eight patients who underwent surgery and were diagnosed as FEVR in our department were retrospectively reviewed. Data were collected including the demographic and clinical characteristics of these patients. FEVR patients were divided into 2 groups according to the diagnostic timing: FEVR diagnosed pre-operatively (23 patients), FEVR diagnosed intra-/post-operatively (25 patients). Multivariable analysis was applied for analyzing the risk factors for diagnostic timing., Results: The clinical characteristics of the FEVR patients were of great variability, including retinal detachment (RD), disappear of anterior chamber, retrolental membrane, epiretinal membrane (ERM), vitreous hemorrhage (VH), myopic foveoschisis (MF), lamellar macular hole (LMH), high myopia (HM). And the referral diagnosis or pre-operative diagnosis were always non-specific. The majority of the referral or preoperative diagnosis were unilateral RD (52.1%), bilateral RD (8.3%), unilateral persistent fetal vasculature (PFV) (8.3%), bilateral PFV (4.2%). There are two risk factors for the complicated FEVR cases diagnosed as FEVR preoperatively: pre-operative ocular manifestations with RD only (OR, 0.104; p-value, 0.022), positive parent's fluorescein angiography (FA) (OR, 0.105; p-value, 0.035)., Conclusions: The phenotypes of FEVR were greatly variable, they can mimic many non-specific vitreoretinal disorders. The most non-specific referral diagnosis/pre-operative diagnosis was unilateral RD, bilateral RD, unilateral PFV, bilateral PFV. A positive family history or a simple ocular presentation with RD only could contribute to diagnose FEVR preoperatively.