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Purpose: The purpose of this study is to report five novel FZD4 mutations identified in familial exudative vitreoretinopathy (FEVR) and to analyze and summarize the pathogenic mechanisms of 34 of 96 reported missense mutations in FZD4., Methods: Five probands diagnosed with FEVR and their family members were enrolled in the study. Ocular examinations and targeted gene panel sequencing were conducted on all participants. Plasmids, each carrying 29 previously reported FZD4 missense mutations and five novel mutations, were constructed based on the selection of mutations from each domain of FZD4. These plasmids were used to investigate the effects of mutations on protein expression levels, Norrin/β-catenin activation capacity, membrane localization, norrin binding ability, and DVL2 recruitment ability in HEK293T, HEK293STF, and HeLa cells., Results: All five novel mutations (S91F, V103E, C145S, E160K, C377F) responsible for FEVR were found to compromise Norrin/β-catenin activation of FZD4 protein. After reviewing a total of 34 reported missense mutations, we categorized all mutations based on their functional changes: signal peptide mutations, cysteine mutations affecting disulfide bonds, extracellular domain mutations influencing norrin binding, transmembrane domain (TM) 1 and TM7 mutations impacting membrane localization, and intracellular domain mutations affecting DVL2 recruitment., Conclusions: We expanded the spectrum of FZD4 mutations relevant to FEVR and experimentally demonstrated that missense mutations in FZD4 can be classified into five categories based on different functional changes.

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/purpose: To report the ocular findings in three patients with a mutation in the ATOH7 gene., Methods: The clinical findings were collected from the medical records including those for magnetic resonance imaging. Three patients of two families who had poor vision since infancy were studied. Genetic testing of the ATOH7 gene was performed., Results: The three patients had varying degrees of intraocular vascular proliferation associated with advanced retinal detachments as falciform retinal folds or total retinal detachments. This state is referred to as congenital retinal nonattachment. One eye of a sibling had fluorescein angiographic findings of excessive branching of the retinal vessels and fluorescent dye leakage that were consistent with those of familial exudative vitreoretinopathy. Bilateral hypoplasia of the optic nerve was found in all three patients by magnetic resonance imaging. Genetic analysis showed a known in-frame deletion of the ATOH7 gene in all three patients., Conclusion: This is the first report of a patient with a mutation in the ATOH7 gene that had typical vascular patterns of familial exudative vitreoretinopathy in the peripheral retina. The ocular features associated with mutations in the ATOH7 gene overlap those with familial exudative vitreoretinopathy at the early and advanced stages.

A monocular 22-year-old man with recalcitrant familial exudative vitreoretinopathy presented with progressive subretinal lipid exudation and lipid maculopathy that responded poorly to repeated aflibercept injections. The subretinal exudation started temporally and gradually progressed, involving the macula and the retinal periphery in all 4 quadrants. At the 22-month follow-up visit, macular and peripheral subretinal exudation persisted despite a total of 29 injections. Faricimab was then injected once every 2 weeks for a total of 3 injections, which resulted in rapid dramatic resolution of the macular and most of the peripheral subretinal exudation. No ocular or systemic adverse events were noted. [ Ophthalmic Surg Lasers Imaging Retina 2023;54:426-428.] .

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).)

Background/purpose: To report a case of Stickler Type IV with familial exudative vitreoretinopathy phenotype., Methods: Retrospective case report., Results: A 24-year-old woman presented with right eye exotropia and decreased vision. She had no facial or typical retinal features of Stickler syndrome but complained of right-sided hearing loss and right-sided neck pain. Examination of the right eye showed a chronic combined exudative and traction retinal detachment with temporal retinal dragging associated with far temporal retinal exudations and fibrovascular proliferations. The left eye had an attached retina with large areas of peripheral temporal retinal nonperfusion on fluorescein angiography, sharply demarcated by end circulation vascular pruning and mild peripheral vascular leakage, consistent with familial exudative vitreoretinopathy phenotype. Genetic analysis identified two heterozygous c.1052C>A and c.1349A>G variants in COL9A1, but did not disclose any mutation in genes classically associated with familial exudative vitreoretinopathy., Conclusion: Familial exudative vitreoretinopathy-like retinal vascular features can be the presenting sign in patients with Stickler syndrome Type IV.

Purpose: To report the concurrent presentation and management of IQCB1 -associated Leber Congenital Amaurosis and NDP- associated Familial Exudative Vitreoretinopathy (FEVR)., Materials and Methods: A 6-month-old Caucasian infant presented with poor visual response, high hypermetropia, and infantile-nystagmus with a provisional diagnosis of Leber Congenital Amaurosis based on clinical findings. Genetic counseling and testing were performed with a 285 gene retinal dystrophy panel (Blueprint Genetics). Clinical characteristics, presentation, ancillary testing results, and management are described., Results: Two previously reported heterozygous pathogenic variants in ICQB1 were identified (c.1518&#95;1519del (p.His506Glnfs*13) and c.1381C>T, p.Arg461*) segregating in trans . In addition, a variation of uncertain significance (VUS) was found in NDP (c.280C>T; p.His94Tyr). Fluorescein angiography was performed demonstrating peripheral avascularity and retinal telangiectasia without frank neovascularization. Peripheral ablative laser was applied to the avascular zone., Conclusions: The NDP VUS likely represents a pathogenic variant given the FEVR phenotype in addition to retinal degeneration, creating a rare dual phenotype. The combination of low oxygen demand from the IQCB1 -associated retinal degeneration and NDP variant may have led to a more attenuated FEVR presentation with uncertain prognosis. A molecular diagnosis informed ocular and renal surveillance, as well as the recurrence risk for future offspring.

Purpose: Familial exudative vitreoretinopathy (FEVR) is an inherited vitreoretinopathy. This study aimed to analyze the ocular phenotypes and systemic features of patients with CTNNB1 mutations., Methods: Whole exome sequencing was performed in the probands, and Sanger sequencing was used to verify the mutations and perform segregation analysis in the available family members. A luciferase assay was used to assess the effect of the mutant β-catenin on transcription. Comprehensive ocular examinations were performed on the probands and family members. Systemic features were evaluated and followed up., Results: A total of 763 FEVR families were enrolled. Seven different CTNNB1 mutations, including 5 novels and 2 known mutations, were detected in 8 families, accounting for 1.05% of all FEVR families. Compared to wild-type CTNNB1, the CTNNB1 mutants failed to induce luciferase reporter activity in SuperTopFlash (STF) cells. Among the 16 eyes of the 8 probands, 2 (12.5%) eyes were classified as stage 2 FEVR, 8 (50.0%) as stage 4, and 6 (37.5%) as stage 5. All the patients had varying degrees of systemic abnormalities and presented with motor, speech, and developmental delays over time. Among the eight families with CTNNB1 mutations, seven were de novo mutations, and one proband inherited the mutation from his asymptomatic mother., Conclusions: This study provides detailed descriptions of the ocular phenotypes of patients with CTNNB1 mutations that presented as severe FEVR, and accompanied with other systemic abnormalities. Five novel mutations identified in this study, expanded the mutation spectrum of CTNNB1-associated FEVR.

Objective: To explore the clinical manifestations and search for the variants of six related genes ( LRP5 , FZD4 , TSPAN12 , NDP , KIF11 and ZNF408 ) in Chinese patients with familial exudative vitreoretinopathy (FEVR), and investigate the correlation between the genetic variants and the clinical characteristics., Patients and Methods: Clinical data, including the retinal artery angle, acquired from wide-field fundus imaging, structural and microvascular features of the retina obtained from optical coherence tomography (OCT) and OCT angiography (OCTA) were collected from 33 pedigrees. Furthermore, mutation screening was performed. Variants filtering, bioinformatics analysis and Sanger sequencing were conducted to verify the variants., Results: Twenty-one variants were successfully detected in 16 of 33 families, of which 10 variants were newly identified. The proportion of variants in LRP5 , FZD4 , TSPAN12 , NDP and KIF11 was 38.1% (8/21), 33.3% (7/21), 19.1% (4/21), 4.8% (1/21) and 4.8% (1/21), respectively. Three new variants were considered to be pathogenic or likely pathogenic. The FEVR group tended to exhibit a smaller retinal artery angle, higher incidence of foveal hypoplasia and lower vascular density compared to the control group. Patients who harboured variants of FZD4 exhibited greater severity of FEVR than those with LRP5 variants. However, those who harboured LRP5 variants tended to possess lower foveal vascular density., Conclusions: Six known pathogenic genes were screened in 33 pedigrees with FEVR in our study, which revealed 10 novel variants. These findings enrich the clinical features and mutation spectrum in Chinese patients with FEVR, revealing the genotype-phenotype relationship, and contributing to the diagnosis and treatment of the disease.Key messagesWe identified 21 variants in 5 genes ( LRP5, FZD4, TSPAN12, NDP and KIF11) associated with FEVR, 10 of which are novel (three were pathogenic or likely pathogenic).The proportion of variants was the highest for the LRP5 gene. FZD4 variants may be responsible for greater FEVR severity than LRP5 variants.

Purpose: To report a case of 16-month-old boy with a novel variant TSPAN12 gene-presenting as unilateral myopia, pediatric cataract, and heterochromia in a patient with familial exudative vitreoretinopathy., Observation: A 16-month-old otherwise healthy boy was referred to Boston Children's Hospital for evaluation of strabismus. Ocular examination revealed intermittent esotropia, left hypotropia, and limited left eye elevation in both adduction and abduction. Full cycloplegic hyperopic correction of +3.50 diopters (D) over both eyes was given to the patient. Over several months, refraction of the right eye showed progressive myopia (-6.00 D) with new onset iris heterochromia. Fundus examination showed there was a large area of chorioretinal atrophy with abrupt ending of the blood vessels; anterior to the ora serrata there were diffuse vitreous bands and veils that reached the lens anteriorly in direct contact with the lenticular opacity. A novel heterozygous nonsense likely pathogenic variant was identified in the TSPAN12 gene (NM&#95;012338.3) c.315T>A (p.Cys105Ter) confirming the diagnosis of FEVR., Conclusion and Importance: Asymmetric FEVR rarely present with unilateral axial myopia however association with acquired heterochromia and cataract has never been reported. We report a case of FEVR caused by a novel TSPAN12 likely pathogenic nonsense variant presenting as unilateral progressive myopia, acquired heterochromia, and pediatric cataract.

Purpose: To investigate causative variants in three Chinese families affected with familial exudative vitreoretinopathy (FEVR)., Methods: Three unrelated Chinese families were recruited in this study. The three probands and their family members experienced a comprehensive age-appropriate eye examination and genetic analysis. Luciferase assay was performed to evaluate impacts of variants on Norrin/β-catenin signaling activity., Results: Here we report two novel NDP variants associated with FEVR in three families, including c.17T>C (p.Leu6Pro) in family 1 and c.58G>A (p.Gly20Arg) in family 2 and 3. These two variants were co-segregated with the disease phenotypes within each family. In addition, both variants resulted in compromised Norrin/β-catenin signaling activity., Conclusion: Our study identified two FEVR-associated pathogenic variants in NDP , which expanded the variant spectrum and provided information for the genetic diagnosis of FEVR.

Purpose: To analyze the clinical features of LRP5 gene mutation-related familial exudative vitreoretinopathy and explore the potential phenotype-genotype correlation on LRP5 gene., Methods: Eighty-seven familial exudative vitreoretinopathy (FEVR) families with LRP5 mutations were selected from 722 FEVR patients, which were divided into 2 groups, including 22 autosomal-recessive FEVR (ar-FEVR) families and 65 autosomal-dominant FEVR (ad-FEVR) families. Clinical and genetic data were retrospectively analyzed. The potential phenotype-genotype correlation was explored from the mutation type and inheritance pattern., Results: No significant difference between the LRP5 null mutation subgroup and the LRP5 missense mutation subgroup was observed in the proportion of FEVR stage and the ratio of ocular involvement. Instead, a significant difference between the LRP5 ar-FEVR subgroup and the LRP5 ad-FEVR subgroup was observed in the proportion of FEVR stage and the ratio of binocularly severe phenotype. The probands with LRP5 gene recessive mutation showed a higher incidence of severe phenotype. Moreover, the ratio of binocularly severe patients in ar-FEVR was nearly 3.5 times higher than that in ad-FEVR., Conclusion: The severity of phenotype was more likely to be related to the synergistic effect of the variants.

Importance: Familial exudative vitreoretinopathy (FEVR) is a nonsyndromic autosomal dominant retinal disorder commonly caused by variants in the FZD4 gene. This study investigates the potential role beyond ocular abnormalities for FZD4 gene variants in patients with FEVR., Objective: To evaluate the role of FZD4 in symptoms beyond those associated with FEVR through a patient with biallelic variants in FZD4., Design, Setting, and Participants: This case series included the DNA testing and phenotyping of 1 patient proband and her parents, combined with signaling assays, to determine the association of patient-derived compound heterozygous variants on FZD4 signaling and biologic function., Main Outcomes and Measures: FZD4 genes were tested using next-generation sequencing and Sanger sequencing. Cell-based assays measured the effect of the variants on FZD4 signaling., Results: The proband presented with absent red reflexes from complete tractional retinal detachments diagnosed at 3 days of age and failed the newborn screening hearing test. Auditory brainstem response at 6 months of age showed bilateral mild to moderate high-frequency sensorineural hearing loss. The patient manifested developmental delays in speech and walking. Intravenous fluorescein angiography (IVFA) of the patient's parents detected stage 1 FEVR. Genetic testing revealed 2 FZD4 variants in the patient, each variant found in 1 parent. Signaling assays confirmed that the presence of both variants was associated with significantly worse signaling activity compared with the heterozygous state., Conclusions and Relevance: Results of this case series suggest that extraocular syndromic FEVR was associated with FZD4 variants. The decrease in FZD4 signaling owing to the biallelic nature of the disease resulted in hearing deficits, developmental delays, and a more severe retinal phenotype.

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).)

Objective: To systematically review the relationship between genotypes and clinical phenotypes of Familial exudative vitreoretinopathy (FEVR) to support risk estimation and therapeutic decisions., Design: Systematic review with meta-analysis., Data Sources: The data of our study were collected from PubMed, Embase, Web of Science, Cochrane, CBM, China National Knowledge Infrastructure (CNKI), WAN FANG and VIP databases since inception to August 2021., Results: A total of 3257 patients from 32 studies were included according to the inclusion and exclusion criteria. Among all the cases, the mutation frequencies of LRP5, FZD4, NDP, TSPAN12, ZNF408 and KIF11 were 13.6%, 11.5%, 4.6%, 6.7%, 1.6%, and 5.7%, respectively. We found that the patients with NDP and FZD4 suffer more severe symptoms, among which 86.4% patients of NDP and 78.6% patients of FZD4 were in the advanced stage of FEVR. Retinal detachment is the most frequent symptom with patients of LRP5 and NDP mutations, accounting for 51.9% and 64.5%, respectively. For the patients with the mutation of TSPAN12, retinal fold is the most common clinical manifestation, and suffer the mildest clinical phenotypes compared with the other three genes., Conclusion: The results of the meta-analysis indicate that different types of genetic mutations occur at different frequencies. In addition, the clinical manifestations of FEVR are related to the type of gene mutation. Therefore, targeted treatment strategies and follow-up recommendations should be adopted for different pathogenic genes of FEVR., Competing Interests: The authors have declared that no competing interests exist.

Competing Interests: None

Objectives: The aim of the study was to present a new genetic association presenting with gastrointestinal tract malformations (GTMs) and familial exudative vitreoretinopathy (FEVR)-like disease and review the genetics of Hedgehog signaling., Materials and Methods: Three neonates were diagnosed with FEVR-like retinal vascular disease upon routine ophthalmological examination during hospitalization in the neonatal surgical intensive care unit for GTMs. Genetic analysis of the neonates was performed., Results: Gestational age of the neonates was 39, 38, and 39 weeks and birth weights were 3,500, 3,600, and 3,300 grams, respectively. All six eyes of the three infants were treated by laser photocoagulation. Recurrence was not seen in any of the eyes. Genetical analysis of all the neonates diagnosed with FEVR-like disease revealed defects in the Hedgehog pathway., Conclusion: FEVR is a genetically well-defined retinal vascular disease. The current study is the first to show an association between FEVR-like retinal vascular disease and GTMs. This study demonstrates the importance of the Hedgehog pathway in retinal vascular and gut development., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors., (©Copyright 2022 by Turkish Ophthalmological Association, Turkish Journal of Ophthalmology, published by Galenos Publishing House.)

Background: Familial exudative vitreoretinopathy (FEVR) is an inherited ocular disease with clinical manifestations of aberrant retinal vasculature. We aimed to identify novel causative variants responsible for FEVR and provided evidence for the genetic counselling of FEVR., Methods: We applied whole-exome sequencing (WES) on the genomic DNA samples from the probands and performed Sanger sequencing for variant validation. Western blot analysis and luciferase assays were performed to test the expression levels and the activity of mutant proteins., Results: We identified one novel heterozygous nonsense variant, and three novel heterozygous frameshift variants including c.1801G>T (p.G601*), c.1965delC (p.H656Tfs*41), c.4445delC (p.S1482Cfs*17), and c.4482delC (p.P1495Rfs*4), which disabled the function of LRP5 on the Norrin/β-catenin signalling. Overexpression of variant-carrying LRP5 proteins resulted in down regulation of the protein levels of β-catenin and the Norrin/β-catenin signalling target genes c-Myc and Glut1., Conclusion: Our study showed that four inherited LRP5 variants can cause autosomal dominant FEVR via down regulation of Norrin/β-catenin signalling and expanded the spectrum of FEVR-associated LRP5 variants., (© 2022 Royal Australian and New Zealand College of Ophthalmologists.)

Background: This study aimed to report the frequency of KIF11-mutations in a large familial exudative vitreoretinopathy (FEVR) population, extend the clinical spectrum of KIF11-associated retinopathy and compare KIF11-associated retinopathy to FEVR with mutations in other genes. Methods: Genetic data collected from 696 FEVR families were reviewed. The ocular phenotypes in patients with KIF11 mutations were analyzed and compared with those of FEVR patients with mutations in other genes (FZD4, TSPAN12, LRP5, NDP and JAG1). Results: In a cohort of 696 FEVR families, disease-causing KIF11 mutations were identified in 3.6% of families (25/696). Among 25 KIF11 mutations, 80% (20/25) carried variants of loss of function and 48% (12/25) of variants were de novo. The phenotypes were variable. Compared with FEVR with disease-causing mutations in other genes, chorioretinal dysplasia was observed in 44.2% (31/70) of eyes with KIF11-associated retinopathy and in only 1.3% (1/70) of eyes with FEVR with mutations in other genes (p < 0.01). Increase and straightening of peripheral vessels (ISPV) was observed in 17.1% (12/70) of eyes with KIF11-associated retinopathy, and in 50% (39/78) of eyes with FEVR with mutations in other genes (p < 0.01). Conclusions: The frequency of the KIF11 mutation in FEVR was 3.6% in our database. The manifestation of KIF11-associated retinopathy was variable and different from the phenotype in FEVR caused by other genes. Chorioretinal dysplasia, instead of retinal folds, was the dominant phenotype in KIF11-associated retinopathy. ISPV was rare in KIF11-associated retinopathy. Moreover, our study revealed that most pathogenic KIF11 mutations were de novo.

Familial exudative vitreoretinopathy (FEVR) is a rare hereditary vitreoretinopathy resulting from mutations in the wnt signaling pathway leading to abnormalities in fetal retinal vasculogenesis, angiogenesis, and retinal vascular maintenance. Severe FEVR may result in congenital retinal detachment resembling Norrie disease. The authors report the first case of planned preterm delivery and treatment of a patient with severe FEVR from biallelic LRP5 mutations whose siblings had congenital tractional retinal detachments with light perception vision outcomes after conventional care. Early intervention allowed laser ablation of avascular retina and functional visual outcome despite a successfully repaired unilateral tractional retinal detachment. [ Ophthalmic Surg Lasers Imaging Retina . 2022;53(4):228-232.] .

Background: Familial exudative vitreoretinopathy (FEVR) is a group of inherited eye diseases characterized by premature arrest of retinal vessel development. The purpose of our study was to characterize the genetic causes and clinical features in eight Chinese families with FEVR using next-generation sequencing (NGS) technology., Materials and Methods: Eight families with FEVR were included in genetic and clinical analyses. We screened the proband and the parents in eight pedigrees with FEVR using targeted NGS approach and in silico analysis to determine the causative mutation for their family's phenotype., Results: Four cases (4/8, 50.0%) were confirmed to harbor mutations in known genes, including 3 novel mutations and one previously reported mutation. Among the detected mutations, TSPAN12 accounted for 75% (3/4). We identified a novel stop codon of TSPAN12 , a heterozygous missense mutation NM&#95;012338.4:c.633T>A, NP&#95;036470.1:p.Tyr211Ter involved in highly conserved residues in the proband. Retrospective analysis of its clinical manifestation showed that the mutant carrier presented mild clinical features., Conclusions: We found the novel stop codon mutation p.Tyr211Ter in the TSPAN12 , which creates a milder phenotype. Discovery of this novel mutation expands the mutation spectrum of TSPAN12 , and would be valuable for future genetic disease diagnosis.

Background: Familial exudative vitreoretinopathy (FEVR) is a complex form of blindness-causing retinal degeneration. This study investigated the potential disease-causing variants in 20 Chinese families with FEVR., Methods: All available family members underwent detailed ophthalmological examinations, including best-corrected visual acuity and fundus examination. All probands and most family members underwent fluorescein fundus angiography. Twenty probands underwent whole exome sequencing; 16 of them also underwent copy number variant and mitochondrial genome analysis. Bioinformatics analysis and Sanger sequencing of available family members were used to confirm the disease-causing gene variant., Results: Twenty families were diagnosed with FEVR based on clinical symptoms, fundus manifestations, and fundus fluorescein angiography. Whole exome sequencing revealed 14 variants in NDP, FZD4, LRP5, and TSPAN12 genes among the 13 families. These variants were predicted to be damaging or deleterious according to multiple lines of prediction algorithms; they were not frequently found in multiple population databases. Seven variants had not previously been reported to cause FEVR: c.1039T>G p.(Phe347Val) in the FZD4 gene; c.1612C>T p.(Arg538Trp) and c.3237-2A>C in the LRP5 gene; and c.77T>A p.(Ile26Asn), c.170dupT p.(Leu57Phe fsTer60), c.236T>G p.(Met79Arg) and c.550dupA p.(Arg184Lys fsTer16) in the TSPAN12 gene. We did not detect any variants in the remaining seven families., Conclusions: These results expand the spectrum of variants in the NDP, FZD4, LRP5, and TSPAN12 genes and provide insights regarding accurate diagnosis, family genetic counseling, and future gene therapy for FEVR., (© 2022. The Author(s).)

Purpose: To evaluate the heterogeneity of both the clinical features and genetics of familial exudative vitreoretinopathy (FEVR) in a Northern Irish population., Methods: A retrospective trawl of a secure pediatric database was completed, as well as communication with all Northern Ireland ophthalmologists to identify adult cases. Cases were cross-referenced with a regional genetics database. Data on patient demographics, clinical findings, genetic testing, and patient treatment were collected., Results: Sixteen patients were identified. Average age at presentation was 11.8 years (range: 4 months to 38 years). Earlier age at presentation was associated with more advanced disease and those presenting later had more subtle signs such as retinal tear or vitreous hemorrhage. Four types of gene mutations were identified in 7 patients ( NDP , TSPAN12 , FZD4 , and KIF11 ). Thirteen patients had complications associated with FEVR and associated systemic conditions were found in 5 patients. Twelve eyes received active treatment to control disease., Conclusions: FEVR is a sight-threatening disease affecting prenatal retinal angiogenesis with a spectrum of disease and diverse genetic basis. Clinicians should look for signs of systemic and other ophthalmic sequelae in patients with FEVR because this could point to a genetic cause. Vigilance should also be exercised in older patients with unexplained vitreous hemorrhage or retinal tear with consideration of widefield angiography if FEVR is suspected. [ J Pediatr Ophthalmol Strabismus . 2022;59(2):102-109.] .

Competing Interests: Competing interests: None declared.

Background: Familial exudative vitreoretinopathy (FEVR) is a rare retinal disorder characterised by incomplete retinal vascular development. Symptoms vary widely from none to blindness even within the same family. Multiple genes related to the Wnt pathway have been found to be associated with FEVR. Recent studies identified tetraspanin 12 ( TSPAN12 ) as a cause of the autosomal dominant inheritance form of FEVR. Here, we describe a novel TSPAN12 mutation in a Chinese family with FEVR., Methods: Targeted next-generation sequencing was performed on the proband to define the TSPAN12 mutation. Sanger sequencing was used to confirm the mutation in five family members (I-1, II-2, II-3, II-4, and III-3) in a three-generation FEVR pedigree. Ophthalmologic examinations and diagnostic imaging related to FEVR were performed., Results: The proband (II-3) was a 32-year-old man with early-stage peripheral retinal vascular anomalies, but no visual acuity problems. DNA sequencing identified a heterozygous missense mutation (c.241 G > A: p.Gly81Arg) in TSPAN12 in the proband. The mutation was in a highly conserved region and was predicted to affect the normal protein structure. The patient's father and daughter were also diagnosed with FEVR and carried the same mutation, with varying degrees of manifestations. Other family members had good vision and normal eye examinations with negative genetic testing., Conclusions: We identified a novel missense mutation in TSPAN12 associated with autosomal dominant FEVR. These results will facilitate the diagnosis, prognosis, and genetic counselling for this disease. Further studies are needed to identify the mechanisms underlying clinical variations among individuals in the family.

Purpose: Familial exudative vitreoretinopathy (FEVR) is an inherited retinal vascular disease genetically heterogeneous with multiple causative genes. The aim of this study is to report five novel copy number variation (CNV) regions in FEVR patients and to investigate the possible contributions of novel CNVs to FEVR., Methods: In this study, 824 FEVR families were collected. All cases were performed using the targeted next generation sequencing (NGS) assay, and families with no definite pathogenic mutations in FEVR genes were screened for CNVs according to the NGS results. Droplet digital polymerase chain reaction (ddPCR) testing was introduced to validate the screened CNV regions. We also reviewed the clinical presentations of the probands and affected family members associated with the novel CNVs and conducted segregation analysis., Results: Five CNVs in five patients were detected in this study: heterozygous deletions of kinesin family member 11 ( KIF11 ) exons 2-4, KIF11 exon 11, KIF11 exons 1-10, tetraspanin-12 ( TSPAN12 ) exons 1-3, and low-density lipoprotein receptor-related protein 5 ( LRP5 ) exons 19-21. Among the five affected families, TSPAN12 exons 1-3 heterozygous deletion and LRP5 exons 19-21 heterozygous deletion originate from the mother and the father of the proband, respectively. No other family members manifested as FEVR except for the probands. The correlation between disease severity and CNV loci seems uncertain., Conclusions: Five novel CNV loci in FEVR patients were uncovered in this study, including one maternally-inherited and one paternally-inherited CNV region. Though there is no evidence of co-segregation between these CNVs and FEVR, our findings suggest novel genetic risk factors for FEVR., (Copyright © 2021 Molecular Vision.)

Purpose: The pathogenic variants in TSPAN12 could lead to familial exudative vitreoretinopathy (FEVR), which has high clinical variability. This study aims to assess the pathogenicity of TSPAN12 variants and their phenotypic spectrum based on exome sequencing from 7092 probands with different eye conditions., Methods: The variants in TSPAN12 were selected from exome sequencing data of samples from 7092 probands with different forms of eye conditions. Potentially pathogenic variants were evaluated through the annotation of types, locations, population frequencies, and in silico predictions of variants from in-house data, gnomAD, and published literature. The clinical features of patients with potentially pathogenic variants in TSPAN12 were assessed., Results: A total of 45 variants in TSPAN12 with coding effects were detected based on the exome data from 7092 probands, among which 31 were classified as pathogenic variants including 15 novels. The 31 variants were identified in 34 probands with various initial diagnoses, including FEVR in 21 probands and diseases other than FEVR in the remaining 13 probands. Biallelic pathogenic variants were identified in one proband with initial diagnosis of high myopia., Conclusion: Truncating variants and the missense variants that are predicted as deleterious are likely pathogenic variants of TSPAN12. Approximately 61.8% of patients with pathogenic variants in this gene had an initial diagnosis of FEVR, and the remaining 38.2% of patients had various initial diagnoses. These findings expand the understanding about variant evaluation of TSPAN12 and phenotypic spectrum of TSPAN12-associated FEVR., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Familial exudative vitreoretinopathy (FEVR) is a rare hereditary disorder characterized by abnormal or incomplete retinal angiogenesis. The peripheral avascularity, irregular neovascularization, and vascular leakage seen in FEVR are similar to changes that may be seen in retinopathy of prematurity (ROP). The authors report a case of atypical macular pigment clumping leading to the diagnosis of ROPER (ie, ROP vs FEVR) in a premature infant born at 23 weeks of gestation with a birth weight of 451 grams, who presented with atypical aggressive posterior ROP and a heterozygous variant in the LRP5 gene. [ Ophthalmic Surg Lasers Imaging Retina . 2021;52:505-508.] .

The vasa hyaloidea propria, a component of the fetal hyaloidal vasculature, is characterized by multiple persistent fetal vasculatures branching into the vitreous. We present a 4-month-old girl with stage 4 familial exudative vitreoretinopathy, with multiple ectopic retinal vessels extending into the vitreous, confirmed with fluorescein angiography, which was consistent with persistent vasa hyaloidea propia/retinae making contact with the retina. The patient underwent vitreoretinal surgery to address the retinal detachment, during which the patent stalks of the persistent vasa hyaloidea propia/retinae were transected., (Copyright © 2020 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Familial exudative vitreoretinopathy (FEVR) is a rare inherited disorder affecting retinal angiogenesis that may present with a wide range of phenotypic characteristics. In this report, the authors describe an atypical presentation of FEVR in a healthy 9-year-old male with progressive decreased visual acuity in the left eye. Fundus examination showed an avascular retina in the temporal periphery bilaterally. The left eye also revealed serpiginous hypopigmented lesions in the superior quadrant, which showed intraretinal location on optical coherence tomography and hyperautofluorescence. Genetic testing revealed LRP5 mutation, confirming a diagnosis of FEVR. The serpiginous lesions represent an unusual finding associated with FEVR not previously described in the literature. [ Ophthalmic Surg Lasers Imaging Retina . 2021;52:155-159.] .

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.

Competing Interests: None

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.

Purpose: To report the identical twins who had mirror fundus and angiographic images of familial exudative vitreoretinopathy (FEVR)., Case Presentation: A pair of 16 year old female twins presented with mirror-image asymmetry of monocular decreased vision. The twins were born full term with normal weights. Neither twin revealed any medical disorders during childhood and there was no known family history of ocular disorders. On ocular examination, the best corrected visual acuity (BCVA) was 20/20 in OD and 20/63 in OS for twin 1. For the twin 2, the BCVAs were 20/63 and 20/20 for OD and OS, respectively. Intraocular pressures were within normal limits and anterior segment examinations were unremarkable for both twins. Dilated fundus examinations and angiographic images revealed characteristics FEVR appearance with mirror image phenomenon in the twins., Conclusion: This is the first report describing identical twins with mirror images of FEVR. This report may confirm a strong underlying genetic inheritance in the pathogenesis of FEVR.

Background: Frizzled family members belong to G-protein coupled receptors and encode proteins accountable for cell signal transduction, cell proliferation and cell death. Members of Frizzled receptor family are considered to have critical roles in causing various forms of cancer, cardiac hypertrophy, familial exudative vitreoretinopathy (FEVR) and schizophrenia., Results: This study investigates the evolutionary and structural aspects of Frizzled receptors, with particular focus on FEVR associated FZD4 gene. The phylogenetic tree topology suggests the diversification of Frizzled receptors at the root of metazoans history. Moreover, comparative structural data reveals that FEVR associated missense mutations in FZD4 effect the common protein region (amino acids 495-537) through a well-known phenomenon called epistasis. This critical protein region is present at the carboxyl-terminal domain and encompasses the K-T/S-XXX-W, a PDZ binding motif and S/T-X-V PDZ recognition motif., Conclusion: Taken together these results demonstrate that during the course of evolution, FZD4 has acquired new functions or epistasis via complex patter of gene duplications, sequence divergence and conformational remodeling. In particular, amino acids 495-537 at the C-terminus region of FZD4 protein might be crucial in its normal function and/or pathophysiology. This critical region of FZD4 protein may offer opportunities for the development of novel therapeutics approaches for human retinal vascular disease.

Competing Interests: Competing interests: None declared.

Purpose: To identify novel mutations in FZD4 and to investigate their pathogenicity in a cohort of Chinese patients with familial exudative vitreoretinopathy (FEVR)., Methods: Next-generation sequencing was performed in patients with a clinical diagnosis of FEVR. Wide-field angiography was performed in probands and family members if available. Clinical data were collected from patient charts. The effect of the mutations in FZD4 on its biologic activity in the Norrin/β-catenin signaling pathway was analyzed with the luciferase reporter assay., Results: Four novel mutations in FZD4 (c.1188&#95;1192del/p.F396fs, c.1220delC/p.A407Vfs*24, c.905G>A/p.C302Y, c.1325T>A/p.V442E) were identified in four unrelated families. The mutations were not detected in 200 healthy individuals. The variability of the ocular phenotypes was not only observed in the probands and parents harboring the same mutation but also between two eyes in one individual. All four novel mutations introduced reduction in luciferase activity. Compared with the wild-type, the FZD4 level of the four mutants also decreased variably., Conclusions: Four novel mutations in FZD4 were identified in Chinese patients with FEVR. No correlation in the reduced luciferase activity and the ocular phenotype was observed in this study. This study further emphasized the complexity of the FEVR-causing machinery.

Familial exudative vitreoretinopathy (FEVR) is a rare hereditary ocular disorder characterized by incomplete or abnormal development of peripheral retinal vasculature. The genes responsible for this disorder are associated with the wingless-related integration site (Wnt) signaling pathway, a critical pathway for the development of normal retinal vasculature. A pathogenic variant in any one of these genes may disrupt retinal vasculogenesis. Furthermore, the type and number of pathogenic variants may influence the severity of disease and clinical course. Here, the authors identify a novel pathogenic variant in the NDP gene, not previously described in the literature. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:120-124.]., (Copyright 2019, SLACK Incorporated.)

A 17-year-old boy, previously diagnosed with familial exudative vitreoretinopathy (FEVR) due to LRP5 mutation, complained of left eye decreased vision. Serial imaging by optical coherence tomography showed vitreomacular traction that progressed to lamellar macular hole (MH), and further evolved to full-thickness MH 3 weeks later. Visual acuity (VA) was 20/200. Pars plana vitrectomy with encircling buckle, internal limiting membrane peeling, and gas tamponade were performed. Three months postoperatively, VA had increased to 20/25 and the MH remained closed. This case illustrates how vitreomacular interface disorders may complicate FEVR, as exemplified for the first time in a case with LRP5 mutation. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e49-e51.]., (Copyright 2019, SLACK Incorporated.)

Purpose: Germline and somatic mutations in CTNNB1 have been found in different types of human diseases. This follow-up study aimed to identify causative germline mutations in CTNNB1 and their associated ocular phenotypes through a comparative analysis of whole-exome sequencing data., Methods: Annotated sequence variations in CTNNB1 were selected from in-house data from whole-exome sequencing of genomic DNA prepared from leucocytes of 3280 unrelated probands with different forms of eye diseases. Potentially pathogenic variants in CTNNB1 were analyzed by multistep bioinformatics analyses. Clinical data from probands with pathogenic variants in CTNNB1 were collected, and potential genotype-phenotype correlations were analyzed., Results: Eleven rare variants that potentially affect the coding regions of CTNNB1 were detected in 11 of the 3280 samples, and four variants were considered to be potentially pathogenic. All four mutations, namely, c.999delC (p.Tyr333*), c.1104delT (p.His369Thrfs*2), c.1738&#95;1742delinsACA (p.Leu580Thrfs*28), and c.1867C>T (p.Gln623*), were heterozygotes and considered to have a germline origin. Three of the four mutations are de novo mutations, and the status of the remaining mutation is unavailable. All four probands had the same class of closely related ocular diseases: one proband had FEVR, and three probands had Norrie-like retinopathy. The molecular results indicated that three probands showed systemic anomalies, as demonstrated by a follow-up survey, but relevant information for the remaining proband was unavailable., Conclusions: The data suggest that germline truncating mutations in CTNNB1 cause autosomal dominant syndromic FEVR or Norrie disease. Patients with mutations in CTNNB1, KIF11, or NDP may have similar or overlapping phenotypes, but this phenomenon needs to be studied further.

Background: Both familial exudative vitreoretinopathy (FEVR) and Norrie disease (ND) are hereditary retinal disorders which can cause severe visual impairment and blindness at a young age. The present study aimed to report the use of antenatal genetic testing and ultrasound in the diagnosis and counseling of FEVR and ND., Methods: Amniocentesis and ultrasonography were performed in high-risk mothers, with children having FEVR or ND, to predict severe ocular abnormalities., Results: Case 1: A homozygous NDP mutation (c.376T>C, NM&#95;000266) was detected in the proband and his mother. Molecular prenatal analysis of the fetal DNA revealed no mutations. No ocular abnormalities were detected on ultrasonography. The pregnancy progressed uneventfully to a normal outcome. Case 2: A novel heterozygous FZD4 mutation (c.1010dupA, NM&#95;012193) was detected in the proband and his mother. The same mutation was detected in the fetus, but ultrasonography showed no ocular abnormalities. A healthy baby boy with stage 1 FEVR was born after an uneventful pregnancy. Case 3: Deletions of exons 2 and 3 in the NDP were found in the proband and his mother. The same deletion mutation was detected in the female fetus, but the ultrasound scan was normal. The pregnancy progressed uneventfully to a normal outcome., Conclusions: To our knowledge, antenatal genetic analyses were used in conjunction with ultrasound for the first time, to diagnose FEVR and ND, and predict the postnatal prognoses in at-risk babies., (© 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Purpose: To evaluate the microstructure of the fovea in patients with familial exudative vitreoretinopathy (FEVR) compared to healthy controls using optical coherence tomography angiography (OCTA)., Methods: In this consecutive, cross-sectional, observational case series, 41 eyes of 41 patients diagnosed as FEVR and 37 eyes in 37 control subjects were studied. OCTA was utilized to automatically measure the foveal avascular zone (FAZ) and the vessel density (VD). Inner retinal thicknesses (IRT) and central retinal thickness (CRT) were measured with the instrument caliper. Targeted next-generation sequencing was performed, and phenotype-genotype association was analyzed., Results: Small FAZ was found in 31.70% (13/41) FEVR eyes but not in controls. Greater CRT and lower superficial foveal VD were noted in FEVR patients. FAZ is negatively correlated with IRT. Persistence of the inner retinal layer (IRL) in fovea was present in 48.78% (20/41) FEVR eyes but not found in controls. Zero percent (0/10) of patients with the low-density lipoprotein receptor-related protein 5 (LRP5) mutation, 50% (1/2) with the frizzled-4 (FZD4) mutation, and 66.67% (3/4) with the tetraspanin-12 (TSPAN12) mutation had preserved foveal IRL and small FAZ., Conclusions: Our data indicate FEVR status is associated with a significantly smaller FAZ, decreased vascular density in both the superficial and deep layers of parafoveal area, a thicker fovea, and an abnormally preserved IRL in fovea. In addition, patients with the LRP5 mutation had a milder phenotype than those with the FDZ4 or TSPAN12 mutations. These novel findings could provide insight into the understanding of the pathogenesis of FEVR.

Background: Loeys-Dietz syndrome (LDS) is a connective tissue disorder that has phenotypic overlap with Marfan syndrome. In LDS, the aortic root dissections can be more aggressive and occur at a younger age than Marfan syndrome., Materials and Methods: Review of two cases., Results: A 7-year old boy with history of LDS was found to have a vitreous hemorrhage in the right eye. Further examination showed findings of Familial Exudative Vitreoretinopathy (FEVR). Both eyes were found to have peripheral non-perfusion and neovascularization. A non-related 25-month-old boy with no molecularly confirmed connective tissue disorder was found to have bilateral peripheral non-perfusion and bilateral tractional retinal detachments. The boy was clinically diagnosed with Larsen syndrome, Ehlers-Danlos syndrome kyphoscoliotic form, and Marfan syndrome before presentation. The FEVR lead to consideration of LDS that was molecularly confirmed. Consequently, he was monitored for aortic root dilation., Conclusion: FEVR findings may lead to diagnosis of LDS and patients with LDS may present with proliferative retinopathy.

Familial exudative vitreoretinopathy (FEVR) is an inherited retinal disorder, which is primarily characterized by abnormal development of retinal vasculature. In this study, we reported a subject presenting the clinical features of FEVR as well as microcephaly. Screening of the KIF11 gene in this patient revealed a novel heterozygous protein-truncating variant (c.2717del, p.(L906*), NM&#95;004523.3). Segregation analysis in the unaffected parents using Sanger sequencing suggested the variant to be present in a mosaic state in the unaffected mother. KIF11 exon 19 which harbors the variant was amplified from the proband and her father, as well as three different tissues of the mother, followed by amplicon-based deep sequencing. This analysis revealed that the variant is present in different tissues of the mother at various rates, i.e. in blood (16.9%), saliva (20.7%), or skin biopsy-derived fibroblast cells (6.6%). These data demonstrate the importance of deep sequencing in unaffected parents upon detection of a genetic defect in isolated cases to detect possible mosaicisms, enabling a  more reliable recurrence risk assessment and thereby improve genetic counseling.

Background: To evaluate the clinical outcome of 25-gauge lens-sparing vitrectomy with dissection of retrolental adhesions on the peripheral retina for familial exudative vitreoretinopathy in infants., Methods: Fifty-one eyes of 39 infants with familial exudative vitreoretinopathy associated with retrolental adhesions on the peripheral retina, retinal fold with macular detachment, and partial lens opacity. A 25-gauge lens-sparing vitrectomy was performed, and retrolental adhesions between the peripheral retina and the posterior lens capsule were surgically dissected. Lens opacification, as assessed or graded by Lens Opacities Classification System III, and the retinal reattachment rate were observed and recorded monthly for up to 7 months postoperatively., Results: After 7 months, the detached retina along the retinal fold was reattached in 42/51 (82.4%) eyes; the macula was reattached completely in 26/51 (51.0%) eyes and partially in 15/51 (29.4%) eyes. There was no statistically significant change in the lens opacity of the posterior capsule or cortex before or after surgery (P > 0.05, paired t test) or in postoperative progression of lens opacity (P > 0.05, modified McNemar's test) according to Lens Opacities Classification System III scores., Conclusions: A 25-gauge lens-sparing vitrectomy with dissection of peripheral retinal retrolental adhesions is helpful for preservation of the lens and reattachment of the macula in infants with FEVR.

Aim: To describe and analyse the clinical and genetic characteristics of digenic familial exudative vitreoretinopathy (FEVR)., Methods: The study cohort consisted of patients with FEVR (n = 13) to identify patients with two mutations in two different genes. A genetic analysis of the LRP5, FZD4, TSPAN12, and ZNF408 genes was performed with next-generation sequencing (NGS). The genotype data obtained from the patients with FEVR were analysed and correlated with their clinical manifestations. They were then further evaluated in conjunction with other data that were available for these genes. The probands and parents/relatives underwent comprehensive age-appropriate ophthalmic examinations., Results: The medical history and genetic reports of 487 patients with FEVR were reviewed. In all, we identified 13 probands (2.67%, 13/487) with simultaneous mutations in two disease-causing genes. A total of 25 of mutations were found, including10 in FZD4, 8 in LRP5, 3 in ZNF408, 2 in NDP, and 2 in TSPAN12. The most frequent mutations were those in FZD4 and LRP5. We identified 8 mutations that had previously been identified and 17 novel variants. Among 26 eyes, 65.38% exhibited a phenotype, and 10 (38.46%) were stage 4, while 7 (26.92%) were stage 5., Conclusions: This is the first study to report a group of patients with digenic FEVR. In most affected eyes, the stage was more severe than stage 3. We speculate that the phenotype of FEVR is more severe in patients with digenic rather than monogenic variants of FEVR-related genes.

Purpose: To identify potentially pathogenic variants (PPVs) in Chinese familial exudative vitreoretinopathy (FEVR) patients in FZD4, LRP5, NDP, TSPAN12, ZNF408, and KIF11 genes., Methods: Blood samples were collected from probands and their parent(s). Genomic DNA was analyzed by next-generation sequencing, and the sequence of selected variants were validated by Sanger sequencing. The potential pathogenicity of a variant was evaluated by in silico analysis and by cosegregation of the variant with disease. Each proband was subjected to comprehensive retinal examinations, and the severity of FEVR was individually graded for each eye. Whenever possible, fundus fluorescein angiography was obtained and analyzed for parent(s) of each proband. Variation in mutation expressivity was analyzed., Results: Three hundred eighty-nine consecutive FEVR patients from 389 families participated in this study. About 74% of the probands were children younger than 7 years old. One hundred one PPVs, 49 variants with unknown significance (VUS), were identified, including 73 novel PPVs and 38 novel VUS. One hundred ten probands carried PPV (28.3%), and 51 probands carried VUS (13.1%). PPVs in FZD4, LRP5, TSPAN12, NDP, ZNF408, and KIF11 were found in 8.48%, 9.00%, 5.91%, 4.63%, 0.77%, and 0.77% of the cohort, respectively. Probands carrying PPVs in NDP and KIF11 had more severe FEVR in general than those carrying PPVs in other genes. Overall, variants in LRP5 and FZD4 showed more significant variation in phenotype than variants in TSPAN12 and NDP genes., Conclusions: Our study expanded the spectrum of PPVs associated with FEVR.