Clinical manifestations of familial exudative vitreoretinopathy in children with nucleotide sequence alterations in the FZD4 gene

Familial exudative vitreoretinopathy (FEVR)is a rare genetically heterogeneous disease with multiple types of inheritance (autosomal dominant, autosomal recessive, X-linked) and widely varying clinical features. Up to 40 % of cases of FEVR are associated with mutations of the FZD4 gene.Purpose: to investigate the clinical manifestations of FEVR in children with nucleotide sequence alterations in the FZD4 gene. Material and methods. The Helmholtz National Medical ResearchCenter of Eye Diseases and the ResearchCentre for MedicalGenetics conducted a joint in-depth ophthalmological examination of 18 patients aged from 3 weeks to 17 years with a diagnosis of FEVR, which included a detailed ophthalmoscopy under drug mydriasis, ultrasound and electrophysiological examination, photographic recording of fundus changes using RetCam and Fundus Foto. Molecular genetic examination was carried out by direct sequencing according to Sanger. Results. Nucleotide sequence alterations in the FZD4 gene were detected in 3 patients(16.7 %)from two unrelated families. In one family, a 12-year-old girl wasfound to display the firstsymptoms of ophthalmic pathology (reduced vision, strabismus) at the age of 3.5 years. In another family, the clinical manifestations of FZD4 gene mutations were observed in two children during the first year of life (at the age of 5 and 11 months).Conclusions. The clinical picture of 3 patients with detected changes in the nucleotide sequence of the FZD4 gene is characterized by early manifestation and bilateral asymmetric ophthalmoscopic damage. The results of the study indicate the need for a timely diagnosis of FEVR in young children, recommend an interdisciplinary approach to the study of the disease, which should contribute to a better understanding of pathogenesis, and the development of an effective diagnostic, treatment and rehabilitation algorithm.

Whole Exome Sequencing Revealed Three Novel Variants in TSPAN12 and LRP5 Genes for Two Families with Familial Exudative Vitreoretinopathy

Background: Familial exudative vitreoretinopathy (FEVR) is a complex form of blindness-causing retinal degeneration. This study investigated the potential disease-causing variant and molecular basis in two Chinese families with FEVR. Methods: All family members underwent detailed ophthalmological examinations, including best-corrected visual acuity, fundus examination, and fluorescein fundus angiography. Whole exome sequencing, bioinformatics analysis, and Sanger sequencing of available family members were used to confirm the disease-causing gene variant. Results: The proband F1-II:1, his mother, and proband F2-II:1 were diagnosed with FEVR based on clinical symptoms, fundus manifestation, and fundus fluorescein angiography. Whole exome sequencing showed that the proband F1-II:1 had a novel heterozygous variant in the TSPAN12 gene, c.236T>G p. (Met79Arg), which may disturb the transmembrane domain of the TSPAN12 protein. The variant was cosegregated with the phenotypes of FEVR in the family. The proband F2-II:1 carried novel compound heterozygous variants, c.1210G>A p. (Gly404Arg) and c.1612C>T p. (Arg538Trp), in the LRP5 gene, which may disturb the second β-propeller motif of the LRP5 protein. These three variants were classified as likely pathogenic variants. The variants were predicted to be damaging or deleterious using multiple lines of prediction algorithms; they were not frequently found in multiple population databases. The residues affected by these variants are highly conserved among different species. The three novel variants may be potential disease-causing variants in the two families. Conclusions: These results expand the spectrum of variants in TSPAN12 and LRP5 genes and enrich the understanding of the molecular etiology of FEVR.

Familial Exudative Vitreoretinopathy (FEVR); Pathophysiology, Findings, Diagnosis, and Treatment

Familial exudative vitreoretinopathy (FEVR) is an inherited disease occurring due to defective retinal angiogenesis. FEVR patients have an avascular peripheral retina which, depending on the degree of ischemia, causes the secondary complications of the disease (retinal neovascularization, exudation, hemorrhage, and retinal detachment) Mutations in the NDP, FZD4, LRP5, TSPAN12 and ZNF08 genes have been shown to contribute to FEVR. Cases can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner, or can affect individuals with no family history. Examination with wide-field fluorescein angiography is essential and can identify the disease in its earlier stages, enabling the timely treatment, in addition to helping identify asymptomatic family members. The current treatment modalities involve laser photocoagulation of the avascular peripheral retina for neovascular complications and vitreoretinal surgery for retinal detachment. Studies are ongoing to better understand the pathogenesis of FEVR and to improve treatment

Whole-Gene Deletions of FZD4 Cause Familial Exudative Vitreoretinopathy

Familial exudative vitreoretinopathy (FEVR) is an inherited disorder characterized by abnormalities in the retinal vasculature. The FZD4 gene is associated with FEVR, but the prevalence and impact of FZD4 copy number variation (CNV) on FEVR patients are unknown. The aim of this study was to better understand the genetic features and clinical manifestations of patients with FZD4 CNVs. A total of 651 FEVR families were recruited. Families negative for mutations in FEVR-associated genes were selected for CNV analysis using SeqCNV. Semiquantitative multiplex polymerase chain reaction and multiplex ligation-dependent probe amplification were conducted to verify the CNVs. Four probands were found to carry whole-gene deletions of FZD4, accounting for 5% (4/80) of probands with FZD4 mutations and 0.6% (4/651) of all FEVR probands. The four probands exhibited similar phenotypes of unilateral retinal folds. FEVR in probands with CNVs was not more severe than in probands with FZD4 missense mutations (p = 1.000). Although this is the first report of FZD4 CNVs and the associated phenotypes, the interpretation of FZD4 CNVs should be emphasized when analyzing the next-generation sequencing data of FEVR patients because of their high prevalence.