A novel splicing variant of VCAN identified in a Chinese family initially diagnosed with familial exudative vitreoretinopathy

Abstract

Background Wagner vitreoretinopathy (WVR) is a rare autosomal dominant vitreoretinopathy caused by pathogenic variants in the VCAN gene. The aim of this study was to report a novel splicing variant in VCAN identified in a three‐generation Chinese family initially diagnosed with familial exudative vitreoretinopathy and to describe the patients' clinical features. Methods Four affected individuals from a three‐generation family underwent detailed ophthalmic examinations, including best‐corrected visual acuity by Snellen E chart, slit‐lamp biomicroscopy, indirect ophthalmoscopy under pupil dilatation, ocular B‐ultrasonography, optical coherence tomography scans, and fundus autofluorescence. Targeted next‐generation sequencing was performed to identify variants of the disease‐causing gene for the proband, followed by co‐segregation analysis using Sanger‐DNA sequencing. Reverse transcriptase‐polymerase chain reaction (RT‐PCR) was carried out to verify the effects of a variant on VCAN pre‐mRNA splicing in the lymphocytes from the patients. Results We detected a novel heterozygous variant c.4004‐4_c.4004‐3delinsCA of VCAN in all four affected individuals. RT‐PCR revealed that the novel variant caused an abnormal splicing in exon 8 of the VCAN and imbalanced versican transcripts. All four patients presented vitreous syneresis and bilateral retinal detachment occurring at different ages. The patients also showed different extents of visual defects and diverse clinical manifestations, including cataract, iris–lens synechiae, inverted papillae, and ectopic foveas. Conclusions Our results expand the mutation spectrum of VCAN and further confirm that the splicing sites for exon 8 are mutation hot spots. Patients with WVR may present high phenotype variation; therefore, molecular analysis is very important for precise diagnosis of patients with inherited vitreoretinopathy.

Early onset high myopia and severe anisometropia associated with familial exudative vitreoretinopathy of irregular dominant inheritance in 12 Chinese families：analysis of refraction features and pathogenic variations

“…It has been previously reported that VCAN variant can lead to Wagner syndrome, which is often comorbid with anterior segment dysplasia, and the diagnosis is founded on the presence of characteristic ocular manifestations and family history consistent with autosomal dominant inheritance. In 2021, Zhong et al [42] , reported the discovery of a novel splice variant of the VCAN in a Chinese family diagnosed with familial exudative vitreoretinopathy, with vitreous syneresis and binocular retinal detachment at different ages in all 4 patients. In our study, family 2 patient in this study had typical fundus changes of FEVR such as vascular rigidity and increased branching of peripheral retinal vessels, but no obvious complaints of anterior segment dysplasia and night blindness, in combination with the literature, led to the nal diagnosis of FEVR in family 2.…”