Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Ophthalmology & Visual Sciences Key Lab, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
Clinical College of Ophthalmology, Tianjin Medical University, Tianjin, China.
Mol Genet Genomic Med. 2023 Feb;11(2):e2083. doi: 10.1002/mgg3.2083. Epub 2022 Nov 5.
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.
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.
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.
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.
Wagner 玻璃体视网膜病变（WVR）是一种罕见的常染色体显性玻璃体视网膜病变，由 VCAN 基因的致病性变异引起。本研究旨在报告一个在中国三代家系中发现的 VCAN 的新型剪接变异体，该家系最初被诊断为家族性渗出性玻璃体视网膜病变，并描述患者的临床特征。
对一个三代家系的 4 名受影响个体进行了详细的眼科检查，包括 Snellen E 图表的最佳矫正视力、裂隙灯生物显微镜检查、瞳孔扩张下间接检眼镜检查、眼部 B 超检查、光学相干断层扫描和眼底自发荧光检查。对先证者进行了靶向下一代测序以鉴定致病基因突变，然后使用 Sanger-DNA 测序进行共分离分析。进行逆转录-聚合酶链反应 (RT-PCR) 以验证该变体对患者淋巴细胞中 VCAN 前体 mRNA 剪接的影响。
我们在所有 4 名受影响个体中均检测到 VCAN 的新型杂合变异 c.4004-4_c.4004-3delinsCA。RT-PCR 显示，该新型变异导致 VCAN 外显子 8 的异常剪接和 versican 转录物的失衡。所有 4 名患者均表现出玻璃体萎缩和双侧视网膜脱离，发生在不同的年龄。患者还表现出不同程度的视力缺陷和不同的临床表现，包括白内障、虹膜晶状体粘连、内翻乳头和异位黄斑。
我们的结果扩展了 VCAN 的突变谱，并进一步证实外显子 8 的剪接位点是突变热点。WVR 患者可能表现出高度的表型变异；因此，分子分析对于遗传性玻璃体视网膜病变患者的精确诊断非常重要。
