389 例中国家系性渗出性玻璃体视网膜病变患者的变异谱。

Spectrum of Variants in 389 Chinese Probands With Familial Exudative Vitreoretinopathy.

机构信息

Department of Ophthalmology, Xin Hua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Department of Ophthalmology, Tianjin Medical University Eye Hospital, Tianjin, China.

出版信息

Invest Ophthalmol Vis Sci. 2018 Nov 1;59(13):5368-5381. doi: 10.1167/iovs.17-23541.

DOI:10.1167/iovs.17-23541

PMID:30452590

Abstract

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.

摘要

目的

在中国家族性渗出性玻璃体视网膜病变（FEVR）患者的 FZD4、LRP5、NDP、TSPAN12、ZNF408 和 KIF11 基因中鉴定潜在致病性变异（PPVs）。

方法

采集先证者及其父母的血样。通过下一代测序分析基因组 DNA，通过 Sanger 测序验证所选变异的序列。通过计算机分析和变异与疾病的共分离来评估变异的潜在致病性。对每个先证者进行全面的视网膜检查，并对每个眼睛的 FEVR 严重程度进行单独分级。只要可能，就对每个先证者的父母进行眼底荧光血管造影检查并进行分析。分析突变表达的变异性。

结果

本研究纳入了 389 个连续的 FEVR 患者来自 389 个家庭。约 74%的先证者是 7 岁以下的儿童。共鉴定出 101 个 PPVs 和 49 个意义不明的变异（VUS），包括 73 个新的 PPVs 和 38 个新的 VUS。110 个先证者携带 PPV（28.3%），51 个先证者携带 VUS（13.1%）。在 FZD4、LRP5、TSPAN12、NDP、ZNF408 和 KIF11 中发现的 PPVs 分别占队列的 8.48%、9.00%、5.91%、4.63%、0.77%和 0.77%。一般来说，携带 NDP 和 KIF11 的 PPV 的先证者的 FEVR 比携带其他基因的 PPV 的先证者更严重。总体而言，LRP5 和 FZD4 中的变异在表型上比 TSPAN12 和 NDP 基因中的变异表现出更显著的变化。