Tang Miao, Ding Xiaoyan, Li Jiaqing, Hu Andina, Yuan Miner, Yang Yu, Zhan Zongyi, Li Zijing, Lu Lin
State Key Laboratory of Ophthalmology, Retina Division, Zhongshan Ophthalmic Center, Sun Yat-sen University, 510060, Guangzhou, Guangdong, China.
Mol Vis. 2016 Jul 30;22:917-32. eCollection 2016.
To identify novel mutations in the frizzled 4 (FZD4) gene in patients with familial exudative vitreoretinopathy (FEVR) in southern China and to delineate the mutation-associated clinical manifestations.
Clinical data and genomic DNA were collected from 100 probands and their family members. The coding regions of FZD4 were screened for mutations with PCR and Sanger sequencing. Cosegregation analysis was used to verify suspected variants, and clinical symptoms in the probands were analyzed.
Fourteen causative heterozygous mutations in FZD4 in 21 unrelated probands were noted, in 21.0% of the index patients (21/100). Four novel missense mutations (C45R, C45S, C53S, and C90R) and three novel deletion mutations (T326fsX356, G492fsX512, and S345_A351del) with a high possibility of pathogenicity were detected. None of these mutations were found in current online databases and 150 ethnically matched control subjects without retinopathy. The majority of the mutations in FZD4 were identified in probands with retinal folds (15/21) and ectopic macula (5/21). No mutations in FZD4 were found in probands with complete tractional retinal detachment in infancy or with mild asymptomatic FEVR in adulthood.
Seven novel mutations found in this study have broadened the spectrum of mutations in FZD4 known to cause FEVR, providing a deeper understanding of this disease. The results show that mutations in FZD4 are associated with the phenotypes of retinal folds or ectopic macula in FEVR but might not be associated with extreme severe bilateral FEVR during infancy, at least in southern Chinese patients.
鉴定中国南方家族性渗出性玻璃体视网膜病变（FEVR）患者中卷曲蛋白4（FZD4）基因的新突变，并描述与突变相关的临床表现。
收集100例先证者及其家庭成员的临床资料和基因组DNA。采用聚合酶链反应（PCR）和桑格测序法筛查FZD4的编码区突变。共分离分析用于验证可疑变异，并分析先证者的临床症状。
在21例无关先证者中发现了14个FZD4致病杂合突变，占索引患者的21.0%（21/100）。检测到4个新的错义突变（C45R、C45S、C53S和C90R）和3个新的缺失突变（T326fsX356、G492fsX512和S345_A351del），具有高度致病性。在当前在线数据库和150名无视网膜病变的种族匹配对照受试者中均未发现这些突变。FZD4的大多数突变见于有视网膜皱褶（15/21）和黄斑异位（5/21）的先证者。在婴儿期有完全性牵拉性视网膜脱离或成年期有轻度无症状FEVR的先证者中未发现FZD4突变。
本研究发现的7个新突变拓宽了已知导致FEVR的FZD4突变谱，为深入了解该疾病提供了依据。结果表明，FZD4突变与FEVR中的视网膜皱褶或黄斑异位表型相关，但可能与婴儿期极端严重的双侧FEVR无关，至少在中国南方患者中如此。
