伴心血管异常的先天性晶状体脱位五家系基因型-表型关联分析

Genotype-phenotype analysis of five families with congenital ectopia lentis accompanied with cardiovascular abnormalities

目的分析5个伴心血管异常的先天性晶状体脱位(CEL)家系基因型与临床表型之间的关联(方法纳入2017年8月至2018年3月中山大学中山眼科中心收治的5个CEL家系共15例家系成员,进行详细相关临床检查和记录,包括裂隙灯显微镜检查扩瞳前后晶状体情况,心脏超声检查评价心血管系统情况,以及X射线成像评价研究对象骨骼系统系统受累程度(采集15例参与者外周静脉血,提取基因组DNA。同期纳入100名无血缘关系的汉族人群作为对照组(利用靶向外显子捕获测序技术筛查FBN1基因突变,回顾各位点既往文献,并分析可能的基因型-表型关联(结果5例先证者均为先天性晶状体脱位患者合并心血管异常,均携带FBG1基因突变,其中4例携带错义突变(c.2741G〉T、c. 2585G〉T、c. 1633C〉T、c.4260C〉G),1例为新发剪切位点突变(c.21142G〉 C)( 5个突变均预测为导致蛋白质结构的改变。结论FBG1基因具高度临床异质性,早期发现眼部表型并结合基因筛查对心血管异常风险的诊断具重要意义。

Objective To analyze the genotype-phenotype correlation in 5 families with congenital ectopia lentis (CEL) accompanied with cardiovascular abnormal manifestation. Methods Detailed clinical data of 15 family members in 5 families were collected from August 2017 to March 2018 in Zhongshan Ophthalmic Center,including examination of the condition of lens before and after mydriasis by slit-lamp,evaluation of the cardiovascular system using transthoracic echocardiography,and evaluation of the degree of involvement of the subjects' skeletal system using X-ray images.Genomic DNAs were extracted from whole blood sample of the 5 probands and 10 relatives,and screened for FBN1 mutation by targeted exome sequencing.The possible genotype-phenotype correlation was analyzed by reviewing previous literatures into these mutation sites.The study followed the principles of the Helsinki Declaration and written informed consent was obtained from each subject prior to any examination. Results All of the five probands were diagnosed as CEL accompanied with cardiovascular abnormal manifestation. FBN1 gene mutations were identified in all of the five probands,including four missense mutations (c.2741G>T,c.2585G>T, c.1633C >T,c.4260C>G) and one splicing mutation (c.2114-1G>C).It was predicted that all of the 5 mutations would alter the protein structure. Conclusions FBN1 gene has a high degree of clinical heterogeneity,and the early detection of ocular phenotypes combined with genetic screening is of great significance in the diagnosis of cardiovascular abnormalities.