结节性硬化症家系的基因诊断及产前诊断  

Mutation screening and prenatal diagnosis of tuberous sclerosis complex

作　　者：李汶[1,2] 周立花[1] 高伯笛 李麓芸[1,2] 钟昌高[1] 龚斐[1,2] 肖红梅[1,2] 宋涛[3] 卢光琇[1,2] 

机构地区：[1]中南大学生殖与干细胞工程研究所,长沙410078 [2]中信湘雅生殖与遗传专科医院 [3]湘雅医院神经外科

出　　处：《中华医学遗传学杂志》2011年第4期361-366,共6页Chinese Journal of Medical Genetics

摘　　要：目的对结节性硬化症（tuberous sclerosis complex，TSC）患者进行基因突变检测，并在基因诊断结果明确的基础上应用于产前诊断。方法应用聚合酶链反应一变性高效液相色谱（polymerase chain reaction-denaturing high-performance liquid chromatography, PCR-DHPLC）、DNA测序技术，对19个家系的21例TSC患者进行TSC1和TSC2基因的突变检测。结果在19个家系21例患者中发现17种不同的基因突变，其中13种突变未见报道，包括TSC1基因的c．2672delA、c．2672insA和TSC2基因的c．4918insCGCC、c．1143delG、Intron27＋1G〉A、c．1957—1958delAG、Intron5＋1G〉A、c．910insCT、c．2753C〉G、c．4078dupAGCAAGTCCAGCTCCTC、Intron11—1G〉A、Intron14＋1G〉A、c．684C〉A。对7个家系进行了产前诊断，其中6个家系的胎儿均未发现其家系先证者所具有的突变，胎儿出生后电话随访至1～4岁无TSC的症状出现。而另一家系的胎儿携带有和母亲一样的突变，经遗传咨询后，家属选择了引产。结论本研究证实的TSC基因突变中，有76．5％（13／17）的突变均未在其他研究中被发现，说明中国人群TSC基因的突变谱可能与其他人群具有较明显的差异；本研究中TSC基因诊断率为89．5％（17／19），提示TSC的发生可能还有其它未知的遗传病因；在有家族史的病例中，TSC1与TSC2有相似的突变比例，而在散发病例中，TSC2的突变更加常见；13种新突变患者的父母均无类似突变，说明TSC致病基因具有较高的自发突变率。Objective To screen mutations of tuberous sclerosis complex （TSC） patients to confirm a clinical diagnosis of TSC, and to perform prenatal diagnosis for families with mutations. Methods In this study, PCR-denaturing high-performance liquid chromatography（DHPLC）, supplemented with sequencing when necessary, was used to screen TSC1 and TSC2 mutations in 21 patients from 19 pedigrees visited author＇s hospital in the last five years. For novel mutations, one hundred unrelated healthy individuals were screened to exclude the possibility of polymorphism. Results Seventeen different mutations were found in 21 patients of 19 pedigrees with 13 being novel mutations, including c. 2672delA, c. 2672insA of TSC1 gene and c. 4918insCGCC, c. 1143delG, Intron27 ＋ 1 G〉 A, c. 1957-1958delAG, Intron5＋ 1 G〉 A, c. 910insCT, c. 2753 C〉G, c. 4078dupAGCAAGTCCAGCTCCTC, Intron 11-1 G〉A, Intron 14 ＋1 G 〉A, c. 684 C〉A of TSC2 gene, indicating a high frequency of de novo mutations in TSC. Three of these mutations were in the TSC1 gene （N762S, c. 2672insA and c. 2672delA）, while all remaining 14 were in the TSC2 gene. Prenatal diagnosis for TSC was performed for 7 fetuses from these pedigrees. The six fetuses that tested negative for TSC mutations were carried to term and, to date, none of these children has shown symptoms of TSC. Conclusion Author＇s data showed that a mutation detection rate of tuberous sclerosis was 89.5%（17/19） among patients in author＇s hospital. The ratio of TSC2 and TSC1 mutations was about 1 ： 1 in the familial cases, but TSC2 mutation was more common than TSC1 mutation in sporadic cases. Author＇s data demonstrated that birth of TSC children for those with familial history of TSC could be prevented through prenatal diagnosis.

关 键 词：结节性硬化症 TSC1基因 TSC2基因 基因突变 产前诊断 

分 类 号：R714.5[医药卫生—妇产科学]