单基因遗传病家系中女性为新发突变携带者的胚胎植入前遗传学诊断策略  

New testing strategy applied in monogenic disease preimplantation genetic diagnosis for the couples with female de novo gene mutation carriers

作　　者：朱小辉[1] 王玉倩 严智强 智旭 闫丽盈[1] 乔杰[1] Zhu Xiaohui;Wang Yuqian;Yan Zhiqiang;Zhi Xu;Yan Liying;Qiao Jie(Center for Reproductive Medicine,Department of Obstetrics and Gynecology,Peking University^ Third Hospital,Beijing 100191,China)

机构地区：[1]北京大学第三医院妇产科生殖医学中心,100191

出　　处：《中华生殖与避孕杂志》2019年第2期120-124,共5页Chinese Journal of Reproduction and Contraception

基　　金：国家自然科学基金项目(31522034,31571544,81521002).

摘　　要：目的探讨适用于特殊单基因遗传病家系(本研究针对夫妻中女方为新发突变携带者)胚胎植入前基因诊断(PGD)的新方法,阻断致病性基因突变向下一代传递。方法以多发性骨软骨瘤致病基因EXT1女性新发突变携带者的胚胎基因诊断为例,阐述针对特殊遗传家系胚胎诊断策略的优势。我们采用直接致病位点检测结合连锁分析的检测策略,利用突变位点检测成功的胚胎和极体单细胞样本的连锁信息,对其他胚胎进行连锁分析,从而判断胚胎是否携带母源基因突变。结果获得12枚胚胎进行遗传学检测,其中3枚胚胎、2个极体突变位点检测成功,随后用于其他胚胎的连锁分析。5枚胚胎经检测不携带母源基因突变,染色体未见异常,可移植。患者移植其中1枚胚胎后,成功妊娠、分娩。PGD新生儿不携带母源突变。结论采用携带突变的胚胎或极体进行连锁分析的创新性检测策略,可以在女方缺少连锁分析所必要成员的情况下,准确判断胚胎母源突变携带情况,从而扩展了单基因胚胎移植前基因诊断技术的适用人群。Objective To investigate new preimplantation genetic diagnosis (PGD) strategy applying to special cases with monogenic inheritance diseases (this study focused on female carriers with de novo gene mutations), to block the transmission of pathogenic gene mutations to the next generation. Methods To clarify the diagnosis strategy, we took an example of a PGD for a hereditary multiple osteochondroma female patient who carrys de novo gene mutaion in EXT1 gene. Pathogenic mutation site detection combined with Linkage analysis was applied in embryonic gene diagnosis, which relied on the embryos and polar bodies with successful mutation site detection. Results Totally 12 embryos as well as their polar bodies were performed genetic testing. The mutation site was detected successfully in 3 embryos and 2 polar bodies (including one heterozygous embryo and one second polar body) which could be applied in linkage analysis for other embryos’ PGD. Finally, 5 embryos were diagnosed as transplantable embryos, free of mutation with normal copy number variation (CNV). One of them was transplanted, and as consequence a healthy PGD baby girl was born who was identified as free of maternal mutation after genetic validation. Conclusion The innovative strategy of using embryo carrying mutation or polar body in embryo genetic diagnosis can expand the applicable patient population.

关 键 词：新发突变 遗传性多发性骨软骨瘤I型 极体 胚胎植入前基因诊断 连锁分析 

分 类 号：R714.8[医药卫生—妇产科学]