通过全基因组SNP基因分型和单倍型分析进行结构重排的植入前基因检测：一项前瞻性多中心临床研究。
Preimplantation genetic testing for structural rearrangements by genome-wide SNP genotyping and haplotype analysis: a prospective multicenter clinical study.
作者信息
Zhang Shuo, Gao Yuan, Wang Xiaohong, Li Qing, Tan Jichun, Liang Bo, Gao Ming, Wu Junping, Ling Xiufeng, Liu Jiayin, Teng Xiaoming, Li Hong, Sun Yun, Huang Weidong, Tong Xianhong, Lei Caixia, Li Hongchang, Wang Jun, Li Shaoying, Xu Xiaoyan, Zhang Junqiang, Wu Wei, Liang Shanshan, Ou Jian, Zhao Qiongzhen, Jin Rentao, Zhang Yueping, Xu Chenming, Lu Daru, Yan Junhao, Sun Xiaoxi, Choy Kwong Wai, Xu Congjian, Chen Zi-Jiang
机构信息
Shanghai Ji Ai Genetics & IVF Institute, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China; Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, 200032, China.
Center for Reproductive Medicine, Shandong University, Jinan, Shandong, 250012, China; Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China; Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, 250012, China; Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, 250012, China; Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, 250012, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, 250012, China.
出版信息
EBioMedicine. 2025 Jan;111:105514. doi: 10.1016/j.ebiom.2024.105514. Epub 2024 Dec 20.
BACKGROUND
Preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR) has been widely utilized to select euploid embryos in patients carrying balanced chromosomal rearrangements (BCRs) by chromosome copy number analysis. However, reliable and extensively validated PGT-SR methods for selecting embryos without BCRs in large-cohort studies are lacking.
METHODS
In this prospective, multicenter, cohort study, carriers with BCRs undergoing PGT-SR were recruited across 12 academic fertility centers within China. PGT-SR was performed using genome-wide SNP genotyping and haplotyping approach. Parental haplotypes were phased by available genotypes from a close relative or an unbalanced embryo. The karyotypes of embryos were inferred from the haplotypes. Only a single embryo was transferred in each cycle.
FINDINGS
Between April 2018 and March 2023, 1298 carriers we randomly enrolled. A total of 7867 blastocysts from 1603 PGT-SR cycles were biopsied, in which 7750 (98.51%) were successfully genotyped and analyzed. Overall, 75.98% (1218/1603) of cycles obtained euploid embryos and 53.15% (852/1603) generated non-carrier embryos. The proportion of carrier and non-carrier embryos was similar in different subgroups. A total of 1030 non-carrier and 439 carrier embryos were transferred, 817 healthy babies were delivered cumulatively. Our results demonstrate that SNP-haplotyping method is highly accurate (sensitivity 95% CI: 98.34%-100%, specificity 95% CI: 96.63%-100%, respectively), and can be applied universally to different BCR types. Moreover, the clinical outcomes were comparable between the carrier and non-carrier embryo groups.
INTERPRETATION
This study demonstrates the effectiveness of preimplantation genetic genome-wide SNP-genotyping and haplotyping method, resulting in the delivery of more babies with a normal karyotype.
FUNDING
This study was funded by the National Key Research and Development Program of China (2022YFC2703200, 2021YFC2700600, 2021YFC2700500), National Natural Science Foundation of China (82201807, 82171639, 82071717). Shanghai Science and Technology Innovation Action Plan Program (18411953800), and the Municipal Human Resources Development Program for Outstanding Young Talents in Medical and Health Sciences in Shanghai (2022YQ075).
背景
植入前染色体结构重排基因检测（PGT-SR）已被广泛用于通过染色体拷贝数分析，为携带平衡染色体重排（BCR）的患者选择整倍体胚胎。然而，在大型队列研究中，缺乏用于选择无BCR胚胎的可靠且经过广泛验证的PGT-SR方法。
方法
在这项前瞻性、多中心队列研究中，在中国的12个学术性生育中心招募了接受PGT-SR的BCR携带者。使用全基因组SNP基因分型和单倍型分析方法进行PGT-SR。通过近亲或不平衡胚胎的可用基因型对亲代单倍型进行分型。从单倍型推断胚胎的核型。每个周期仅移植单个胚胎。
结果
2018年4月至2023年3月期间，我们随机招募了1298名携带者。对来自1603个PGT-SR周期的7867个囊胚进行了活检，其中7750个（98.51%）成功进行了基因分型和分析。总体而言，75.98%（1218/1603）的周期获得了整倍体胚胎，53.15%（852/1603）产生了非携带者胚胎。不同亚组中携带者和非携带者胚胎的比例相似。共移植了1030个非携带者胚胎和439个携带者胚胎，累计分娩817名健康婴儿。我们的结果表明，SNP单倍型分析方法高度准确（敏感性95%可信区间：98.34%-100%，特异性95%可信区间：96.63%-100%），并且可以普遍应用于不同的BCR类型。此外，携带者和非携带者胚胎组的临床结局相当。
解读
本研究证明了植入前全基因组SNP基因分型和单倍型分析方法的有效性，从而分娩出更多核型正常的婴儿。
资助
本研究由中国国家重点研发计划（2022YFC2703200、2021YFC2700600、2021YFC2700500）、国家自然科学基金（82201807、82171639、82071717）、上海市科技创新行动计划项目（18411953800）以及上海市医疗卫生优秀青年人才培养计划（2022YQ075）资助。
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