Preimplantation genetic testing for structural rearrangements by genome-wide SNP genotyping and haplotype analysis: a prospective multicenter clinical study

Shuo Zhang; Yuan Gao; Xiaohong Wang; Qing Li; Jichun Tan; Bo Liang; Ming Gao; Junping Wu; Xiufeng Ling; Jiayin Liu; Xiaoming Teng; Hong Li; Yun Sun; Weidong Huang; Xianhong Tong; Caixia Lei; Hongchang Li; Jun Wang; Shaoying Li; Xiaoyan Xu; Junqiang Zhang; Wei Wu; Shanshan Liang; Jian Ou; Qiongzhen Zhao; Rentao Jin; Yueping Zhang; Chenming Xu; Daru Lu; Junhao Yan; Xiaoxi Sun; Kwong Wai Choy; Congjian Xu; Zi-Jiang Chen

doi:10.1016/j.ebiom.2024.105514

Preimplantation genetic testing for structural rearrangements by genome-wide SNP genotyping and haplotype analysis: a prospective multicenter clinical study

EBioMedicine. 2024 Dec 20:111:105514. doi: 10.1016/j.ebiom.2024.105514. Online ahead of print.

Authors

Shuo Zhang¹, Yuan Gao², Xiaohong Wang³, Qing Li⁴, Jichun Tan⁵, Bo Liang⁶, Ming Gao², Junping Wu¹, Xiufeng Ling⁷, Jiayin Liu⁸, Xiaoming Teng⁹, Hong Li¹⁰, Yun Sun¹¹, Weidong Huang¹², Xianhong Tong¹³, Caixia Lei¹⁴, Hongchang Li², Jun Wang³, Shaoying Li⁴, Xiaoyan Xu⁵, Junqiang Zhang⁷, Wei Wu⁸, Shanshan Liang⁹, Jian Ou¹⁰, Qiongzhen Zhao¹², Rentao Jin¹³, Yueping Zhang¹⁵, Chenming Xu¹⁶, Daru Lu¹⁷, Junhao Yan², Xiaoxi Sun¹, Kwong Wai Choy¹⁸, Congjian Xu¹⁹, Zi-Jiang Chen²⁰

Affiliations

¹ 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.
² 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.
³ Department of Gynecology & Obstetrics, Center for Reproductive Medicine, Tang Du Hospital, The Air Force Medical University, Xi'an, Shaanxi, 710038, China.
⁴ Department of Obstetrics and Gynecology, Experimental Department of Obstetrics and Gynecology Institute, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁵ Department of Obstetrics and Gynecology, Center of Reproductive Medicine, Shengjing Hospital of China Medical University, Shenyang, China; Key Laboratory of Reproductive Dysfunction Disease and Fertility Remodeling of Liaoning Province, Shenyang, China.
⁶ Department of Bioinformatics and Biostatistics, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
⁷ Department of Reproduction, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, China.
⁸ State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China.
⁹ Department of Assisted Reproductive Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.
¹⁰ Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China.
¹¹ Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200135, China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, 200135, China.
¹² Xinjiang Jiayin Hospital, Urumqi, Xinjiang, 830000, China.
¹³ Reproductive and Genetic Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
¹⁴ Shanghai Ji Ai Genetics & IVF Institute, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China.
¹⁵ Shanghai Ji Ai Genetics & IVF Institute, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China; Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200135, China.
¹⁶ Shanghai Ji Ai Genetics & IVF Institute, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China; Institute of Reproduction and Development, Fudan University, Shanghai, 200011, China.
¹⁷ State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, 200438, China; NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning, Science and Technology Research Institute, Chongqing, China.
¹⁸ Fertility Preservation Research Centre, Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, SAR, China.
¹⁹ 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; Institute of Reproduction and Development, Fudan University, Shanghai, 200011, China. Electronic address: xucongjian@fudan.edu.cn.
²⁰ 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; Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200135, China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, 200135, China. Electronic address: chenzijiang@hotmail.com.

PMID: 39708428
DOI: 10.1016/j.ebiom.2024.105514

Abstract

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).

Keywords: Chromosomal rearrangements; Genome-wide SNP genotyping; Non-carrier embryos; Preimplantation genetic haplotyping; Preimplantation genetic testing.