Preimplantation Genetic Testing for Structural Rearrangements Through Genome-Wide SNP Genotyping and Haplotype Analysis: A Prospective, Multicenter, Cohort Study

Abstract

Background: Preimplantation genetic testing for structural rearrangements (PGT-SR) by chromosome copy number analysis has been widely applied in balanced chromosomal rearrangement (BCR) carriers to select euploid embryos for transfer. However, these methods only identify normal or balanced rearrangements versus unbalanced rearrangements within embryos. Reliable and extensively validated methods capable of selecting an embryo prior to transfer, without BCRs, 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 microarray-based genome-wide SNP genotyping and haplotype analysis. 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 PGT-SR cycle.

Findings: Between April 2018 and December 2021, 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. The rate of euploid embryos was 51.79%, 47.26% and 30.94% in Robertsonian translocation, inversion and reciprocal translocation carriers, respectively. The proportion of carrier embryos and non-carrier embryos was similar in different subgroups. Overall, 24.02% (385/1603) of cycles failed to get a euploid embryo and 53.15% of cycles (852/1603) generated non-carrier embryos. The clinical outcomes were comparable between the carrier and non-carrier embryo groups. A total of 775 healthy babies were delivered cumulatively, and the fetal karyotypes were all concordant with the PGT-SR analysis, in which 579 (74.71%) had normal karyotypes and 196 (25.29%) are carriers.

Interpretation: PGT-SR by genome-wide SNP genotyping and haplotype analysis allows the accurate identification of chromosomal imbalances/aneuploidies as well as distinguishing BCR carrier embryos from non-carrier embryos in one test, avoiding transmission of BCRs to the next generation.

Trial Registration: This research was registered at the Chinese Clinical Trial Registry (number ChiCTR-1800015863).

Funding: This trial was funded by the National Key Research and Development Program of China (2022YFC2703200,2021YFC2700600), National Natural Science Foundation of China (82201807), National Natural Science Foundation of China (82171639), National Natural Science Foundation of China (82071717), Shanghai Science and Technology Innovation Action Plan Program (18411953800, 20Y11907200), and the Municipal Human Resources Development Program for Outstanding Young Talents in Medical and Health Sciences in Shanghai (2022YQ075).

Declaration of Interest: C-JX reports grants from the Shanghai Science and Technology Innovation Action Plan Program during the conduct of the study. YG reports grants from the National Key Research and Development Program of China during the conduct of the study. SZ reports grants from the Shanghai Science and Technology Innovation Action Plan Program during the conduct of the study. BL reports employment with Basecare. All other authors declare no competing interests.

Ethical Approval: The study was approved by the Ethics Committee for Human Subject Research of the Obstetrics and Gynecology Hospital of Fudan University, and other participating clinical centers in China (2018-22-X1). All the enrolled couples provided written informed consent before participation.

Keywords: Preimplantation genetic testing, chromosomal rearrangement, genome-wide SNP genotyping, genome-wide haplotype analysis, chromosomal imbalances, BCR carrier embryos, non-carrier embryos