P–525 Analysis of segregation patterns of trivalent structure and the effect on genome stability in Robertsonian translocation carriers

Abstract

Abstract Study question What are the factors that affect the separation pattern of Robertsonian translocation trivalent, and whether the structure of the trivalent affected the chromosome stability? Summary answer The meiotic segregation modes can be affected by the carrier’s sex and special chromosome, and a trivalent structure can affect the stability of the genome. What is known already Robertson translocation occurs when two proximal acrocentric chromosomes fuse at the centromere, and forms a trivalent structure during meiosis. This structure will affect the fertility of Robertsonian translocation carriers, and may destroy the stability of the genome by affecting the separation of other chromosomes, which is called Inter-Chromosomal Effect (ICE). Previous research have confirmed that the use of PGT in Robertsonian translocation carriers can effectively reduce abortion and increase live birth. But some studies dispute this conclusion and the existence of ICE. However, there is no large data study to verify these controversies. Study design, size, duration PGT results of 928 oocyte retrieval cycles in 763 couples(one of the couples is a Robertsonian translocation carrier) were analysied from December 2012 to June 2020. A total of 1492 couples who received PGT-A were collected as control group, and matched according to age and testing time stage. The study was approved by the ethics committee(LL-SC-SG–2006–008 and LL-SC-SG–2014–016). Participants/materials, setting, methods Cytogenetic analysis was performed using GTG standard method (trypsin and GiemsaG banding) to analyze the chromosomes of peripheral blood lymphocytes. Blastocysts obtained by standard IVF procedure were biopsied on the 5th or 6th morning after fertilization, and the trophoblast cells were amplified by PicoPLEX whole genome amplification kit (Rubicon Genology) or Repli-g Single Cell Kit(Qiagen). PGT-SR was performed using SNP array or NGS as previously described. Main results and the role of chance In this study, a total of 3423 blastocysts from 763 couples were analysed using SNP-array or NGS. Among them, the rate of alternate segregation of male Robertsonian translocation carriers was significantly higher than that in female carriers (82.26% vs 59.96%, P < 0.001), and meiotic segregation modes could be affected by the special chromosome such as 13 in female(P = 0.042) and 15 in male(P = 0.045) involved. A trivalent structure can affect the stability of the genome during mitosis, which is associated with an increase in the propotion of chromosome mosaic compared with the PGT-A control group(1.18% vs 0.53%, P < 0.01). In addition, we found an interesting phenomenon: in the meiotic segregation of female Robertsonian translocation carriers associated with chromosomes 21 and 22, the chromosome 21 or 22 of the two chromosomes involved in translocation are more likely to be abnormal, and according to our results, the effect of chromosome 21 seems to be greater. Limitations, reasons for caution (1) Limitations of retrospective analysis; (2) The results are not fully representative of the general population; (3) PGT-A patients always had repeated implantation failure or recurrent aboration, which may cause deviation to the results. Wider implications of the findings: This study analyzed the influencing factors of the separation patterns of trivalent, and verified the existence of ICE. This suggest that PGT-SR can have a better outcome in patients with Robertsonian translocation, especially in male carriers. These results will provide carrier couple with more appropriate genetic counseling. Trial registration number no