Purpose

The aim of this study was to determine factors affecting the chromosome imbalance in blastocysts and reproductive outcomes by a comparison between the reciprocal translocation (REC), inversion (INV), and Robertsonian translocation (ROB) carriers.

Methods

Couples with one partner carrying translocation or inversion underwent preimplantation genetic testing for chromosomal structural rearrangement (PGT-SR) cycles, including 215 PGT-SR cycles performed in subsequent 164 frozen-thawed embryo transfer cycles and 61 prenatal diagnoses of fetuses and 59 normal live birth babies. A total of 899 samples were processed by whole-genome amplification followed by next-generation sequencing (NGS). Karyotype and chromosome microarray analyses were used to confirm the PGT results from the amniotic fluid samples.

Results

A total of 843 blastocysts from 124 REC, 21 INV, and 35 ROB carriers were diagnosed by PGT-SR. The percentage of unbalanced blastocysts was significantly higher in REC than in INV and ROB carriers (64.31% vs. 28.05% vs. 37.02%). Stratification analysis of female carrier age and gonadotropin doses showed no significant increase in unbalanced chromosomal abnormalities in the three groups. Also, the different breakpoints in chromosomal arms did not affect the rate of unbalanced chromosomes in the embryos. Logistic regression indicated blastocyst quality as a statistically significant risk factor associated with unbalanced chromosomal abnormalities from translocation carriers (P < 0.001). The source of abnormalities in the three groups showed significant differences such that the abnormalities in REC mostly originated from parental translocation but the abnormalities in INV were mainly de novo variations. 164 blastocysts were transferred, and there were no significant differences in the clinical pregnancy rate and miscarriage rate. A total of 59 healthy babies were born, and there were no significant differences in the gender ratio and birth height, except the birth weight of boys between INV and ROB groups (P = 0.02). The results of amniocentesis revealed that more fetuses have normal chromosomal karyotypes than balanced carriers, particularly in the REC group.

Conclusions

Reciprocal translocation carriers have more risk of unbalanced rearrangement, but embryonic chromosome abnormalities of inversion carriers come mainly from de novo variations. This is the first study specifically comparing three different PGT-SRs using the NGS method and evaluating their reproductive outcomes. Our findings will provide the reciprocal translocation, inversion, and Robertsonian translocation carrier couples with more accurate genetic counseling on the reproductive risk of chromosomal imbalance.

中文翻译：

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从植入前基因检测到生殖结果的染色体异常评估：基于下一代测序的三种不同结构重排的比较

目的

本研究的目的是通过比较相互易位 (REC)、倒位 (INV) 和罗伯逊易位 (ROB) 携带者之间的比较来确定影响囊胚中染色体失衡和生殖结果的因素。

方法

一对携带易位或倒位伴侣的夫妇接受了染色体结构重排 (PGT-SR) 周期的植入前基因检测，包括在随后的 164 个冻融胚胎移植周期和 61 个胎儿产前诊断和 59 个正常活产中进行的 215 个 PGT-SR 周期婴儿。通过全基因组扩增和下一代测序 (NGS) 处理了总共 899 个样本。核型和染色体微阵列分析用于确认羊水样本的 PGT 结果。

结果

PGT-SR 诊断出来自 124 个 REC、21 个 INV 和 35 个 ROB 携带者的总共 843 个囊胚。REC中不平衡囊胚的百分比显着高于INV和ROB携带者（64.31% vs. 28.05% vs. 37.02%）。女性携带者年龄和促性腺激素剂量的分层分析显示，三组不平衡染色体异常没有显着增加。此外，染色体臂中的不同断点不会影响胚胎中染色体不平衡的比率。Logistic 回归表明囊胚质量是与易位携带者染色体不平衡异常相关的具有统计学意义的危险因素（P< 0.001)。三组异常来源差异显着，REC异常多源于亲代易位，而INV异常主要为新生变异。移植164个囊胚，临床妊娠率和流产率无显着差异。共出生健康婴儿59例，除INV组和ROB组男孩出生体重外，性别比和出生身高无显着差异（P =0.02）。羊膜穿刺术的结果显示，与平衡携带者相比，具有正常染色体核型的胎儿更多，特别是在 REC 组中。

结论

相互易位携带者发生不平衡重排的风险更大，但倒位携带者的胚胎染色体异常主要来自从头变异。这是第一项使用 NGS 方法专门比较三种不同 PGT-SR 并评估其生殖结果的研究。我们的研究结果将为相互易位、倒位和罗伯逊易位携带者夫妇提供关于染色体失衡生殖风险的更准确的遗传咨询。