平衡易位携带者行胚胎植入前遗传学诊断的胚胎染色体异常类型分析及妊娠结局分析

发布时间：2018-10-05 15:58

【摘要】：背景:平衡易位是常见的染色体异常。平衡易位携带者可在配子形成的过程中产生高比例的非整倍体异常配子,从而导致产生不孕、流产及胎儿异常等不良孕产的发生。胚胎植入前遗传学诊断(Preimplantation genetic diagnosis,PGD)能通过检测胚胎染色体的整倍性,发现非整倍体胚胎,从而显著减少移植胚胎后因染色体异常原因引起的流产、胎儿畸形等的发生率。早期针对胚胎的染色体异常检测使用荧光原位杂交技术(Fluorescencein si/u hybridization,FISH),仅能检测特定的染色体,随着技术的发展,微阵列比较基因组杂交技术(Array comparative genome hybridization;array-CGH)等技术均能检测24条染色体的整倍性,提高了检测的水平。使用24条染色体检测技术检测出胚胎的染色体异常情况及患者临床结局等数据分析是遗传咨询中重要的参考资料。目的:本研究旨在回顾性分析染色体平衡易位携带至夫妇行基于array-CGH的PGD检测后胚胎中的来源于亲缘易位的异常染色体以及新发异常的比例和异常分布。方法:收集了 2012-2014年于我院使用array-CGH行PGD的平衡易位携带者夫妇胚胎的检测结果并进行分析。共计261对夫妇(夫妇一方为染色体平衡易位携带者),968枚囊胚。根据检测结果将信号异常胚胎是否发生在与亲缘携带的平衡易位相关进行分类。进一步统计非父母易位染色体异常在1-22号常染色体及性染色体上的分布情况。结果:在968枚胚胎中,934(97.4%934/981)枚胚胎成功检测。其中27.8%(262/943)为整倍体胚胎,72.2%(681/943)为异常胚胎。在异常胚胎中,异常仅发生在在亲缘易位的染色体的胚胎为52.6%(358/681),异常仅发生在非亲缘平衡易位的染色体上的胚胎有23.3%(159/681),混合染色体异常的胚胎有24.1%(164/681)。出现异常的染色体见于1-22号常染色体及性染色体,以16,15,22,13,10号染色体异常最常见。胚胎分类在不同平衡易位携带者性别分组上分布无统计学意义,不同女方年龄分组的异常胚胎分布差异有统计学意义。结论:24条染色体检测对于平衡易位携带者是一个有效减少不良妊娠结局的助孕方法。平衡易位患者胚胎染色体异常不仅涉及亲属平衡易位染色体,非平衡易位相关的新发染色体异常涵盖1-22号染色体及性染色体,异常最多见于16号染色体,最少见于12号染色体。背景:平衡易位携带者有自然流产、复发性流产、后代有胎儿异常等高生育风险。PGD技术的兴起有效的减少了流产率、提高了活产率。但是少有研究关注平衡易位携带者PGD助孕前后胎儿胎儿异常的变化。根据相关文献报道,在PGD助孕前,平衡易位携带者后代常见的胎儿异常有心脏结构异常、神经发育迟滞、先天愚型等等,但是很少文献报道经过PGD助孕后先天缺陷的变化。目的:随访使用PGD助孕前后的平衡易位携带者夫妇的妊娠结局;详细列举PGD助孕前后其发生胎儿胎儿异常的具体类型并分析。方法:2012年-2014年就诊于山东大学附属生殖医院,并根据染色体核型分析结果诊断为平衡易位并选择array-CGH技术行PGD助孕的215对夫妇,共计249个周期。记录PGD助孕前平衡易位携带者夫妇的妊娠情况及移植检测未见异常的胚胎后的妊娠结局。并记录和分析PGD助孕前后所发生的胎儿异常。结果:在PGD助孕前,妊娠结局中最常见的是早期流产64.1%(223/348),最少见的是中晚期流产1.1%(4/348);胎儿异常(不良孕产)占5.7%(20/348)。在PGD助孕后,妊娠结局中14.6%(18/123)为早期流产,73.1%(90/123)为正常活产,2.4%(3/123)有胎儿异常。在PGD助孕后,早期流产率相较于PGD助孕前的早期流产率有统计学差异(P0.001);正常活产率有统计学差异(P0.001);而胎儿异常率无统计学差异(P=0.156)。PGD助孕前,在胎儿先天发育异常中:30.4%(7/23)为心脏发育异常最见,17.4%(4/23)为颈部水囊瘤位列其次,13%(3/23)为脑瘫。PGD助孕后,出现三例先天缺陷:分别为先天性心脏结构缺陷,多指及喉喘鸣,各占33.3%。结论:PGD可有效的降低平衡易位携带者的早期流产率,提高活产率。经PGD助孕后,胎儿/婴儿常见胎儿异常降低,但是与助孕前对比无统计学意义。在PGD助孕后,平衡易位携带者后代出现与染色体相关的胎儿异常减少,提示PGD助孕有益于减少因染色体异常导致的胎儿异常的发生。
[Abstract]:Background: Balanced translocation is a common chromosomal anomaly. A balanced translocation carrier can produce a high proportion of non-ploidy abnormal gametes during gamete formation, leading to the occurrence of unwanted pregnancies such as infertility, miscarriage, and fetal abnormalities. The pre-implantation genetic diagnosis (PGD) can detect the incidence of abortion, fetal malformation and the like caused by chromosomal abnormalities after embryo transfer by detecting the ploidy of the embryo chromosome. fluorescence in situ hybridization (FISH) is used in the early detection of chromosomal abnormalities in embryos, and only specific chromosomes can be detected. With the development of technology, microarray comparative genomic hybridization (ARray-CGH) techniques can detect the ploidy of 24 chromosomes. the level of detection is improved. The analysis of chromosomal abnormalities and clinical outcomes of embryos using 24 chromosome testing techniques is an important reference in genetic counseling. Objective: The purpose of this study was to retrospectively analyze the chromosome balance translocation and the proportion and abnormal distribution of abnormal chromosomes derived from genetic translocation in embryo derived from the PGD based on array-CGH. Methods: The results were collected from 2012 to 2014 in our hospital using array-CGH line PGD, and the results were analyzed. A total of 261 couples (one of whom were chromosome balanced translocation carriers) and a total of 68 blastocyst. The abnormal embryo of the signal is classified according to the detection result whether or not the abnormal embryo of the signal takes place in relation to the balanced translocation carried by the relatives. The distribution of non-parental translocation chromosome abnormalities on chromosome 1-22 and sex chromosome is further counted. Results: 934 (97.4% 934/ 981) embryos were detected successfully in the embryos. Of these, 27. 8% (262/ 943) were ploploid embryos and 72.2% (681/ 943) were abnormal embryos. In the abnormal embryo, only 26.6% (358/ 681) of the embryos in the chromosome of the genetic translocation occurred, and the abnormality occurred only in 23. 3% (159/ 681) of the embryos on the chromosome of the non-related balanced translocation, and the embryo of the mixed chromosome abnormality was 24. 1% (164/ 681). The abnormal chromosomes were found in the chromosome 1-22 and sex chromosomes, and chromosomes 16, 15, 22, 13 and 10 were most common. There was no statistically significant difference in the distribution of embryos in the sex groups of different balanced translocation carriers, and the difference of abnormal embryo distribution among different age groups was statistically significant. Conclusion: 24 chromosome detection is an effective way to reduce adverse pregnancy outcomes for balanced translocation carriers. The abnormal chromosome abnormality of balanced translocation is not only related to family balance translocation chromosome, but the new chromosome abnormalities related to non-balanced translocation include chromosome 1-22 and sex chromosome, the abnormality is most seen in chromosome 16, and at least chromosome 12. BACKGROUND: Balanced translocation carriers have high fertility risks such as spontaneous abortion, recurrent spontaneous abortion, and fetal abnormalities in offspring. The emergence of PGD technology effectively reduces the rate of miscarriage and increases the live birth rate. However, it is rare to focus on the change of fetal fetal abnormalities after PGD for balanced translocation carriers. According to the relevant literature, there are common fetal abnormalities in the offspring of PGD promoter and balanced translocation carriers, such as cardiac structural abnormality, neurodevelopmental delay, congenital disorder, and so on, but few literature reports the change of congenital defects after PGD assisted pregnancy. Objective: To follow up the pregnant outcome of the balanced translocation carriers after the use of PGD and to give a detailed list of the specific types and analysis of fetal fetal abnormalities after PGD. Methods: From 2012 to 2014, I went to the affiliated reproductive hospital of Shandong University, diagnosed as balanced translocation according to the chromosome karyotype analysis, and selected the 215 couples of the array-CGH technique line PGD assisted pregnancy for a total of 249 cycles. To record the pregnancy outcome of the PGD promoter balanced translocation carrier and the post-embryo pregnancy outcome of the transplantation test. and recording and analyzing fetal abnormalities after the PGD promoter. Results: The most common in the outcome of pregnancy was 64.1% (223/ 348) in early abortion and 1% (4/ 348) in middle and late abortion, and 5. 7% (20/ 348) of fetal abnormality (bad pregnancy). After PGD assisted pregnancy, 14. 6% (18/ 123) of the pregnancy outcomes were early miscarriages, 73.1% (90/ 123) were normal live births and 2.4% (3/ 123) had fetal abnormalities. There was a statistically significant difference in the early abortion rate compared with the early abortion rate (P = 0.001) after PGD assisted pregnancy; the normal live birth rate was statistically different (P = 0. 156); and the fetal abnormality rate was not statistically different (P = 0.156). 17. 4% (4/ 23) ranked second and 13% (3/ 23) were cerebral palsy. Three congenital defects occurred after PGD assisted pregnancy: congenital heart structural defects, cerebral palsy and respiratory wheeze, accounting for 33. 3% respectively. Conclusion: PGD can effectively reduce the early abortion rate of balanced translocation carriers and increase the live birth rate. There was no statistically significant difference in fetal/ infant common fetal abnormalities after PGD assisted pregnancy. After PGD assisted pregnancy, the offspring of balanced translocation carriers showed decreased fetal abnormalities associated with chromosomes, suggesting that PGD assisted pregnancy would be beneficial to reduce fetal abnormalities due to chromosomal abnormalities.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R714.8

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