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通讯作者:

高媛(1972-),女,山东济南人,研究员,主要从事胚胎植入前遗传学检测技术及规范化研究、单基因遗传病相关方面的研究等。E-mail:gaoyuan@sduivf.com

中图分类号:[R715.5]

文献标识码:A

文章编号:2096-8965(2022)04-0079-06

DOI:10.12287/j.issn.2096-8965.20220410

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参考文献 19
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目录contents

    摘要

    目的 探索染色体平衡易位是否影响基因组稳定性。方法 利用回顾性分析将2019年1月至2020年12月在山东大学附属生殖医院行胚胎植入前染色体结构重排检测患者分成两组,实验组为染色体平衡易位携带者来源的异常染色体,对照组为平衡易位携带者的配偶来源的异常染色体,通过单体型分析确认异常胚胎中非易位相关异常染色体的双亲来源,探索平衡易位是否会引起更多染色体异常的发生,从而明确平衡易位对于基因组稳定性的影响。结果 非易位相关染色体片段异常亲本来源分析结果显示,实验组显著高于对照组,即平衡易位携带者来源的片段异常显著高于正常核型来源的片段异常,对于整条染色体异常和嵌合染色体异常,两组无显著性差异。结论 在减数分裂过程中,染色体平衡易位可能是导致染色体片段异常增加的因素之一,最终影响基因组的稳定性。

    Abstract

    Objective To explore the effect of chromosome balanced translocation on genomic stability.Methods Abnormal embryos from patients with preimplantation genetic testing for structural rearrangements (PGT-SR) indication between January 2019 and December 2020 in Reproductive Hospital Affiliated of Shandong University were divided into two groups. The experimental group was the abnormal chromosome derived from the carriers of the balanced translocation, and the control group was the abnormal chromosome derived from the spouse of the balanced translocation carriers. The parental origin of abnormal chromosomes was identified by haploid analysis to explore the effect of balanced translocation on genomic stability. Results The results of parental origin of non-translocation related abnormal chromosomal fragments showed the experimental group was significantly higher than the control group. As for the whole and mosaic chromosomal abnormality,there was no significant difference between the two groups. Conclusion During meiosis, balanced translocation could affect genome stability by increasing abnormal chromosomal fragments.

  • 染色体平衡易位是最常见的染色体结构异常,其发生率约为1/500 [1]。染色体平衡易位通常不会造成遗传物质的缺失或增加,因此,大多数平衡易位携带者的临床表型正常。在减数分裂过程中,同源染色体的姐妹染色单体通过形成四价体结构而产生单倍体的配子,而平衡易位携带者在这一过程中,极易形成染色体不平衡配子,从而导致不孕不育、复发性流产、胚胎停育和出生缺陷等不良妊娠结局[23]。在减数分裂过程中,染色体平衡易位四价体结构可以引起非易位相关染色体异常增加,可能由于染色体间效应 (Interchromosomal Effect,ICE) 干扰其他染色体的正常配对和分离,从而导致非易位染色体异常增加,提示染色体平衡易位可能会影响基因组稳定性[45]。由于技术局限性,如荧光原位杂交技术 (Fluorescence In Situ Hybridization,FISH)、微阵列 (Microarray) 及新一代测序 (Next Generta⁃ tion Sequencing,NGS) 等技术均无法直接分析染色体的双亲来源,从而限制了相关研究的深入,使得染色体间是否存在干预效应仍无定论[5-14]。因此,染色体平衡易位是否会影响基因组稳定性并不明确。

  • 随着测序技术的发展,应用于胚胎植入前染色体结构重排检测 (Preimplantation Genetic Testing for Structural Rearrangements, PGT-SR) 技术日益增多,这些技术不仅能够检测胚胎染色体非整倍体,还能鉴定出整倍体胚胎是平衡易位携带型和非携带型[15-19],基于 SNP 微阵列芯片的胚胎植入前基因单体型分析技术 (Preimplantation Genetic Haplotyping, PGH) 就是其中之一[18],而且利用 PGH 检测数据对胚胎家系进行连锁分析,还能够鉴定异常染色体或片段的双亲来源,使明确平衡易位是否会增加染色体异常从而影响基因组稳定性的研究成为可能。

  • 本研究利用 PGH 技术对行 PGT-SR 干预的患者胚胎行异常染色体和片段来源分析,探讨染色体平衡易位对基因组稳定性的影响,以期为临床医生对平衡易位携带者的遗传咨询提供依据。

  • 1 材料与方法

  • 1.1 研究对象

  • 本研究收集了 2019 年 1 月至 2020 年 12 月在山东大学附属生殖医院行 PGT-SR 且需区分平衡易位携带类型胚胎的PGH数据,共纳入372对平衡易位携带者夫妇,累计 460 个 PGT-SR 周期,根据平衡易位携带者性别分为 2组,包括女性平衡易位携带者夫妇 (男方核型正常) 207对 (260个PGT-SR周期),男性平衡易位携带者夫妇 (女方核型正常) 165 对 (200 个 PGT-SR 周期)。本研究方案已经通过山东大学附属生殖医院伦理委员会审核,所有患者均知情同意并签署PGT-SR知情同意书。

  • 1.2 胚胎培养与活检

  • 所有患者均按照常规临床方案完成促排卵、胞浆内单精子显微注射技术 (Intracytoplasmic Sperm Injection,ICSI) 的体外受精,胚胎培养至第5-6天时,活检 3~5 个囊胚滋养外胚层细胞用于 PGH 检测,同时,活检后的胚胎置于液氮中冷冻保存。

  • 1.3 胚胎植入前基因单体型分析技术

  • 利用多重置换扩增技术 (Multiple Displacement Amplification,MDA)对活检细胞进行全基因组扩增 (货号:150343,REPLI-g Single Cell kit,Qiagen),采用基于 SNP 微阵列芯片技术 (Human-CytoSNP-12 v2.1 BeadChip Kit,Illumina) 进行染色体非整倍体检测,包含约30万个对细胞遗传学分析具有重要作用区域的 SNP 位点,利用 BlueFuse Multi 软件进行胚胎染色体非整倍体、4 Mb以上染色体缺失和重复以及单体型分析等。对平衡易位断裂点上下游 2 Mb 区域 SNP 进行单体型分析,可以鉴定胚胎平衡易位的携带状态、异常染色体 (包括整条、片段和嵌合异常) 的双亲来源。

  • 1.4 统计学分析

  • 根据非易位相关异常染色体的亲本来源分为两组,实验组为平衡易位携带者来源的异常染色体,对照组为平衡易位携带者配偶来源的异常染色体,比较实验组与对照组在双亲来源异常染色体的差异。易位相关异常定义为易位染色体(上)的异常; 非易位相关定义为易位染色体之外的染色体异常。

  • 染色体三体异常发生在减数分裂时期,称为双亲本同源染色体三体 (Both Parental Homologs, BPH),通常包含三种等位基因;染色体三体异常发生在有丝分裂时期,称为单亲本同源染色体三体 (Single Parental Homologs,SPH),通常包含两种等位基因。利用PGH数据分析三体的亲本来源。

  • 应用 STATA V15.0 统计分析软件,组间比较采用χ2 检验分析,设置P <0.05为差异有统计学意义。

  • 2 结果

  • 2.1 临床特征

  • 本研究共纳入372对平衡易位携带者夫妇,460 个取卵周期,包括 207对女性平衡易位携带者夫妇和 165对男性平衡易位携带者夫妇。女性平衡易位携带者夫妇共进行 260 个 PGT-SR 取卵周期,获得 1 473 枚囊胚,190 枚未行 PGT-SR 检测,获得整倍体胚胎322枚 (173枚非易位携带型,136枚易位携带型胚胎,13枚无法区分),嵌合胚胎 94枚,染色体异常胚胎 849 枚 (617 枚发生易位相关染色体异常,121枚发生易位和非易位相关染色体异常,111 枚发生非易位相关染色体异常);男性平衡易位携带者夫妇共进行 200 个 PGT-SR 取卵周期,获得 1 129枚囊胚,104枚未行 PGT-SR 检测,获得整倍体胚胎273枚 (133枚非易位携带型,133枚易位携带型胚胎,7 枚无法区分),嵌合胚胎 80 枚,染色体异常胚胎 649 枚 (425 枚发生易位相关染色体异常,117枚发生易位和非易位相关染色体异常,107 枚发生非易位相关染色体异常)。将发生非易位相关染色体异常的胚胎进行统计分析 (见图1)。

  • 图1 平衡易位携带者及胚胎检测结果流程图

  • 2.2 非易位相关异常双亲来源比较

  • 在女方来源的异常染色体中,实验组为女性平衡易位携带者来源 (易位因素) 的异常染色体,对照组为男性平衡易位携带者配偶 (非易位因素) 来源的异常染色体。在男方来源的异常染色体中,实验组为男性平衡易位携带者来源 (易位因素) 的异常染色体,对照组为女性平衡易位携带者配偶 (非易位因素) 来源的异常染色体 (见表1)。

  • 表1 非易位相关异常染色体双亲来源比较

  • 对于女方来源整条染色体异常,实验组与对照组的比例分别为 77.38% 和 84.80%,其中,染色体三体的比例分别为 84.13% 和 86.57%,染色体单体的比例分别为 73.33% 和 83.65%,两组比较均无统计学差异;女方来源染色体片段异常,实验组与对照组比例分别为 43.24% 和 25.68%,实验组显著高于对照组;女方来源单倍体异常比例分别为83.33% 和100%,三倍体异常比例均为100%。

  • 对于男方来源整条染色体异常,实验组与对照组的比例分别为 15.20% 和 22.62%,其中,染色体三体的比例分别为 13.43% 和 15.87%,染色体单体的比例分别为 16.35% 和 26.67%,两组无统计学差异;男方来源染色体片段异常,实验组与对照组比例分别为 74.32% 和 56.76%,实验组显著高于对照组;男方来源单倍体异常比例分别为 0 和 16.67%,三倍体异常比例均为0%。

  • 2.3 嵌合染色体双亲来源比较

  • 对于女方来源整条染色体嵌合,实验组与对照组的比例分别为47.37%和44.12%,其中,染色体嵌合三体的比例分别为54.00%和43.33%,染色体嵌合单体的比例分别为40.00%和44.74%,两组比较均无统计学差异; 女方来源染色体片段嵌合,实验组与对照组比例分别为 28.57%和31.25%两组比较均无统计学差异。对于男方来源整条染色体嵌合,实验组与对照组的比例分别为 55.88%和52.63%,其中,染色体嵌合三体的比例分别为56.67%和46.00%,染色体嵌合单体的比例分别为 55.26%和60.00%,两组比较均无统计学差异;男方来源染色体片段嵌合,实验组与对照组比例分别为68.75% 和71.43%,两组比较均无统计学差异(见表2)。

  • 表2 非易位相关嵌合染色体双亲来源比较

  • 3 讨论

  • 本研究对 372 例染色体平衡易位携带者异常染色体双亲来源行回顾性分析,结果提示染色体平衡易位会导致非易位相关染色体片段异常增加,但是不影响整条或嵌合染色体异常的发生。因此,染色体平衡易位可能会通过引起片段异常而影响基因组的稳定性。

  • 染色体平衡易位携带者的易位衍生染色体和正常染色体在减数分裂前期 I 通过同源区域配对形成四价体结构,四价体结构按照不同的分离模式形成 32种配子,其中仅对位分离产生的 2种配子为正常或者携带型配子,其他配子均为染色体异常,这也是引发不孕症的重要原因。染色体片段异常通常是由于 DNA 双链断裂 (Double Stranded Breaks, DSBs) 修复异常引起,可以被各种内源性和外源性的因素诱导。氧化应激反应和DNA复制叉的阻滞是导致 DSBs 的常见因素,DSBs 形成后一般会通过同源重组 (Homologous Recombination,HR) 和非同源末端连接途径 (Non-Homologous End Joining, NHEJ) 完成修复,当 DSBs发生及修复途径受到损伤,会导致染色体片段异常、易位等染色体结构畸变[20-22]。由于平衡易位染色体四价体结构的特殊性,平衡易位是否会影响DSBs的发生和修复有待明确。

  • 已有研究发现,平衡易位携带者通过对位分离形成的囊胚比例约占45%,而染色体整倍体胚胎比例不足30%;平衡易位携带者发生非易位相关染色体异常是核型正常组的1.43倍,提示平衡易位可以显著增加染色体异常的发生频率[2324]。另外一些研究表明,平衡易位和罗氏易位可能会通过染色体间效应导致染色体非整倍体胚胎的增加[51013]。然而,上述研究均未对异常染色体的来源进行分析,无法提供平衡易位导致异常染色体发生的直接证据。本研究通过对平衡易位携带者夫妇胚胎非易位相关异常染色体双亲来源分析,证明平衡易位会导致非易位相关染色体片段异常增加 (P <0.05),提示在减数分裂过程中,平衡易位形成的四价体结构可能会影响DSB修复过程,从而导致非易位相关染色体片段异常的发生。

  • 本研究发现,女性易位携带者组中实验组与对照组引起的染色体三体分别为 84.13% 和 86.57%,其中 BPH 三体的比例分别为 82.54% 和 88.06%,发生染色体单体的比例分别为 73.33% 和 83.65%,两者无差异,提示大多数整条染色体异常为母源减数分裂起源,与之前的研究报道基本一致[23-25]。对于嵌合染色体的双亲来源分析结果显示,整条的嵌合染色体双亲来源比例均为50%左右,约70%的片段嵌合来源于父亲,与之前报道的正常核型片段异常主要来源父方因素结果一致[23],女性和男性两组的嵌合染色体双亲来源分析结果均无显著性差异,提示平衡易位不会影响嵌合染色体的发生。

  • 综上所述,本研究发现染色体平衡易位可能导致非易位相关染色体片段异常增加,而与整条染色体异常和嵌合体胚胎形成无关,提示染色体平衡易位可能通过染色体间效应影响基因组稳定性,为平衡易位携带者的临床遗传咨询提供了理论基础。

  • 参考文献

    • [1] SCRIVEN P N,HANDYSIDE A H,OGILVIE C M.Chromosome translocations:segregation modes and strategies for preimplantation genetic diagnosis[J].Prenat Diagn,1998,18(13):1437-1449.

    • [2] UEHARA S,TAKABAYASHI T,OKAMURA K,et al.The outcome of pregnancy and prenatal chromosomal diagnosis of fetuses in couples including a translocation carrier[J].Prenat Diagn,1992,12(12):1009-1018.

    • [3] STERN C,PERTILE M,NORRIS H,et al.Chromosome translocations in couples with in-vitro fertilization implantation failure[J].Hum Reprod,1999,14(8):2097-2101.

    • [4] LEJEUNE J.Autosomal disorders[J].Pediatrics,1963,32(3):326-337.

    • [5] ALFARAWATI S,FRAGOULI E,COLLS P,et al.Embryos of robertsonian translocation carriers exhibit a mitotic interchromosomal effect that enhances genetic instability during early development[J].PLoS Genet,2012,8(10):e1003025.

    • [6] OLIVER-BONET M,BENET J,SUN F,et al.Meiotic studies in two human reciprocal translocations and their association with spermatogenic failure[J].Hum Reprod,2005,20(3):683-688.

    • [7] ANTON E,VIDA F L,BLANCO J.Interchromosomal effect analyses by sperm FISH:incidence and distribution among reorganization carriers[J].Syst Biol Reprod Med,2011,57(6):268-278.

    • [8] PUJOL A,BENET J,STAESSEN C,et al.The importance of aneuploidy screening in reciprocal translocation carriers[J].Reproduction,2006,131(6):1025-1035.

    • [9] GIANAROLI L,MAGLI M C,FERRARETTI A P,et al.Possible interchromosomal effect in embryos generated by gametes from translocation carriers[J].Hum Reprod,2002,17(12):3201-3207.

    • [10] BOYNUKALIN F K,GULTOMRUK M,TURGUT N E,et al.The impact of patient,embryo,and translocation characteristics on the ploidy status of young couples undergoing preimplantation genetic testing for structural rearrangements(PGT-SR)by next generation sequencing(NGS)[J].J Assist Reprod Genet,2021,38(2):387-396.

    • [11] XIE Y X,XU Y,WANG J,et al.Preliminary analysis of numerical chromosome abnormalities in reciprocal and robertsonian translocation preimplantation genetic diagnosis cases with 24-chromosomal analysis with an aCGH/SNP microarray[J].J Assist Reprod Genet,2018,35(1):177-186.

    • [12] MUNNE S,ESCUDERO T,FISCHER J,et al.Negligible interchromosomal effect in embryos of robertsonian translocation carriers[J].Reprod Biomed Online,2005,10(3):363-369.

    • [13] MATEU-BRULL E,RODRIGO L,PEINADO V,et al.Interchromosomal effect in carriers of translocations and inversions assessed by preimplantation genetic testing for structural rearrangements(PGT-SR)[J].J Assist Reprod Genet,2019,36(12):2547-2555.

    • [14] ESTOP A M,CIEPLY K,MUNNE S,et al.Is there an interchromosomal effect in reciprocal translocation carriers?Sperm FISH studies[J].Hum Genet,2000,106(5):517-524.

    • [15] TREFF N R,TAO X,SCHILLINGS W J,et al.Use of single nucleotide polymorphism microarrays to distinguish between balanced and normal chromosomes in embryos from a translocation carrier[J].Fertil Steril,2011,96(1):e58-e65.

    • [16] HU L,CHENG D H,GONG F,et al.Reciprocal translocation carrier diagnosis in preimplantation human embryos[J].EBio Medicine,2016,14:139-147.

    • [17] GAO M,WANG L J,XU P W,et al.Noncarrier embryo selection and transfer in preimplantation genetic testing cycles for reciprocal translocation by Oxford Nanopore Technologies[J].J Genet Genomics,2020,47(11):718-721.

    • [18] ZHANG S,LEI C,WU J,et al.The establishment and application of preimplantation genetic haplotyping in embryo diagnosis for reciprocal and robertsonian translocation carriers[J].BMC Med Genomics,2017,10(1):60.

    • [19] XU J,ZHANG Z,NIU W,et al.Mapping allele with resolved carrier status of robertsonian and reciprocal translocation in human preimplantation embryos[J].Proc Natl Acad Sci U S A,2017,114(41):E8695-E8702.

    • [20] MEHTA A,HABER J E.Sources of DNA double-strand breaks and models of recombinational DNA repair[J].Cold Spring Harb Perspect Biol,2014,6(9):a016428.

    • [21] JANSSEN A,VAN DER BURG M,SZUHAI K,et al.Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations[J].Science,2011,333(6051):1895-1898.

    • [22] SANCAR A,LINDSEY-BOLTZ L A,ÜNSAL-KAÇMAZ K,et al.Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints[J].Annu Rev Biochem,2004,73:39-85.

    • [23] KUBICEK D,HORNAK M,HORAK J,et al.Incidence and origin of meiotic whole and segmental chromosomal aneuploidies detected by karyomapping[J].Reprod Biomed Online,2019,38(3):330-339.

    • [24] NAGAOKA S I,HASSOLD T J,HUNT P A.Human aneuploidy:mechanisms and new insights into an age-old problem[J].Nat Rev Genet,2012,13(7):493-504.

    • [25] HANDYSIDE A H,MONTAG M,MAGLI M C,et al.Multiple meiotic errors caused by predivision of chromatids in women of advanced maternal age undergoing in vitro fertilisation[J].Eur J Hum Genet,2012,20(7):742-747.

  • 参考文献

    • [1] SCRIVEN P N,HANDYSIDE A H,OGILVIE C M.Chromosome translocations:segregation modes and strategies for preimplantation genetic diagnosis[J].Prenat Diagn,1998,18(13):1437-1449.

    • [2] UEHARA S,TAKABAYASHI T,OKAMURA K,et al.The outcome of pregnancy and prenatal chromosomal diagnosis of fetuses in couples including a translocation carrier[J].Prenat Diagn,1992,12(12):1009-1018.

    • [3] STERN C,PERTILE M,NORRIS H,et al.Chromosome translocations in couples with in-vitro fertilization implantation failure[J].Hum Reprod,1999,14(8):2097-2101.

    • [4] LEJEUNE J.Autosomal disorders[J].Pediatrics,1963,32(3):326-337.

    • [5] ALFARAWATI S,FRAGOULI E,COLLS P,et al.Embryos of robertsonian translocation carriers exhibit a mitotic interchromosomal effect that enhances genetic instability during early development[J].PLoS Genet,2012,8(10):e1003025.

    • [6] OLIVER-BONET M,BENET J,SUN F,et al.Meiotic studies in two human reciprocal translocations and their association with spermatogenic failure[J].Hum Reprod,2005,20(3):683-688.

    • [7] ANTON E,VIDA F L,BLANCO J.Interchromosomal effect analyses by sperm FISH:incidence and distribution among reorganization carriers[J].Syst Biol Reprod Med,2011,57(6):268-278.

    • [8] PUJOL A,BENET J,STAESSEN C,et al.The importance of aneuploidy screening in reciprocal translocation carriers[J].Reproduction,2006,131(6):1025-1035.

    • [9] GIANAROLI L,MAGLI M C,FERRARETTI A P,et al.Possible interchromosomal effect in embryos generated by gametes from translocation carriers[J].Hum Reprod,2002,17(12):3201-3207.

    • [10] BOYNUKALIN F K,GULTOMRUK M,TURGUT N E,et al.The impact of patient,embryo,and translocation characteristics on the ploidy status of young couples undergoing preimplantation genetic testing for structural rearrangements(PGT-SR)by next generation sequencing(NGS)[J].J Assist Reprod Genet,2021,38(2):387-396.

    • [11] XIE Y X,XU Y,WANG J,et al.Preliminary analysis of numerical chromosome abnormalities in reciprocal and robertsonian translocation preimplantation genetic diagnosis cases with 24-chromosomal analysis with an aCGH/SNP microarray[J].J Assist Reprod Genet,2018,35(1):177-186.

    • [12] MUNNE S,ESCUDERO T,FISCHER J,et al.Negligible interchromosomal effect in embryos of robertsonian translocation carriers[J].Reprod Biomed Online,2005,10(3):363-369.

    • [13] MATEU-BRULL E,RODRIGO L,PEINADO V,et al.Interchromosomal effect in carriers of translocations and inversions assessed by preimplantation genetic testing for structural rearrangements(PGT-SR)[J].J Assist Reprod Genet,2019,36(12):2547-2555.

    • [14] ESTOP A M,CIEPLY K,MUNNE S,et al.Is there an interchromosomal effect in reciprocal translocation carriers?Sperm FISH studies[J].Hum Genet,2000,106(5):517-524.

    • [15] TREFF N R,TAO X,SCHILLINGS W J,et al.Use of single nucleotide polymorphism microarrays to distinguish between balanced and normal chromosomes in embryos from a translocation carrier[J].Fertil Steril,2011,96(1):e58-e65.

    • [16] HU L,CHENG D H,GONG F,et al.Reciprocal translocation carrier diagnosis in preimplantation human embryos[J].EBio Medicine,2016,14:139-147.

    • [17] GAO M,WANG L J,XU P W,et al.Noncarrier embryo selection and transfer in preimplantation genetic testing cycles for reciprocal translocation by Oxford Nanopore Technologies[J].J Genet Genomics,2020,47(11):718-721.

    • [18] ZHANG S,LEI C,WU J,et al.The establishment and application of preimplantation genetic haplotyping in embryo diagnosis for reciprocal and robertsonian translocation carriers[J].BMC Med Genomics,2017,10(1):60.

    • [19] XU J,ZHANG Z,NIU W,et al.Mapping allele with resolved carrier status of robertsonian and reciprocal translocation in human preimplantation embryos[J].Proc Natl Acad Sci U S A,2017,114(41):E8695-E8702.

    • [20] MEHTA A,HABER J E.Sources of DNA double-strand breaks and models of recombinational DNA repair[J].Cold Spring Harb Perspect Biol,2014,6(9):a016428.

    • [21] JANSSEN A,VAN DER BURG M,SZUHAI K,et al.Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations[J].Science,2011,333(6051):1895-1898.

    • [22] SANCAR A,LINDSEY-BOLTZ L A,ÜNSAL-KAÇMAZ K,et al.Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints[J].Annu Rev Biochem,2004,73:39-85.

    • [23] KUBICEK D,HORNAK M,HORAK J,et al.Incidence and origin of meiotic whole and segmental chromosomal aneuploidies detected by karyomapping[J].Reprod Biomed Online,2019,38(3):330-339.

    • [24] NAGAOKA S I,HASSOLD T J,HUNT P A.Human aneuploidy:mechanisms and new insights into an age-old problem[J].Nat Rev Genet,2012,13(7):493-504.

    • [25] HANDYSIDE A H,MONTAG M,MAGLI M C,et al.Multiple meiotic errors caused by predivision of chromatids in women of advanced maternal age undergoing in vitro fertilisation[J].Eur J Hum Genet,2012,20(7):742-747.

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