Principles guiding embryo selection following genome-wide haplotyping of preimplantation embryos
Principles guiding embryo selection following genome-wide haplotyping of preimplantation embryos
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DOI：
10.1093/humrep/dex011
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发表时间：
2017-03-01
影响因子：
6.1
通讯作者：
Vermeesch, Joris Robert
中科院分区：
文献类型：
--
作者：
Dimitriadou, Eftychia;Melotte, Cindy;Vermeesch, Joris Robert
研究问题：在进行全基因组单倍型分析后，如何在 PGD 过程中选择和优先考虑胚胎？总结答案：除了遗传疾病特异性信息外，选择用于移植的胚胎还基于排序标准，包括有丝分裂和/或减数分裂非整倍体的存在，但不包括导致隐性遗传疾病的突变的携带。已知的信息：单基因疾病的胚胎选择主要使用针对特定疾病的检测进行。最近，这些靶向方法得到了通用全基因组遗传分析方法的补充，例如核型定位或单倍体分析，这些方法基于从胚胎活检的细胞的基因组单倍型重建。这不仅提供了有关孟德尔疾病等位基因遗传的信息，还提供了有关染色体数值和结构异常以及全基因组单倍型的信息。目前还缺乏对如何在诊断实验室中使用这些信息的思考。 研究设计、规模、持续时间：我们展示了在 UZ Leuven 人类遗传学中心使用 haplarithmisis 进行的前 101 个 PGD 周期（373 个胚胎）的结果。由临床遗传学家、生育专家和伦理学家组成的多学科团队解决了提出的问题。 参与者/材料、背景、方法：63 对夫妇参加了基于全基因组单倍型的 PGD 计划。家庭呈现出导致已知疾病的遗传性基因变异和/或可能导致后代不平衡易位的染色体重排。主要结果和机会的作用：根据疾病等位基因、三体性或其他导致已知发育障碍的染色体异常的存在或不存在来选择胚胎。此外，根据是否存在其他染色体不平衡和/或载体信息，优先考虑形态正常的第 5 天胚胎进行移植。 局限性、注意原因：所做的一些选择和提出的原则专门针对基于卵裂阶段的基因检测。拟议的指南将根据世界各地许多不同中心实施全基因组 PGD 方法所积累的知识以及正在进行的科学研究的结果不断更新。研究结果的广泛影响：我们的胚胎选择原则对 PGD 操作的组织以及遗传单位、生育诊所和患者之间传输的信息具有深远的影响。这些原则对于组织咨询前和咨询后也很重要，并影响着床前基因分型结果的解释和报告。由于胚胎选择的新的全基因组方法正在彻底改变生殖遗传学领域，因此有必要进行国家和国际讨论以制定一般准则。
STUDY QUESTION: How to select and prioritize embryos during PGD following genome-wide haplotyping?SUMMARY ANSWER: In addition to genetic disease-specific information, the embryo selected for transfer is based on ranking criteria including the existence of mitotic and/or meiotic aneuploidies, but not carriership of mutations causing recessive disorders.WHAT IS KNOWN ALREADY: Embryo selection for monogenic diseases has been mainly performed using targeted disease-specific assays. Recently, these targeted approaches are being complemented by generic genome-wide genetic analysis methods such as karyomapping or haplarithmisis, which are based on genomic haplotype reconstruction of cell(s) biopsied from embryos. This provides not only information about the inheritance of Mendelian disease alleles but also about numerical and structural chromosome anomalies and haplotypes genome-wide. Reflections on how to use this information in the diagnostic laboratory are lacking.STUDY DESIGN, SIZE, DURATION: We present the results of the first 101 PGD cycles (373 embryos) using haplarithmisis, performed in the Centre for Human Genetics, UZ Leuven. The questions raised were addressed by a multidisciplinary team of clinical geneticist, fertility specialists and ethicists.PARTICIPANTS/MATERIALS, SETTING, METHODS: Sixty-three couples enrolled in the genome-wide haplotyping-based PGD program. Families presented with either inherited genetic variants causing known disorders and/or chromosomal rearrangements that could lead to unbalanced translocations in the offspring.MAIN RESULTS AND THE ROLE OF CHANCE: Embryos were selected based on the absence or presence of the disease allele, a trisomy or other chromosomal abnormality leading to known developmental disorders. In addition, morphologically normal Day 5 embryos were prioritized for transfer based on the presence of other chromosomal imbalances and/or carrier information.LIMITATIONS, REASONS FOR CAUTION: Some of the choices made and principles put forward are specific for cleavage-stage-based genetic testing. The proposed guidelines are subject to continuous update based on the accumulating knowledge from the implementation of genome-wide methods for PGD in many different centers world-wide as well as the results of ongoing scientific research. WIDERIMPLICATIONS OF THE FINDINGS: Our embryo selection principles have a profound impact on the organization of PGD operations and on the information that is transferred among the genetic unit, the fertility clinic and the patients. These principles are also important for the organization of pre-and post-counseling and influence the interpretation and reporting of preimplantation genotyping results. As novel genome-wide approaches for embryo selection are revolutionizing the field of reproductive genetics, national and international discussions to set general guidelines are warranted.