背景:不孕和妊娠流产是长期存在的问题。成功的受精和高质量的胚胎是持续怀孕的先决条件。研究证明,人类生殖过程的每个阶段都受到多个基因和任何问题的调节,在任何一步,可能导致受精失败(FF)或早期胚胎停滞(EEA)。医生可以通过遗传学方法诊断FF和EEA的致病因素。随着新基因技术的发展,例如单细胞RNA分析和全外显子组测序,为我们直接研究人类生殖细胞和生殖发育开辟了一种新的方法。这些发现将帮助我们确定导致FF和EEA的独特机制,以便找到潜在的治疗方法。
目的:本综述的目的是汇编当前与FF和EEA相关的遗传知识,阐明其发病机制,为临床诊断和治疗提供线索。
方法:PubMed用于搜索相关研究文章和评论,从1978年1月到2023年6月,主要关注英语出版物。搜索词包括受精失败,早期胚胎逮捕,遗传,表观遗传,全外显子组测序,DNA甲基化,染色体,非编码RNA,和其他相关关键词。通过搜索参考文献列表确定了其他研究。这篇综述主要集中在人类进行的研究。然而,适用时,它还纳入了动物模型的相关数据。结果以描述性方式呈现,并且未评估个体研究质量.
结果:最终评审共纳入233篇相关文章,从最初确定的3925条记录中。该综述概述了人类生殖过程中涉及的遗传因素和机制。系统综述了FF和EEA的基因突变及其他遗传机制,例如,球精子症,卵母细胞激活失败,母体效应基因突变,合子基因组激活异常,染色体异常,和表观遗传异常。此外,综述了不同基因缺陷的治疗进展,为临床诊断和治疗提供新的见解。
结论:本综述提供的信息将有助于开发更准确的分子筛查工具,用于使用人类生殖发育中的遗传标记和网络诊断不孕症。这些发现还将通过确定基于特定基因突变的适当干预措施来帮助指导临床实践。例如,当个体具有与FF相关的明显基因突变时,建议使用ICSI代替IVF。然而,在遗传缺陷的情况下,如磷脂酶Czeta1(PLCZ1),肌动蛋白-like7A(ACTL7A),肌动蛋白样9(ACTL9),和含IQ基序的N(IQCN),ICSI也可能无法受精。我们可以考虑使用ICSI的人工卵母细胞激活技术来提高受精率并减少金钱和时间成本。在未来,有望通过干扰或补充相关基因来改善或恢复生育力。
BACKGROUND: Infertility and pregnancy loss are longstanding problems. Successful
fertilization and high-quality embryos are prerequisites for an ongoing pregnancy. Studies have proven that every stage in the human reproductive process is regulated by multiple genes and any problem, at any step, may lead to
fertilization failure (FF) or early embryonic arrest (EEA). Doctors can diagnose the pathogenic factors involved in FF and EEA by using genetic methods. With the progress in the development of new genetic technologies, such as single-cell RNA analysis and whole-exome sequencing, a new approach has opened up for us to directly study human germ cells and reproductive development. These findings will help us to identify the unique mechanism(s) that leads to FF and EEA in order to find potential treatments.
OBJECTIVE: The goal of this review is to compile current genetic knowledge related to FF and EEA, clarifying the mechanisms involved and providing clues for clinical diagnosis and treatment.
METHODS: PubMed was used to search for relevant research articles and reviews, primarily focusing on English-language publications from January 1978 to June 2023. The search terms included
fertilization failure, early embryonic arrest, genetic, epigenetic, whole-exome sequencing, DNA methylation, chromosome, non-coding RNA, and other related keywords. Additional studies were identified by searching reference lists. This
review primarily focuses on research conducted in humans. However, it also incorporates relevant data from animal models when applicable. The results were presented descriptively, and individual study quality was not assessed.
RESULTS: A total of 233 relevant articles were included in the final review, from 3925 records identified initially. The review provides an overview of genetic factors and mechanisms involved in the human reproductive process. The genetic mutations and other genetic mechanisms of FF and EEA were systematically reviewed, for example, globozoospermia, oocyte activation failure, maternal effect gene mutations, zygotic genome activation abnormalities, chromosome abnormalities, and epigenetic abnormalities. Additionally, the review summarizes progress in treatments for different gene defects, offering new insights for clinical diagnosis and treatment.
CONCLUSIONS: The information provided in this review will facilitate the development of more accurate molecular screening tools for diagnosing infertility using genetic markers and networks in human reproductive development. The findings will also help guide clinical practice by identifying appropriate interventions based on specific gene mutations. For example, when an individual has obvious gene mutations related to FF, ICSI is recommended instead of IVF. However, in the case of genetic defects such as phospholipase C zeta1 (PLCZ1), actin-like7A (ACTL7A), actin-like 9 (ACTL9), and IQ motif-containing N (IQCN), ICSI may also fail to fertilize. We can consider artificial oocyte activation technology with ICSI to improve
fertilization rate and reduce monetary and time costs. In the future, fertility is expected to be improved or restored by interfering with or supplementing the relevant genes.