Reproductive Medical Center, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Andrology, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China.
Hum Reprod Update. 2024 Jan 3;30(1):48-80. doi: 10.1093/humupd/dmad026.
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.
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.
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.
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.
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.
不孕和妊娠丢失是长期存在的问题。成功受精和高质量胚胎是持续妊娠的前提。研究已经证明，人类生殖过程的每个阶段都受多种基因调控，任何步骤的任何问题都可能导致受精失败（FF）或早期胚胎阻滞（EEA）。医生可以通过遗传方法诊断 FF 和 EEA 涉及的致病因素。随着单细胞 RNA 分析和全外显子组测序等新遗传技术的发展，为我们直接研究人类生殖细胞和生殖发育开辟了新途径。这些发现将有助于我们确定导致 FF 和 EEA 的独特机制，以寻找潜在的治疗方法。
本综述的目的是汇编与 FF 和 EEA 相关的当前遗传知识，阐明所涉及的机制，并为临床诊断和治疗提供线索。
使用 PubMed 搜索相关研究文章和综述，主要侧重于 1978 年 1 月至 2023 年 6 月的英文出版物。检索词包括受精失败、早期胚胎阻滞、遗传、表观遗传、全外显子组测序、DNA 甲基化、染色体、非编码 RNA 等相关关键词。通过查阅参考文献列表确定了其他研究。本综述主要关注在人类中进行的研究，但在适用的情况下也纳入了来自动物模型的相关数据。结果以描述性方式呈现，未评估个别研究的质量。
最终综述共纳入 233 篇相关文章，最初从 3925 条记录中筛选得出。该综述提供了人类生殖过程中遗传因素和机制的概述。系统综述了 FF 和 EEA 的遗传突变和其他遗传机制，例如，球状精子症、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，该综述总结了针对不同基因缺陷的治疗进展，为临床诊断和治疗提供了新的见解。
本综述提供的信息将有助于开发更准确的分子筛查工具，使用人类生殖发育的遗传标记和网络诊断不孕不育。研究结果还将通过根据特定基因突变识别适当的干预措施来指导临床实践。例如，当个体存在与 FF 明显相关的基因突变时，建议使用 ICSI 而不是 IVF。然而，在磷脂酶 C zeta1（PLCZ1）、肌动蛋白样 7A（ACTL7A）、肌动蛋白样 9（ACTL9）和 IQ 基序包含 N（IQCN）等基因缺陷的情况下，ICSI 也可能无法受精。我们可以考虑使用 ICSI 进行人工卵母细胞激活技术，以提高受精率并降低金钱和时间成本。未来，预计通过干扰或补充相关基因来改善或恢复生育能力。
