PDF(Pubmed)
Abstract：
Genomic mosaicism arising from mosaic variants is a phenomenon that describes the presence of a cell or cell populations with different genome compositions from the germline cells of an individual. It comprises all types of genetic variants. A large proportion of childhood genetic disorders are defined as being de novo, meaning that the disease-causing mutations are only detected in the proband, not in any of the parents. Population studies show that 80% of the de novo mutations arise from the paternal haplotype, that is, from paternal sperm mosaicism. This review provides a summary of the types and detection strategies of sperm mosaicism. In addition, it provides discussions on how recent studies demonstrated that genomic mosaic mutations in parents, especially those in the paternal sperms, could be inherited by the offspring and cause childhood disorders. According to the previous findings of the author\'s research team, sperm mosaicism derived from early embryogenesis and primordial germ cell stages can explain 5% to 20% of the de novo mutations related to clinical phenotypes and can serve as an important predictor of both rare and complex disorders. Sperm mosaicism shows great potential for clinical genetic diagnosis and consultations. Based on the published literature, the author suggests that, large-scale screening for de novo sperm mosaic mutations and population-based genetic screening should be conducted in future studies, which will greatly enhance the risk assessment in the offspring and effectively improve the genetic health at the population level. Implementation of direct sperm detection for de novo mutations will significantly increase the efficiency of the stratification of patient cohorts and improve recurrence risk assessment for future births. Future research in the field should be focused on the impact of environmental and lifestyle factors on the health of the offspring through sperms and their modeling of mutation signatures. In addition, targeted in vitro modeling of sperm mutations will also be a promising direction.
摘要：
由镶嵌变体产生的基因组镶嵌是描述具有与个体的种系细胞不同的基因组组成的细胞或细胞群体的存在的现象。它包括所有类型的遗传变异。很大一部分儿童遗传疾病被定义为从头，这意味着仅在先证者中检测到致病突变，不在任何父母。人口研究表明，80％的从头突变来自父系单倍型，也就是说,父系精子镶嵌症。本文就精子镶嵌的类型和检测策略作一综述。此外,它提供了关于最近的研究如何证明父母的基因组马赛克突变的讨论，尤其是父系精子中的那些，可能由后代遗传并导致儿童疾病。根据作者研究小组之前的发现,来自早期胚胎发生和原始生殖细胞阶段的精子镶嵌可以解释5％至20％的与临床表型相关的从头突变，并且可以作为罕见和复杂疾病的重要预测指标。精子镶嵌显示出临床遗传诊断和咨询的巨大潜力。根据已发表的文献，作者认为，在未来的研究中，应进行大规模的从头精子镶嵌突变筛查和基于人群的遗传筛查，这将大大增强后代的风险评估，并有效改善种群水平的遗传健康。实施从头突变的直接精子检测将显着提高患者队列分层的效率，并改善未来出生的复发风险评估。该领域的未来研究应集中在环境和生活方式因素对精子及其突变特征模型对后代健康的影响上。此外,精子突变的靶向体外建模也将是一个有希望的方向。
