Riera-Escamilla Antoni, Nagirnaja Liina
Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA.
Andrology. 2025 Jul;13(5):999-1010. doi: 10.1111/andr.13753. Epub 2024 Sep 19.
Primary spermatogenic disorders represent a severe form of male infertility whereby sperm production is impaired due to testicular dysfunction, leading to reduced quality or quantity of spermatozoa. Gene-centered research has certainly demonstrated the importance of the genetic factor in the etiology of both poor sperm morphology or motility and reduced sperm count. In the last decade, next-generation sequencing has expanded the research to whole exome which has transformed our understanding of male infertility genetics, but uncertainty persists in its diagnostic yield, especially in large unrelated populations.
To evaluate the utility of exome sequencing in detecting genetic factors contributing to various traits of primary spermatogenic disorders, which is a crucial step before interpreting the diagnostic yield of the platform.
We manually curated 415 manuscripts and included 19 research studies that predominantly performed whole exome sequencing in cohorts of unrelated cases with primary spermatogenic defects.
The detection rate, defined as the fraction of cases with an identifiable genetic cause, typically remained below 25% for quantitative defects of spermatozoa, whereas improved rates were observed for traits of abnormal sperm morphology/motility and in populations enriched with consanguineous families. Unlike the quantitative defects, the genetic architecture of the qualitative issues of spermatozoa featured a small number of recurrent genes describing a large fraction of studied cases. These observations were also in line with the lower biological complexity of the pathways affected by the reported genes.
This review demonstrates the variability in detection rates of exome sequencing across semen phenotypes, which may have an impact on the expectations of the diagnostic yield in the clinical setting.
原发性生精障碍是男性不育的一种严重形式，由于睾丸功能障碍导致精子生成受损，从而使精子的质量或数量下降。以基因为中心的研究确实已经证明了遗传因素在精子形态不佳、活力不足以及精子数量减少的病因学中的重要性。在过去十年中，下一代测序技术已将研究扩展到全外显子组，这改变了我们对男性不育遗传学的理解，但在其诊断效率方面仍存在不确定性，尤其是在大型非亲缘人群中。
评估外显子组测序在检测导致原发性生精障碍各种特征的遗传因素方面的效用，这是解释该平台诊断效率之前的关键步骤。
我们人工筛选了415篇手稿，并纳入了19项研究，这些研究主要在患有原发性生精缺陷的非亲缘病例队列中进行了全外显子组测序。
对于精子数量的定量缺陷，定义为具有可识别遗传原因的病例比例的检测率通常保持在25%以下，而对于精子形态/活力异常的特征以及在近亲家庭富集的人群中观察到检测率有所提高。与定量缺陷不同，精子定性问题的遗传结构特征是少数反复出现的基因，这些基因描述了大部分研究病例。这些观察结果也与受报告基因影响的通路较低的生物学复杂性一致。
本综述表明，外显子组测序在不同精液表型中的检测率存在差异，这可能会影响临床环境中对诊断效率的预期。
