Abstract：
Male infertility affects approximately 17% of all men and represents a complex disorder in which not only semen parameters such as sperm motility, morphology, and number of sperm are highly variable, but also testicular phenotypes range from normal spermatogenesis to complete absence of germ cells. Genetic factors significantly contribute to the disease but chromosomal aberrations, mostly Klinefelter syndrome, and microdeletions of the Y-chromosome have remained the only diagnostically and clinically considered genetic causes. Monogenic causes remain understudied and, thus, often unidentified, leaving the majority of the male factor couple infertility pathomechanistically unexplained. This has been changing mostly because of the introduction of exome sequencing that allows the analysis of multiple genes in large patient cohorts. As a result, pathogenic variants in single genes have been associated with non-syndromic forms of all aetiologic sub-categories in the last decade. This review highlights the contribution of exome sequencing to the identification of novel disease genes for isolated (non-syndromic) male infertility by presenting the results of a comprehensive literature search. Both, reduced sperm count in azoospermic and oligozoospermic patients, and impaired sperm motility and/or morphology, in asthenozoospermic and/or teratozoospermic patients are highly heterogeneous diseases with well over 100 different candidate genes described for each entity. Applying the standardized evaluation criteria of the ClinGen gene curation working group, 70 genes with at least moderate evidence to contribute to the disease are highlighted. The implementation of these valid disease genes in clinical exome sequencing is important to increase the diagnostic yield in male infertility and, thus, improve clinical decision-making and appropriate genetic counseling. Future advances in androgenetics will continue to depend on large-scale exome and genome sequencing studies of comprehensive international patient cohorts, which are the most promising approaches to identify additional disease genes and provide reliable data on the gene-disease relationship.
摘要：
男性不育影响大约17％的男性，代表了一种复杂的疾病，其中不仅精液参数，如精子活力，形态学,精子的数量变化很大，而且睾丸表型的范围从正常的精子发生到完全没有生殖细胞。遗传因素对该疾病有重要贡献，但染色体畸变，主要是Klinefelter综合征,Y染色体的微缺失仍然是唯一的诊断和临床考虑的遗传原因。单基因原因仍未得到充分研究，因此，通常身份不明，离开大多数男性因素夫妇不育的病理机制无法解释。这种情况一直在变化，主要是因为引入了外显子组测序，可以分析大型患者队列中的多个基因。因此,在过去十年中,单基因的致病变异与所有病因学亚类的非综合征形式相关.这篇综述通过提供全面的文献检索结果，强调了外显子组测序对鉴定分离的（非综合征型）男性不育的新疾病基因的贡献。两者,无精子症和少精子症患者的精子数量减少，精子运动和/或形态受损，在弱精子症和/或畸形精子症患者中，是高度异质性的疾病，每个实体描述了超过100种不同的候选基因。应用ClinGen基因策展工作组的标准化评价标准,突出显示了至少有中度证据导致该疾病的70个基因。在临床外显子组测序中实施这些有效的疾病基因对于提高男性不育症的诊断率非常重要,因此，改善临床决策和适当的遗传咨询。未来男性遗传学的进展将继续依赖于全面的国际患者队列的大规模外显子组和基因组测序研究。这是最有希望的方法来识别额外的疾病基因，并提供可靠的数据的基因-疾病关系。
