Purpose

Male infertility remains poorly understood at the molecular level. We aimed in this study to investigate the yield of a “genomics first” approach to male infertility.

Methods

Patients with severe oligospermia and nonobstructive azoospermia were investigated using exome sequencing (ES) in parallel with the standard practice of chromosomal analysis.

Results

In 285 patients, 10.5% (n = 30) had evidence of chromosomal aberrations while nearly a quarter (n = 69; 24.2%) had a potential monogenic form of male infertility. The latter ranged from variants in genes previously reported to cause male infertility with or without other phenotypes in humans (24 patients; 8.4%) to those in novel candidate genes reported in this study (37 patients; 12.9%). The 33 candidate genes have biological links to male germ cell development including compatible mouse knockouts, and a few (TERB1 [CCDC79], PIWIL2, MAGEE2, and ZSWIM7) were found to be independently mutated in unrelated patients in our cohort. We also found that male infertility can be the sole or major phenotypic expression of a number of genes that are known to cause multisystemic manifestations in humans (n = 9 patients; 3.1%).

Conclusion

The standard approach to male infertility overlooks the significant contribution of monogenic causes to this important clinical entity.

中文翻译：

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男性不育症的基因组学方法。

目的

男性不育症在分子水平上仍然知之甚少。我们在这项研究中旨在调查“基因组学优先”方法对男性不育症的效果。

方法

使用外显子组测序 (ES) 与染色体分析的标准实践并行研究患有严重少精子症和非阻塞性无精子症的患者。

结果

在 285 名患者中，10.5% ( n  = 30) 有染色体畸变的证据，而近四分之一 ( n  = 69; 24.2%) 有潜在的单基因男性不育症。后者的范围从先前报道的导致男性不育的基因变异（有或没有人类其他表型）（24 名患者；8.4%）到本研究中报道的新候选基因（37 名患者；12.9%）。33 个候选基因与雄性生殖细胞发育具有生物学联系，包括兼容的小鼠基因敲除，以及一些（TERB1 [ CCDC79 ]、PIWIL2、MAGEE2和ZSWIM7) 被发现在我们队列中无关的患者中发生独立突变。我们还发现男性不育可能是已知会导致人类多系统表现的许多基因的唯一或主要表型表达（n  = 9 名患者；3.1%）。

结论

男性不育症的标准方法忽略了单基因原因对这一重要临床实体的重大贡献。