Background: Genetic etiology is the main cause of non-obstructive azoospermia, but little is known about the landscape of the disease causative genes. Objective: To identify the association of non-obstructive azoospermia and the putative causative genetic factors. Design, setting, and participants: A single-center perspective case-control study of 133 patients, with clinicopathologic non-obstructive azoospermia and 495 fertile men control was performed. Eleven trio families were available and enrolled from the 133 patients families. Outcome measurements and statistical analysis: Whole exome sequencing based rare variant association study between the cases and controls was performed by means of gene burden association testing. Linkage analysis on the trio family was also described to screen the causative genes. Results and limitations: Totally 80 genes (p < 0.05) were identified associated with non-obstructive azoospermia (2 of which were previously reported), meanwhile 5 novel genes out of which were also found potentially causative through the linkage analysis on the trio families. The pathway enrichment analysis was also provided to assess the potential interaction between genes identified in this study and previously reported together. The 5 novel identified overlap genes by both above mentioned test with the rare mutations account for an overall 20% (26 /133 patients) incidence, together with the 2 known genes together would account for an overall 20% incidence for non-obstructive azoospermia in this study. The study is limited by the lack of functional biological study. Conclusions: Five novel genes were identified associated with non-obstructive azoospermia by means of both rare variant association study and linkage analysis through trio families. They could account for about 20% clinical incidence among the patients in our study. Patient summary: 133 infertile patients (11 of them with parents enrolled) with idiopathic non-obstructive azoospermia and 300 fertile male controls were recruited from single clinic center. All patients underwent semen analyses at least on three different occasions.

中文翻译：

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整个外显子组测序可鉴定与非阻塞性无精症相关的基因

背景：遗传病因是非阻塞性无精症的主要原因，但对疾病致病基因的了解甚少。目的：确定非阻塞性无精子症与可能的致病遗传因素的关系。设计，地点和参与者：进行了133名患者的单中心透视病例对照研究，这些患者具有临床病理学非阻塞性无精症和495名可育男性。共有来自133个患者家庭的11个三人家庭。结果测量和统计分析：通过基因负荷关联测试，在病例和对照之间进行基于全外显子组测序的罕见变异关联研究。还描述了三重家族的连锁分析，以筛选致病基因。结果和局限性：总共鉴定出与非阻塞性无精子症相关的80个基因（p <0.05）（先前已报道其中2个），同时通过对这三个家族的连锁分析，还发现其中5个新基因可能具有致病性。还提供了途径富集分析，以评估在本研究中鉴定的基因和先前一起报告的基因之间的潜在相互作用。通过上述两项测试鉴定出的5个新颖的重叠基因，具有罕见突变，占总发生率的20％（26/133位患者），连同2个已知基因一起占非阻塞性无精子症的总发生率20％。这项研究。这项研究由于缺乏功能性生物学研究而受到限制。结论：通过罕见变体关联研究和通过三重家族的连锁分析，鉴定出与非阻塞性无精子症相关的五个新基因。在我们的研究中，他们可能占到大约20％的临床发病率。患者摘要：从单一诊所中心招募了133名不育患者（其中11名父母参加了研究），他们患有特发性非阻塞性无精症和300名可育男性对照。所有患者至少在三种不同情况下进行了精液分析。从单个诊所中心招募了133名不育患者（其中11名父母入组），患有特发性非阻塞性无精子症和300名可育男性对照。所有患者至少在三种不同的情况下进行了精液分析。从单一诊所中心招募了133名不育患者（其中11名父母入组），患有特发性非阻塞性无精子症和300名可育男性对照。所有患者至少在三种不同的情况下进行了精液分析。