Recurrent deletions of the X chromosome linked CNV64, CNV67, and CNV69 shows geographic differences across China and no association with idiopathic infertility in men

A recent study found that three recurrent deletions of X chromosome linked copy number variations (CNVs), CNV64, CNV67 and CNV69 were associated with idiopathic male infertility in Spanish and Italian populations, especially CNV67 resembling the azoospermia factor deletions. That merits further investigations among different populations. This study was conducted to examine the prevalence of the three CNVs deletions and their associations with idiopathic male infertility in Chinese Han population. The present study included a large population of 1550 Chinese Han subjects recruited between 2014 and 2016. In total, 714 infertile participants were diagnosed as idiopathic infertility with different conditions (288 with non-obstructive azoospermia, 210 oligozoospermia and 216 asthenospermia) and 836 fertile participants (vasectomized men). The fertile participants were recruited from the representative areas: the north (Hebei and Shanxi), center (Hubei and Jiangsu), and south (Guangdong) of China. All patients were recruited from Hubei province. A multiplex PCR system was established to screen the deletion of the three CNVs, and deletion was confirmed by general PCR. Similar rates of these deletions were observed in infertile men and fertile participants (Hubei), and among the different conditions of infertility. Moreover, CNV64 and CNV67 map distribution geographically differed across China. The three CNVs in fertile groups of other regions were similar, except for Guangdong. No association between the three CNVs deletions and idiopathic male infertility was observed. CNV67 is rare in central China, albeit large sample size study for confirmation is warranted. It seems that the association between these CNVs deletions and idiopathic male infertility is ethnic dependent. There is still need to screen the CNVs deletions in other ethnicities. We suggested to consider the stratification patterns and geographic differences when prescribing CNVs deletions screening as a test in male infertility.

近期一项研究发现，X染色体连锁拷贝数变异（copy number variations, CNVs）的三种复发性缺失，即CNV64、CNV67与CNV69，在西班牙与意大利人群中与特发性男性不育相关，其中CNV67的表型与无精子症因子缺失（azoospermia factor deletions）类似。该结论有待在不同人群中开展进一步验证。本研究旨在探究中国汉族人群中上述三种拷贝数变异缺失的患病率及其与特发性男性不育的关联。本研究纳入了2014至2016年间招募的1550名中国汉族受试者，其中714名不育受试者被诊断为特发性不育，涵盖不同表型：288例非梗阻性无精子症、210例少精子症及216例弱精子症；另有836名已生育男性（均为输精管结扎术后男性）作为对照。对照人群分别来自中国具有代表性的区域：北方（河北、山西）、中部（湖北、江苏）及南方（广东），所有不育患者均招募自湖北省。本研究建立了多重聚合酶链反应（multiplex PCR）体系以筛查三种拷贝数变异的缺失情况，并通过普通聚合酶链反应（general PCR）确认缺失结果。在不育男性与湖北地区对照人群中，以及不同不育表型组间，上述缺失的检出率均无显著差异。此外，CNV64与CNV67的地理分布在全国范围内存在差异；除广东地区外，其余区域对照人群的三种拷贝数变异检出率均较为相似。本研究未观察到三种拷贝数变异缺失与特发性男性不育存在关联。CNV67在中国中部地区较为罕见，不过仍需开展大样本量研究以进一步确认。上述拷贝数变异缺失与特发性男性不育的关联似乎存在种族依赖性，仍需在其他种族人群中开展相关筛查。我们建议，在将拷贝数变异缺失筛查作为男性不育的检测项目时，应考虑人群分层特征及地理分布差异。