Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China.
National Clinical Research Center for Obstetrics and Gynecology, Beijing 100191, China.
Asian J Androl. 2023 Jan-Feb;25(1):66-72. doi: 10.4103/aja202275.
Nonobstructive azoospermia (NOA) is a severe condition in infertile men, and increasing numbers of causative genes have been identified during the last few decades. Although certain causative genes can explain the presence of NOA in some patients, a proportion of NOA patients remain to be addressed. This study aimed to investigate potential high-risk genes associated with spermatogenesis in idiopathic NOA patients by whole-exome sequencing. Whole-exome sequencing was performed in 46 male patients diagnosed with NOA. First, screening was performed for 119 genes known to be related to male infertility. Next, further screening was performed to determine potential high-risk causative genes for NOA by comparisons with 68 healthy male controls. Finally, risk genes with high/specific expression in the testes were selected and their expression fluctuations during spermatogenesis were graphed. The frequency of cystic fibrosis transmembrane conductance regulator (CFTR) gene pathogenic variant carriers was higher in the NOA patients compared with the healthy controls. Potential risk genes that may be causes of NOA were identified, including seven genes that were highly/specifically expressed in the testes. Four risk genes previously reported to be involved in spermatogenesis (MutS homolog 5 [MSH5], cilia- and flagella-associated protein 54 [CFAP54], MAP7 domain containing 3 [MAP7D3], and coiled-coil domain containing 33 [CCDC33]) and three novel risk genes (coiled-coil domain containing 168 [CCDC168], chromosome 16 open reading frame 96 [C16orf96], and serine protease 48 [PRSS48]) were identified to be highly or specifically expressed in the testes and significantly different in the 46 NOA patients compared with 68 healthy controls. This study on clinical NOA patients provides further evidence for the four previously reported risk genes. The present findings pave the way for further functional investigations and provide candidate risk genes for genetic diagnosis of NOA.
非梗阻性无精子症（NOA）是男性不育症中的一种严重病症，在过去几十年中，已经发现了越来越多的致病基因。尽管某些致病基因可以解释某些患者的 NOA 存在，但仍有一部分 NOA 患者需要进一步研究。本研究旨在通过全外显子组测序，探讨与特发性 NOA 患者生精相关的潜在高危基因。对 46 名被诊断为 NOA 的男性患者进行全外显子组测序。首先，对 119 个已知与男性不育相关的基因进行了筛选。其次，通过与 68 名健康男性对照比较，对潜在的导致 NOA 的高风险致病基因进行了进一步筛选。最后，选择在睾丸中高/特异性表达的风险基因，并绘制其在生精过程中的表达波动。与健康对照组相比，NOA 患者中囊性纤维化跨膜电导调节因子（CFTR）基因突变携带者的频率更高。鉴定出了可能导致 NOA 的潜在风险基因，包括在睾丸中高/特异性表达的七个基因。四个先前报道与精子发生有关的风险基因（MutS 同源物 5 [MSH5]、纤毛和鞭毛相关蛋白 54 [CFAP54]、MAP7 结构域包含 3 [MAP7D3] 和卷曲螺旋结构域包含 33 [CCDC33]）和三个新的风险基因（卷曲螺旋结构域包含 168 [CCDC168]、染色体 16 开放阅读框 96 [C16orf96] 和丝氨酸蛋白酶 48 [PRSS48]）被鉴定为在睾丸中高度或特异性表达，并且在 46 名 NOA 患者与 68 名健康对照之间存在显著差异。本研究对临床 NOA 患者提供了进一步的证据，证实了四个先前报道的风险基因。本研究为进一步的功能研究铺平了道路，并为 NOA 的遗传诊断提供了候选风险基因。
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