非梗阻性无精子症(NOA)是男性不育的严重和常见原因,通常通过睾丸精子提取,然后进行卵胞浆内精子注射。这项研究的目的是提高NOA的基因诊断,通过鉴定与人类NOA有关的新基因,并根据个体的基因型更好地评估成功提取精子的机会。对常规遗传测试阴性的96名受NOA影响的个体进行了外显子组测序。生物信息学分析仅限于一组151个基因,这些基因被选为NOA的已知因果或候选基因。仅保留高度有害的纯合或半合子变体作为候选物。在总共22个人(23%)的16个基因中发现了可能的因果缺陷。在人类中没有描述过6个基因(DDX25,HENMT1,MCMDC2,MSH5,REC8,TDRKH),以前报道过10个基因(C14orf39,DMC1,FANCM,GCNA,HFM1,MCM8,MEIOB,PDHA2、TDRD9、TERB1)。七个人在piwi或DNA修复途径的基因中有缺陷,涉及减数分裂后成熟的三个基因,12在减数分裂过程中。有趣的是,所有有减数分裂基因缺陷的个体精子回收都不成功,这表明TESE之前的基因诊断可以帮助识别精子成功回收机会低或无效的个体,从而避免不成功的手术。
Non-obstructive azoospermia (NOA) is a severe and frequent cause of male infertility, often treated by testicular sperm extraction followed by intracytoplasmic sperm injection. The aim of this study is to improve the genetic diagnosis of NOA, by identifying new genes involved in human NOA and to better assess the chances of successful sperm extraction according to the individual\'s genotype. Exome sequencing was performed on 96 NOA-affected individuals negative for routine genetic tests. Bioinformatics analysis was limited to a panel of 151 genes selected as known causal or candidate genes for NOA. Only highly deleterious homozygous or hemizygous variants were retained as candidates. A likely causal defect was identified in 16 genes in a total of 22 individuals (23%). Six genes had not been described in man (DDX25, HENMT1, MCMDC2, MSH5, REC8, TDRKH) and 10 were previously reported (C14orf39, DMC1, FANCM, GCNA, HFM1, MCM8, MEIOB, PDHA2, TDRD9, TERB1). Seven individuals had defects in genes from piwi or DNA repair pathways, three in genes involved in post-meiotic maturation, and 12 in meiotic processes. Interestingly, all individuals with defects in meiotic genes had an unsuccessful sperm retrieval, indicating that genetic diagnosis prior to TESE could help identify individuals with low or null chances of successful sperm retrieval and thus avoid unsuccessful surgeries.