Genome-Phenome Relationship Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy.
Division of Experimental Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy.
PLoS One. 2023 Aug 4;18(8):e0288336. doi: 10.1371/journal.pone.0288336. eCollection 2023.
Almost 40% of infertile men cases are classified as idiopathic when tested negative to the current diagnostic routine based on the screening of karyotype, Y chromosome microdeletions and CFTR mutations in men with azoospermia or oligozoospermia. Rare monogenic forms of infertility are not routinely evaluated. In this study we aim to investigate the unknown potential genetic causes in couples with pure male idiopathic infertility by applying variant prioritization to whole exome sequencing (WES) in a cohort of 99 idiopathic Italian patients. The ad-hoc manually curated gene library prioritizes genes already known to be associated with more common and rare syndromic and non-syndromic male infertility forms. Twelve monogenic cases (12.1%) were identified in the whole cohort of patients. Of these, three patients had variants related to mild androgen insensitivity syndrome, two in genes related to hypogonadotropic hypogonadism, and six in genes related to spermatogenic failure, while one patient is mutant in PKD1. These results suggest that NGS combined with our manually curated pipeline for variant prioritization and classification can uncover a considerable number of Mendelian causes of infertility even in a small cohort of patients.
当对无精子症或严重少精子症患者进行基于核型、Y 染色体微缺失和 CFTR 基因突变筛查的当前诊断常规检测呈阴性时，近 40%的不孕男性病例被归类为特发性。罕见的单基因形式的不育症通常不会进行常规评估。在这项研究中，我们通过对 99 名意大利特发性男性不育患者进行全外显子组测序（WES）的变异优先级排序，旨在研究纯男性特发性不育夫妇中未知的潜在遗传原因。专门手工整理的基因库优先考虑已知与更常见和罕见的综合征和非综合征男性不育形式相关的基因。在整个患者队列中发现了 12 例单基因病例（12.1%）。其中，3 名患者的变异与轻度雄激素不敏感综合征有关，2 名患者的变异与促性腺激素低下性性腺功能减退症有关，6 名患者的变异与精子发生失败有关，而 1 名患者的 PKD1 基因发生突变。这些结果表明，即使在一小部分患者中，NGS 结合我们手动整理的变异优先级排序和分类管道也可以发现相当数量的不育症孟德尔病因。
