Although the evolutionary history of the X chromosome indicates its specialization in male fitness, its role in spermatogenesis has largely been unexplored. Currently only three X chromosome genes are considered of moderate-definitive diagnostic value. We aimed to provide a comprehensive analysis of all X chromosome-linked protein-coding genes in 2,354 azoospermic/cryptozoospermic men from four independent cohorts. Genomic data were analyzed and compared with data in normozoospermic control individuals and gnomAD. While updating the clinical significance of known genes, we propose 21 recurrently mutated genes strongly associated with and 34 moderately associated with azoospermia/cryptozoospermia not previously linked to male infertility (novel). The most frequently affected prioritized gene, , was found mutated in ten men across all cohorts, and our functional studies in support its role in germ stem cell maintenance. Collectively, our study represents a significant step towards the definition of the missing genetic etiology in idiopathic severe spermatogenic failure and significantly reduces the knowledge gap of X-linked genetic causes of azoospermia/cryptozoospermia contributing to the development of future diagnostic gene panels.

中文翻译：

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对 2,354 名不育男性的 X 染色体进行大规模分析，发现与生精失败相关的反复受影响的基因


尽管 X 染色体的进化史表明它在男性健康方面具有特殊性，但它在精子发生中的作用在很大程度上尚未被探索。目前，只有三个 X 染色体基因被认为具有中等确定的诊断价值。我们的目的是对来自四个独立队列的 2,354 名无精症/隐精症男性的所有 X 染色体连锁蛋白编码基因进行全面分析。对基因组数据进行了分析，并与正常精子对照个体和 gnomAD 的数据进行了比较。在更新已知基因的临床意义的同时，我们提出了 21 个与无精症/隐精症密切相关的反复突变基因和 34 个与无精症/隐精症中度相关的基因，这些基因以前与男性不育症无关（新颖）。最常受影响的优先基因，在所有队列中的 10 名男性中被发现发生突变，我们的功能研究支持其在生殖干细胞维持中的作用。总的来说，我们的研究代表了在特发性严重生精衰竭中缺失遗传病因学定义方面迈出的重要一步，并显着缩小了无精子症/隐精子症的 X 连锁遗传原因的知识差距，有助于未来诊断基因组的开发。