Andrology Department, Fundació Puigvert, Universitat Autònoma de Barcelona, Instituto de Investigaciones Biomédicas Sant Pau, Barcelona, 08025 Catalonia, Spain.
Institute of Human Genetics, University of Münster, Vesaliusweg 12-14, 48149 Münster, Germany.
Am J Hum Genet. 2022 Aug 4;109(8):1458-1471. doi: 10.1016/j.ajhg.2022.06.007. Epub 2022 Jul 8.
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, RBBP7, was found mutated in ten men across all cohorts, and our functional studies in Drosophila 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.
尽管 X 染色体的进化历史表明其在男性健康方面具有特异性，但它在精子发生中的作用在很大程度上仍未得到探索。目前仅认为三个 X 染色体基因具有中等明确的诊断价值。我们旨在对来自四个独立队列的 2354 名无精子症/严重少精子症男性的所有 X 染色体连锁蛋白编码基因进行全面分析。分析了基因组数据，并将其与正常精子症对照个体和 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 个与无精子症/严重少精子症强烈相关的反复突变基因和 34 个与无精子症/严重少精子症中度相关但以前与男性不育无关的基因（新发现）。最常受影响的优先基因 RBBP7 在所有队列中的 10 名男性中均发生突变，我们在果蝇中的功能研究支持其在生殖干细胞维持中的作用。总之，我们的研究代表了朝着确定特发性严重精子发生失败中缺失的遗传病因迈出的重要一步，并大大缩小了 X 连锁遗传原因导致无精子症/严重少精子症的知识差距，为未来的诊断基因图谱的发展做出贡献。
