Infertility affects one in six couples, half of which are caused by a male factor. Male infertility can be caused by both, qualitative and quantitative defects, leading to Oligo- astheno-terato-zoospermia (OAT; impairment in ejaculate sperm cell concentration, motility and morphology). Azoospermia defined as complete absence of sperm cells in the ejaculation. While hundreds of genes are involved in spermatogenesis the genetic etiology of men’s infertility remains incomplete.We identified a hemizygous stop gain pathogenic variation (PV) in the X-linked Germ Cell Nuclear Acidic Peptidase (GCNA), in an Azoospermic patient by exome sequencing. Assessment of the prevalence of pathogenic variations in this gene in infertile males by exome sequence data of 11 additional unrelated patients identified a probable hemizygous causative missense PV in GCNA in a severe OAT patient. Expression of GCNA in the patients’ testes biopsies and the stage of spermatogonial developmental arrest were determined by immunofluorescence and immunohistochemistry. The Azoospermic patient presented spermatogenic maturation arrest with an almost complete absence of early and late primary spermatocytes and thus the complete absence of sperm. GCNA is critical for genome integrity and its loss results in genomic instability and infertility in Drosophila, C. elegans, zebrafish, and mouse. PVs in GCNA appear to be incompatible with male fertility in humans as well: A stop-gain PV caused Azoospermia and a missense PV caused severe OAT with very low fertilization rates and no pregnancy in numerous IVF treatments.

不孕症影响六对夫妇中的一对，其中一半是由男性因素引起的。男性不育可能由定性和定量缺陷引起，导致少弱畸胎症（OAT；射精精子细胞浓度、活力和形态受损）。无精子症定义为射精时完全没有精子细胞。虽然数百个基因参与精子发生，但男性不育的遗传病因学仍然不完整。我们在 X 连锁生殖细胞核酸性肽酶 ( GCNA ) 中发现了半合子停止增益致病变异 (PV)), 在无精子症患者中通过外显子组测序。通过 11 名其他无关患者的外显子组序列数据评估该基因在不育男性中的致病性变异的普遍性，确定了严重 OAT 患者GCNA中可能的半合子致病性错义 PV。GCNA在患者睾丸活检中的表达和精原细胞发育停滞的阶段通过免疫荧光和免疫组织化学确定。无精子症患者表现出生精成熟停滞，早期和晚期初级精母细胞几乎完全缺失，因此完全没有精子。GCNA对基因组完整性至关重要，它的丢失会导致果蝇、秀丽隐杆线虫、斑马鱼和小鼠的基因组不稳定和不育。GCNA中的PV似乎也与人类的男性生育能力不相容：停止增益 PV 导致无精子症，错义 PV 导致严重的 OAT，受精率非常低，并且在许多 IVF 治疗中没有怀孕。