Nonobstructive azoospermia (NOA) and diminished ovarian reserve (DOR) are two disorders that can lead to infertility in males and females. Genetic factors have been identified to contribute to NOA and DOR. However, the same genetic factor that can cause both NOA and DOR remains largely unknown. To explore the candidate pathogenic gene that causes both NOA and DOR, we conducted whole-exome sequencing (WES) in a non-consanguineous family with two daughters with DOR and a son with NOA. We detected one pathogenic frameshift variant (NM_007068:c.28delG, p. Glu10Asnfs*31) following a recessive inheritance mode in a meiosis gene DMC1 (DNA meiotic recombinase 1). Clinical analysis showed reduced antral follicle number in both daughters with DOR, but metaphase II oocytes could be retrieved from one of them. For the son with NOA, no spermatozoa were found after microsurgical testicular sperm extraction. A further homozygous Dmc1 knockout mice study demonstrated total failure of follicle development and spermatogenesis. These results revealed a discrepancy of DMC1 action between mice and humans. In humans, DMC1 is required for spermatogenesis but is dispensable for oogenesis, although the loss of function of this gene may lead to DOR. To our knowledge, this is the first report on the homozygous frameshift mutation as causative for both NOA and DOR and demonstrating that DMC1 is dispensable in human oogenesis.

中文翻译：

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致病性 DMC1 移码突变导致人类非阻塞性无精子症，但不会导致原发性卵巢功能不全

非阻塞性无精子症 (NOA) 和卵巢储备减少 (DOR) 是两种可导致男性和女性不育的疾病。已确定遗传因素有助于 NOA 和 DOR。然而，可导致 NOA 和 DOR 的相同遗传因素在很大程度上仍然未知。为了探索导致 NOA 和 DOR 的候选致病基因，我们在一个有两个女儿患有 DOR 和一个儿子患有 NOA 的非近亲家庭中进行了全外显子组测序 (WES)。我们在减数分裂基因 DMC1（DNA 减数分裂重组酶 1）中以隐性遗传模式检测到一种致病性移码变异（NM_007068:c.28delG，p. Glu10Asnfs*31）。临床分析显示，两个 DOR 女儿的窦卵泡数量减少，但可以从其中一个中取出中期 II 卵母细胞。对于有 NOA 的儿子，显微手术睾丸取精后未发现精子。进一步的纯合 Dmc1 敲除小鼠研究表明卵泡发育和精子发生完全失败。这些结果揭示了小鼠和人类之间 DMC1 作用的差异。在人类中，DMC1 是精子发生所必需的，但对于卵子发生是可有可无的，尽管该基因的功能丧失可能导致 DOR。据我们所知，这是第一份关于纯合移码突变作为 NOA 和 DOR 致病原因的报告，并证明 DMC1 在人类卵子发生中是可有可无的。DMC1 是精子发生所必需的，但对于卵子发生是可有可无的，尽管该基因的功能丧失可能导致 DOR。据我们所知，这是第一份关于纯合移码突变作为 NOA 和 DOR 致病原因的报告，并证明 DMC1 在人类卵子发生中是可有可无的。DMC1 是精子发生所必需的，但对于卵子发生是可有可无的，尽管该基因的功能丧失可能导致 DOR。据我们所知，这是第一份关于纯合移码突变作为 NOA 和 DOR 致病原因的报告，并证明 DMC1 在人类卵子发生中是可有可无的。