Ovarian deficiency, including diminished ovarian reserve and premature ovarian insufficiency, represents one of the main causes of female infertility. Little is known of the genetic basis of diminished ovarian reserve, while premature ovarian insufficiency often has a genetic basis, with genes affecting various processes. NR5A1 is a key gene required for gonadal function, and variants are associated with a wide phenotypic spectrum of disorders of sexual development, and are found in 0.26-8% of patients with premature ovarian insufficiency. As there is some debate about the extent of involvement of NR5A1 in the pathogenesis of ovarian deficiency, we performed an in-depth analysis of NR5A1 variants detected in a cohort of 142 patients with premature ovarian insufficiency, diminished ovarian reserve, or unexplained infertility associated with normal ovarian function. We identified rare non-synonymous protein-altering variants in 2.8 % of women with ovarian deficiency and no such variants in our small cohort of women with infertility but normal ovarian function. We observed previously reported variants associated with premature ovarian insufficiency in patients with diminished ovarian reserve, highlighting a genetic relationship between these conditions. We confirmed functional impairment resulting from a p.Val15Met variant, detected for the first time in a patient with premature ovarian insufficiency. The remaining variants were associated with preserved transcriptional activity and localization of NR5A1, indicating that rare NR5A1 variants may be incorrectly curated if functional studies are not undertaken, and/or that NR5A1 variants may have only a subtle impact on protein function and/or confer risk of ovarian deficiency via oligogenic inheritance.

中文翻译：

---

142例卵巢早衰、卵巢储备功能减退或不明原因不孕患者的NR5A1分析

卵巢缺陷，包括卵巢储备减少和卵巢功能不全，是女性不孕的主要原因之一。对卵巢储备减少的遗传基础知之甚少，而卵巢早衰通常具有遗传基础，基因影响各种过程。NR5A1 是性腺功能所需的关键基因，其变异与广泛的性发育障碍表型相关，在 0.26-8% 的卵巢早衰患者中发现。由于关于 NR5A1 在卵巢缺陷发病机制中的参与程度存在一些争论，我们对 142 名卵巢早衰、卵巢储备减少、或与正常卵巢功能相关的原因不明的不孕症。我们在 2.8% 的卵巢缺陷女性中发现了罕见的非同义蛋白质改变变异，而在我们的不育但卵巢功能正常的小规模女性队列中没有发现此类变异。我们观察到先前报道的与卵巢储备减少的患者卵巢功能不全相关的变异，突出了这些疾病之间的遗传关系。我们确认了 p.Val15Met 变异导致的功能障碍，这是首次在一名卵巢功能不全患者中检测到。其余的变异与保留的转录活性和 NR5A1 的定位相关，表明如果不进行功能研究，罕见的 NR5A1 变异可能会被错误地处理，