Infertility, a global problem affecting up to 15% of couples, can have varied causes ranging from natural aging to the pathological development or function of the reproductive organs. One form of female infertility is premature ovarian insufficiency (POI), affecting up to 1 in 100 women and characterised by amenorrhea and elevated follicle stimulating hormone before the age of 40. POI can have a genetic basis, with over 50 causative genes identified. Non-obstructive azoospermia (NOA), a form of male infertility characterised by the absence of sperm in semen, has an incidence of 1% and is similarly heterogeneous. The genetic basis of male and female infertility is poorly understood with the majority of cases having no known cause. Here, we study a case of familial infertility including a proband with POI and her brother with NOA. We performed whole-exome sequencing (WES) and identified a homozygous STAG3 missense variant that segregated with infertility. STAG3 encodes a component of the meiosis cohesin complex required for sister chromatid separation. We report the first pathogenic homozygous missense variant in STAG3 and the first STAG3 variant associated with both male and female infertility. We also demonstrate limitations of WES for the analysis of homologous DNA sequences, with this variant being ambiguous or missed by independent WES protocols and its homozygosity only being established via long-range nested PCR.

中文翻译：

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STAG3 纯合错义变异导致原发性卵巢功能不全和男性非梗阻性无精子症。

不孕症是一个影响多达 15% 夫妇的全球性问题，其原因多种多样，从自然衰老到生殖器官的病理发育或功能。女性不孕症的一种形式是卵巢早衰 (POI)，每 100 名女性中就有 1 人受到影响，其特征是在 40 岁之前闭经和促卵泡激素升高。 POI 可能具有遗传基础，已识别出 50 多个致病基因。非梗阻性无精子症 (NOA) 是一种男性不育症，其特征是精液中没有精子，其发病率为 1%，并且具有类似的异质性。男性和女性不育的遗传基础知之甚少，大多数病例没有已知原因。在这里，我们研究了一个家族性不孕症病例，包括一名患有 POI 的先证者和她患有 NOA 的兄弟。与不育症分离的STAG3错义变体。STAG3编码姐妹染色单体分离所需的减数分裂cohesin复合物的一个组分。我们报告了STAG3 中的第一个致病纯合错义变异和第一个与男性和女性不育相关的STAG3变异。我们还证明了 WES 在分析同源 DNA 序列方面的局限性，这种变体不明确或被独立的 WES 协议遗漏，其纯合性只能通过远程嵌套 PCR 建立。