Yao Chencheng, Hou Dong, Ji Zhiyong, Pang Dongmei, Li Peng, Tian Ruhui, Zhang Yuxiang, Ou Ningjing, Bai Haowei, Zhi Erlei, Huang Yuhua, Qin Yingying, Zhao Jingpeng, Wang Chenchen, Zhou Zhi, Guo Ting, Li Zheng
Department of Andrology, Center for Men's Health, Department of ART, Institute of Urology, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
Clin Genet. 2022 May;101(5-6):507-516. doi: 10.1111/cge.14129. Epub 2022 Mar 16.
The genetic causes of idiopathic premature ovarian insufficiency (POI) and nonobstructive azoospermia (NOA) remain unclear. We performed whole-exome sequencing (WES) in members of a consanguineous family with two POI and two NOA patients to screen for potential pathogenic variants for familial POI and NOA. And a homozygous variant in SPATA22 (c.400C>T:p.R134X) was identified. Histological analysis and spermatocyte spreading assay demonstrated that the spermatogenesis was arrested at a zygotene-like stage in the proband with NOA. The candidate gene was further screened in the in-house WES database of idiopathic POI-affected patients. One additional compound heterozygous variant in SPATA22 (c.900+1G>A and c.31C>T:p.R11X) was found in one patient with sporadic POI and validated by minigene assay. Thus, this is the first report identifying SPATA22 as the causative gene for human POI. Combined with the observations in the familial patient with NOA, our findings highlighted the essential role of meiotic HR genes in gametogenesis and gonadal function maintenance.
特发性卵巢早衰（POI）和非梗阻性无精子症（NOA）的遗传原因尚不清楚。我们对一个近亲家庭中的成员进行了全外显子组测序（WES），该家庭中有两名POI患者和两名NOA患者，以筛选家族性POI和NOA的潜在致病变异。并鉴定出SPATA22基因中的一个纯合变异（c.400C>T:p.R134X）。组织学分析和精母细胞铺展试验表明，先证者（NOA患者）的精子发生停滞在偶线期样阶段。在特发性POI患者的内部WES数据库中进一步筛选该候选基因。在一名散发性POI患者中发现了SPATA22基因中的另一个复合杂合变异（c.900+1G>A和c.31C>T:p.R11X），并通过小基因检测进行了验证。因此，这是首次报道将SPATA22鉴定为人类POI的致病基因。结合家族性NOA患者的观察结果，我们的研究结果突出了减数分裂同源重组（HR）基因在配子发生和性腺功能维持中的重要作用。
