Department of Andrology, Center for Men's Health, Department of ART, Institute of Urology, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
J Med Genet. 2021 Oct;58(10):679-686. doi: 10.1136/jmedgenet-2020-107042. Epub 2020 Sep 8.
The genetic causes of human idiopathic non-obstructive azoospermia (NOA) with meiotic arrest remain unclear.
Two Chinese families with infertility participated in the study. In family 1, two brothers were affected by idiopathic NOA. In family 2, the proband was diagnosed with idiopathic NOA, and his elder sister suffered from infertility. Whole-exome sequencing (WES) was conducted in the two patients in family 1, the proband in family 2 and 362 additional sporadic patients with idiopathic NOA. Sanger sequencing was used to verify the WES results. Periodic acid-Schiff (PAS), immunohistochemistry (IHC) and meiotic chromosomal spread analyses were carried out to evaluate the stage of spermatogenesis arrested in the affected cases.
We identified compound heterozygous loss of function (LoF) variants of (c.C1582T:p.R528X and c.231_232del:p.L78Sfs9, respectively) in both affected cases with NOA from family 1. In family 2, homozygous LoF variant in (c.1194delA:p.L400Cfs7) was identified in the siblings with infertility. PAS, IHC and meiotic chromosomal spread analyses demonstrated that the spermatogenesis was arrested at zygotene stage in the three patients with NOA. Consistent with the autosomal recessive mode of inheritance, all of these variants were inherited from heterozygous parental carriers. Intriguingly, WES of 362 sporadic NOA cases revealed one additional NOA case with a bi-allelic LoF variant (c.1464delT:p.D489Tfs*13).
To the best of our knowledge, this is the first report identifying as the causative gene for human NOA. Furthermore, our study showed an autosomal recessive mode of inheritance in the NOA caused by deficiency.
人类非梗阻性无精子症（NOA）伴减数分裂阻滞的遗传病因仍不清楚。
两个有生育问题的中国家庭参与了这项研究。在家庭 1 中，两名兄弟患有特发性 NOA。在家庭 2 中，先证者被诊断为特发性 NOA，他的姐姐患有不孕。对家庭 1 中的两名患者、家庭 2 中的先证者和 362 名额外的特发性 NOA 散发病例进行了全外显子组测序（WES）。Sanger 测序用于验证 WES 结果。进行过碘酸希夫（PAS）、免疫组织化学（IHC）和减数分裂染色体铺展分析，以评估受影响病例中阻滞的生精阶段。
我们在来自家庭 1 的两名患有 NOA 的患者中发现了 （c.C1582T：p.R528X 和 c.231_232del：p.L78Sfs9，分别）复合杂合失活（LoF）变异。在家庭 2 中，患有不育的兄弟姐妹中发现了 （c.1194delA：p.L400Cfs7）纯合 LoF 变异。PAS、IHC 和减数分裂染色体铺展分析表明，这 3 名 NOA 患者的生精过程在合线期停滞。与常染色体隐性遗传模式一致，所有这些 变异均由杂合父母携带者遗传。有趣的是，对 362 名散发性 NOA 病例的 WES 分析显示，另有 1 例 NOA 病例存在 双等位基因 LoF 变异（c.1464delT：p.D489Tfs*13）。
据我们所知，这是首次报道将 鉴定为人类 NOA 的致病基因。此外，我们的研究显示， 缺乏导致的 NOA 呈常染色体隐性遗传模式。
