Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Department of Reproductive Medical Center, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, China.
J Assist Reprod Genet. 2023 Oct;40(10):2493-2498. doi: 10.1007/s10815-023-02907-8. Epub 2023 Aug 14.
Non-obstructive azoospermia (NOA) is an essential cause of male infertility for which treatment options are limited. The pathogenic mechanism of NOA, especially idiopathic NOA, remains unclear. Gene variations are associated with the occurrence of NOA. Our study was performed to investigate the genetic causes of NOA.
Whole exome sequencing (WES) was performed in two probands diagnosed with NOA from a Chinese family. Sanger sequencing was applied to verify the pathogenic variants. A minigene assay was carried out to identify the effect of the splicing variants.
We detected a novel homozygous variant (c.2681-3 T > A) in the HFM1 gene in the two siblings diagnosed with NOA, and their parents carried heterozygous mutations in the same gene. The results of the minigene assay revealed this splicing variant results in exon25 of HFM1 being skipped, leading to a protein truncation (p.Trp894Cysfs*44).
Our results showed that a deleterious splicing variant in HFM1 was related to NOA in these two patients. This novel variant of HFM1 may serve as a potential genetic biomarker for NOA patients.
非阻塞性无精子症（NOA）是男性不育的重要原因，其治疗选择有限。NOA 的发病机制，特别是特发性 NOA 的发病机制尚不清楚。基因变异与 NOA 的发生有关。我们的研究旨在探讨 NOA 的遗传原因。
对来自一个中国家庭的 2 名被诊断为 NOA 的先证者进行了全外显子组测序（WES）。应用 Sanger 测序验证致病性变异。进行了小基因试验以鉴定剪接变异的影响。
我们在 2 名被诊断为 NOA 的兄弟姐妹中检测到 HFM1 基因中的一个新的纯合变异（c.2681-3T > A），其父母在同一基因中携带杂合突变。小基因试验的结果表明，这种剪接变异导致 HFM1 的外显子 25 缺失，导致蛋白截断（p.Trp894Cysfs*44）。
我们的结果表明，HFM1 中的有害剪接变异与这 2 名患者的 NOA 有关。HFM1 的这种新型变异可能成为 NOA 患者的潜在遗传生物标志物。
