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Original research
Bi-allelic SHOC1 loss-of-function mutations cause meiotic arrest and non-obstructive azoospermia
  1. Chencheng Yao1,2,
  2. Chao Yang1,
  3. Liangyu Zhao1,2,
  4. Peng Li1,
  5. Ruhui Tian1,
  6. Huixing Chen1,
  7. Ying Guo3,
  8. Yuhua Huang1,
  9. Erlei Zhi1,
  10. Jing Zhai1,
  11. Hongfang Sun1,
  12. Jianxiong Zhang1,
  13. Yan Hong1,
  14. Li Zhang1,
  15. Zhiyong Ji1,
  16. Feng Zhang4,5,
  17. Zhi Zhou2,
  18. Zheng Li1
  1. 1Department 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
  2. 2School of Life Science and Technology, ShanghaiTech University, Shanghai, China
  3. 3The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  4. 4Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, China
  5. 5State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
  1. Correspondence to Professor Zheng Li, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; lizhengboshi{at}; Professor Zhi Zhou, School of Life Science and Technology, ShanghaiTech University, Shanghai, China; zhouzhi{at}; Professor Feng Zhang, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China; zhangfeng{at}


Background The genetic causes of human idiopathic non-obstructive azoospermia (NOA) with meiotic arrest remain unclear.

Methods 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.

Results We identified compound heterozygous loss of function (LoF) variants of SHOC1 (c.C1582T:p.R528X and c.231_232del:p.L78Sfs*9, respectively) in both affected cases with NOA from family 1. In family 2, homozygous LoF variant in SHOC1 (c.1194delA:p.L400Cfs*7) 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 SHOC1 variants were inherited from heterozygous parental carriers. Intriguingly, WES of 362 sporadic NOA cases revealed one additional NOA case with a bi-allelic SHOC1 LoF variant (c.1464delT:p.D489Tfs*13).

Conclusion To the best of our knowledge, this is the first report identifying SHOC1 as the causative gene for human NOA. Furthermore, our study showed an autosomal recessive mode of inheritance in the NOA caused by SHOC1 deficiency.

  • Loss of function mutation

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  • CY, CY and LZ contributed equally.

  • Contributors ZL, ZZ and FZ designed the research; CCY, CY and LYZ performed the research; PL, RHT, HXC, YG, YHH, ELZ and JZ performed the bioinformatics analysis; HFS, JXZ, YH and LZ analysed the data; CCY, CY, ZYJ and LYZ wrote and revised the paper.

  • Funding This work was supported by the National Key Research and Development Program of China (2017YFC1002003), National Natural Science Foundation of China (81871215) and Shanghai Sailing Program (20YF1439500 and 20YF1453700).

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Ethics approval This study was approved by the Institutional Ethical Review Committee of Shanghai General Hospital, Shanghai Jiao Tong University (Permit Number 2018KY052), and an informed consent of clinical data and testicular tissues for research was obtained from the donors.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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