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Bi-allelic KCTD19 variants associated with meiotic arrest and non-obstructive azoospermia in humans

Journal of Human Genetics volume 70, pages 427–437 (2025)Cite this article

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Abstract

Non-obstructive azoospermia (NOA) represents the severe form of male infertility, affecting approximately 1% of men during their reproductive years. It is marked by the absence of sperm production caused by testicular dysfunction and has many genetic origins. However, the genetic factors underlying most NOA cases are still unclear. Meiosis, a crucial process ensuring accurate chromosome segregation and generating genetic diversity in gametes, is susceptible to genetic disruptions that may result in NOA. In this study, whole exome sequencing (WES) was conducted on 969 NOA patients, identifying six compound heterozygous KCTD19 variants in three Chinese pedigrees. KCTD19 has been demonstrated to interact with ZFP541 and HDAC1, thereby participating in the modulation of chromatin remodeling and transcriptional programs during meiosis in mice. Herein, our findings expand the phenotypic and mutational spectrum of KCTD19 in male infertility and provide further insights into its role during meiosis. This research underscores the importance of KCTD19 in meiotic progression and male fertility, highlighting the need for further investigation into the molecular mechanisms underlying gametogenic failure in NOA.

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Acknowledgements

The authors express their gratitude to the participating patient’s family for their invaluable contribution to this study.

Funding

This study was supported by National Key Research and Development Program of China (2022YFC2702701), National Natural Science Foundation of China (82401869, 82371616), Inner Mongolia Academy of Medical Sciences Public Hospital Joint Science and Technology Project (2023GLLH0045), Specific Project of Shanghai Jiao Tong University for “Invigorating Inner Mongolia through Science and Technology”(2022XYJG001-01-19), and Scientific Research Startup Funding for High-Level Talents of Taizhou School of Clinical Medicine (TZKY2023RC01).

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Author notes

  1. These authors contributed equally: Shuai Xu, Chenwang Zhang, Chencheng Yao.

Authors and Affiliations

  1. 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

    Shuai Xu, Chencheng Yao, Zizhou Meng, Yifan Sun, Cunzhong Deng, Furong Bai, Jianxiong Zhang, Peng Li, Yuhua Huang, Zheng Li, Na Li & Yuxiang Zhang

  2. State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, China

    Chenwang Zhang, Wanze Ni, Dewei Qian & Zheng Li

  3. School of Life Science and Technology, ShanghaiTech University, Shanghai, China

    Zhi Zhou

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  1. Shuai Xu
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Contributions

All the authors participated in the development and design of the study. YXZ, NL, and ZL designed the research; SX and CWZ performed the research; Clinical data were collected by CWZ, WZN, DWQ, and ZZM. PL, YHH, JXZ, CZD and FRB collected and prepared clinical samples. SX, CCY and YFS performed the bioinformatics analysis; JXZ, ZZ, NL and YXZ analyzed the data; SX, CWZ, CCY and YXZ wrote and revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Zheng Li, Na Li or Yuxiang Zhang.

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The authors declare no competing interests.

Ethical approval

All participants gave written informed consent to take part in the study. The research was approved by the Institutional Ethical Review Committee of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine (license number 2022SQ294). Consent was obtained from the donors for the use of clinical data and testicular tissue in research.

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Xu, S., Zhang, C., Yao, C. et al. Bi-allelic KCTD19 variants associated with meiotic arrest and non-obstructive azoospermia in humans. J Hum Genet 70, 427–437 (2025). https://doi.org/10.1038/s10038-025-01350-0

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