ORIGINAL RESEARCH article
Front. Endocrinol.
Sec. Reproduction
This article is part of the Research TopicMolecular and cellular challenges and threats to human fertilityView all articles
Novel Loss-of-Function SPAG17 homozygous Variant segregated in a family with Severe Asthenozoospermia: Upgrading Gene-Disease Validity to Strong
Provisionally accepted
Wang Li1
Jinli Li2
Ling Huang1Jialing Wang1Li Zhou1Li Ding1Jia Li1
Qinghua Zhang1*
Junyu Zhang3,4*Guangmei Xie1*- 1Gansu Provincial Maternity and Child Care Hospital, Lanzhou, China
- 2Shanghai First Materity and Infant Hospital, Shanghai, China
- 3Obstetrics and Gynecology Hospital of Tongji University, Shanghai, China
- 4Shanghai First Maternity and Infant Hospital, Shanghai, China
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Background: Severe asthenozoospermia is a significant cause of male infertility, commonly associated with genetic defects affecting sperm motility. However, the specific genetic contributors remain underexplored. Objective: This study aimed to identify a genetic variant responsible for severe asthenozoospermia in two siblings and to evaluate the clinical validity of the gene-disease relationship between SPAG17 and this condition. Methods: Whole exome sequencing (WES) was performed on two siblings diagnosed with severe asthenozoospermia. Sperm motility and morphology were assessed through standard semen analysis and transmission electron microscopy (TEM). The gene-disease validity was evaluated using the ClinGen Gene–Disease Validity SOP, incorporating both genetic and experimental evidence. Results: A novel homozygous nonsense variant in SPAG17 (NM_206996.4: c.2188C>T; p.Q730*) was identified in both affected siblings. Semen analysis revealed significantly reduced sperm motility and abnormal sperm morphology, including malformed flagella. TEM showed severe axonemal defects, such as absent central-pair microtubules and disorganized axonemal structures. The gene-disease validity between SPAG17 and severe asthenozoospermia was upgraded to "Strong", with a cumulative score of 13.4 points based on genetic (9.4 points) and experimental (4 points) evidence. Conclusion: We identified a novel homozygous nonsense variant in SPAG17 in two siblings with severe asthenozoospermia, emphasizing its critical role in sperm motility and male fertility. The upgraded "Strong" gene-disease validity strengthens SPAG17's clinical utility for genetic diagnostics and counseling.
Keywords: gene-disease validity, male infertility, severe asthenozoospermia, SPAG17, sperm ultrastructural abnormalities
Received: 25 Nov 2025; Accepted: 03 Feb 2026.
Copyright: © 2026 Li, Li, Huang, Wang, Zhou, Ding, Li, Zhang, Zhang and Xie. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Qinghua Zhang
Junyu Zhang
Guangmei Xie
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