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Original research
Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA
  1. Shixiong Tian1,2,
  2. Chaofeng Tu3,4,
  3. Xiaojin He5,6,7,
  4. Lanlan Meng3,4,
  5. Jiaxiong Wang8,
  6. Shuyan Tang1,
  7. Yang Gao5,6,
  8. Chunyu Liu1,
  9. Huan Wu5,6,7,
  10. Yiling Zhou1,
  11. Mingrong Lv5,6,7,
  12. Ge Lin3,4,
  13. Li Jin1,
  14. Yunxia Cao5,6,7,
  15. Dongdong Tang5,6,7,
  16. Feng Zhang1,2,
  17. Yue-Qiu Tan3,4
  1. 1 Institute of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, Human Phenome Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
  2. 2 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Institute of Reproduction and Development, Fudan University, Shanghai, China
  3. 3 Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, China
  4. 4 Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China
  5. 5 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
  6. 6 NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, China
  7. 7 Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People’s Republic of China, Hefei, China
  8. 8 Center for Reproduction and Genetics, State Key Laboratory of Reproductive Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China
  1. Correspondence to Professor Feng Zhang, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China; zhangfeng{at}; Dr Dongdong Tang, The First Affiliated Hospital of Anhui Medical University, Hefei, China; 15856389914{at}; Prof Yue-Qiu Tan, Central South University, Changsha, China; tanyueqiu{at}


Background Spermatogenic impairments can lead to male infertility by different pathological conditions, such as multiple morphological abnormalities of the sperm flagella (MMAF) and non-obstructive azoospermia (NOA). Genetic factors are involved in impaired spermatogenesis.

Methods and results Here, we performed genetic analyses through whole-exome sequencing in a cohort of 334 Han Chinese probands with severe MMAF or NOA. Biallelic variants of CFAP54 were identified in three unrelated men, including one homozygous frameshift variant (c.3317del, p.Phe1106Serfs*19) and two compound heterozygous variants (c.878G>A, p.Arg293His; c.955C>T, p.Arg319Cys and c.4885C>T, p.Arg1629Cys; c.937G>A, p.Gly313Arg). All of the identified variants were absent or extremely rare in the public human genome databases and predicted to be damaging by bioinformatic tools. The men harbouring CFAP54 mutations exhibited abnormal sperm morphology, reduced sperm concentration and motility in ejaculated semen. Significant axoneme disorganisation and other ultrastructure abnormities were also detected inside the sperm cells from men harbouring CFAP54 mutations. Furthermore, immunofluorescence assays showed remarkably reduced staining of four flagellar assembly-associated proteins (IFT20, IFT52, IFT122 and SPEF2) in the spermatozoa of CFAP54-deficient men. Notably, favourable clinical pregnancy outcomes were achieved with sperm from men carrying CFAP54 mutations after intracytoplasmic sperm injection treatment.

Conclusion Our genetic analyses and experimental observations revealed that biallelic deleterious mutations of CFAP54 can induce severe MMAF and NOA in humans.

  • Genetics, Medical

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. Not applicable.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. Not applicable.

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  • Contributors FZ, YT and S Tian conceived and designed the investigation. S Tang and LM performed bioinformatic analyses. S Tian and YC performed genetic analysis and wrote the manuscript. S Tian and YZ performed immunofluorescence staining analyses. S Tian, DT and JW contributed to sample collection, processing and conducted clinical evaluations. CT, YG, HW, CL and XH analysed the data. S Tian, ML and LJ contributed to the discussion of the data. FZ and GL supervised the study. FZ is responsible for the overall content as guarantor. All authors have read and agreed to the published version of the manuscript.

  • Funding This investigation was supported by the National Key Research and Development Program of China (2018YFC1004901 and 2021YFC2700901), the National Natural Science Foundation of China (32288101, 32100480, 81971447, 82171608, 82101961, 81971441 and 82171607), the Scientific Research (TP202002) from Anhui Medical University, the China Postdoctoral Science Foundation (2020TQ0072) and the Key Grant of Prevention and Treatment of Birth Defect from Hunan Province (2019SK1012).

  • Competing interests None declared.

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

  • 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.