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Peer-reviewedCC BY-NC-NDBMC medical genomics

Identification and splicing assessment of a novel homozygous CFAP65 splice-site variant associated with oligozoospermia and complete asthenozoospermia.

  • Congcong Teng1,2
  • Xinhua Tang1,3,4
  • Lin Li2,5
  • Yaxian Ma5
  • Yuancun Zhao3,4
  • Qing Chen3,4
  • Hong Shi6
  • Jie Zhang7,8,9,10
10 affiliations
  1. 1Medical School, the First People's Hospital of Yunnan Province, Kunming University of Science and Technology, Kunming, 650500, China.
  2. 2State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, China.
  3. 3Department of Medical Genetics, the First People's Hospital of Yunnan Province, Kunming, 650032, China.
  4. 4Yunnan Provincial Key Laboratory for Birth Defects and Genetic Diseases, National Health Commission Key Laboratory of Preconception Health Birth in Western China, the First People's Hospital of Yunnan Province, Kunming, 650032, China.
  5. 5Department of Reproductive Medicine, NHC Key Laboratory of Healthy Birth and Birth Defect Prevention in Western China, the First People's Hospital of Yunnan Province, Kunming, 650032, China.
  6. 6State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, 650500, China. [email protected].
  7. 7Medical School, the First People's Hospital of Yunnan Province, Kunming University of Science and Technology, Kunming, 650500, China. [email protected].
  8. 8Department of Medical Genetics, the First People's Hospital of Yunnan Province, Kunming, 650032, China. [email protected].
  9. 9Department of Hematology, the First People's Hospital of Yunnan Province, Kunming, 650032, China. [email protected].
  10. 10Yunnan Provincial Key Laboratory for Birth Defects and Genetic Diseases, National Health Commission Key Laboratory of Preconception Health Birth in Western China, the First People's Hospital of Yunnan Province, Kunming, 650032, China. [email protected].
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Abstract

Background

Pathogenic variants in CFAP65 have been reported in male infertility with sperm motility defects. This study investigated a novel homozygous CFAP65 splice-site variant identified in a consanguineous family in which the proband presented with oligozoospermia and complete asthenozoospermia.Methods

Whole-exome sequencing was performed to identify candidate variants, followed by population- and disease-database annotation. Kinship and runs of homozygosity analyses were used to assess familial relatedness and autozygosity. RNA Splicer prediction and a minigene assay in HEK-293T cells were performed to evaluate the splicing effect of the identified variant.Results

Semen analysis showed a sperm concentration of 8.1 × 10⁶/mL, with total and progressive motility of 0%. Whole-exome sequencing identified a novel homozygous canonical splice-site variant in CFAP65 (NM_194302.4:c.645 + 1G > A), which was classified as pathogenic according to ACMG guidelines. ROH analysis showed increased autosomal homozygosity in the proband (FROH = 7.88%), supporting parental consanguinity. The minigene assay demonstrated complete exon 6 skipping, resulting in a 103-bp transcript deletion and a predicted frameshifted truncated protein p.(Pro182ArgfsTer29).Conclusion

This study expands the CFAP65 mutational spectrum and supports exon 6 skipping-mediated loss of function as the likely pathogenic mechanism. These findings highlight the value of genetic screening and functional splicing assessment in male infertility with sperm motility defects.

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Cite

BibTeXRIS
BibTeX
@article{teng2026identification,
  title = {{Identification and splicing assessment of a novel homozygous CFAP65 splice-site variant associated with oligozoospermia and complete asthenozoospermia.}},
  author = {Congcong Teng and Xinhua Tang and Lin Li and Yaxian Ma and Yuancun Zhao and Qing Chen and Hong Shi and Jie Zhang},
  journal = {BMC medical genomics},
  year = {2026},
  month = sep,
  doi = {10.1186/s12920-026-02466-8},
  url = {https://europepmc.org/article/MED/42875786},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Identification and splicing assessment of a novel homozygous CFAP65 splice-site variant associated with oligozoospermia and complete asthenozoospermia.
AU  - Congcong Teng
AU  - Xinhua Tang
AU  - Lin Li
AU  - Yaxian Ma
AU  - Yuancun Zhao
AU  - Qing Chen
AU  - Hong Shi
AU  - Jie Zhang
PY  - 2026
DA  - 2026/09/08
JO  - BMC medical genomics
DO  - 10.1186/s12920-026-02466-8
UR  - https://europepmc.org/article/MED/42875786
AB  - Background  Pathogenic variants in CFAP65 have been reported in male infertility with sperm motility defects. This study investigated a novel homozygous CFAP65 splice-site variant identified in a consanguineous family in which the proband presented with oligozoospermia and complete asthenozoospermia.Methods  Whole-exome sequencing was performed to identify candidate variants, followed by population- and disease-database annotation. Kinship and runs of homozygosity analyses were used to assess familial relatedness and autozygosity. RNA Splicer prediction and a minigene assay in HEK-293T cells were performed to evaluate the splicing effect of the identified variant.Results  Semen analysis showed a sperm concentration of 8.1 × 10⁶/mL, with total and progressive motility of 0%. Whole-exome sequencing identified a novel homozygous canonical splice-site variant in CFAP65 (NM_194302.4:c.645 + 1G > A), which was classified as pathogenic according to ACMG guidelines. ROH analysis showed increased autosomal homozygosity in the proband (FROH = 7.88%), supporting parental consanguinity. The minigene assay demonstrated complete exon 6 skipping, resulting in a 103-bp transcript deletion and a predicted frameshifted truncated protein p.(Pro182ArgfsTer29).Conclusion  This study expands the CFAP65 mutational spectrum and supports exon 6 skipping-mediated loss of function as the likely pathogenic mechanism. These findings highlight the value of genetic screening and functional splicing assessment in male infertility with sperm motility defects.
SN  - 1755-8794
ER  -