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Genetic analysis and intracytoplasmic sperm injection outcomes of Chinese patients with congenital bilateral absence of vas deferens

  • Genetics
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Abstract

Purpose

Congenital bilateral absence of the vas deferens (CBAVD) is a major cause of obstructive azoospermia and male factor infertility. CBAVD is mainly caused by mutations in the genes encoding CFTR (cystic fibrosis transmembrane conductance regulator) and ADGRG2 (adhesion G protein-coupled receptor G2). This study aimed to describe CFTR and ADGRG2 variations in 46 Chinese CBAVD patients and evaluated sperm retrieval and assisted reproductive technology outcomes.

Methods

The CFTR and ADGRG2 genes were sequenced and analyzed by whole-exome sequencing (WES), and variations were identified by Sanger sequencing. Bioinformatic analysis was performed. We retrospectively reviewed the outcomes of patients undergoing sperm retrieval surgery and intracytoplasmic sperm injection (ICSI).

Results

In total, 35 of 46 (76.09%) patients carried at least one variation in CFTR, but no copy number variants or ADGRG2 variations were found. In addition to the IVS9-5 T allele, there were 27 CFTR variations, of which 4 variations were novel and predicted to be damaging by bioinformatics. Spermatozoa were successfully retrachieved in 46 patients, and 39 of the patients had their own offspring through ICSI.

Conclusion

There are no obvious hotspot CFTR mutations in Chinese CBAVD patients besides the IVS9-5 T allele. Therefore, WES might be the best detection method, and genetic counseling should be different from that provided to Caucasian populations. After proper counseling, all patients can undergo sperm retrieval from their epididymis or testis, and most of them can have their own children through ICSI.

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References

  1. Jequier AM, Ansell ID, Bullimore NJ. Congenital absence of the vasa deferentia presenting with infertility. J Androl. 1985;6(1):15–9.

    CAS  PubMed  Google Scholar 

  2. Quinzii CC. Castellani, The cystic fibrosis transmembrane regulator gene and male infertility. J Endocrinol Invest. 2000;23(10):684–9.

    Article  CAS  PubMed  Google Scholar 

  3. Lotti FM. Maggi, Ultrasound of the male genital tract in relation to male reproductive health. Hum Reprod Update. 2015;21(1):56–83.

    Article  PubMed  Google Scholar 

  4. Dumur V, Gervais R, Rigot JM, Delomel-Vinner E, Decaestecker B, Lafitte JJ, et al. Congenital bilateral absence of the vas deferens (CBAVD) and cystic fibrosis transmembrane regulator (CFTR): correlation between genotype and phenotype. Hum Genet. 1996;97(1):7–10.

    Article  CAS  PubMed  Google Scholar 

  5. Oates RDJA. Amos, The genetic basis of congenital bilateral absence of the vas deferens and cystic fibrosis. J Androl. 1994;15(1):1–8.

    CAS  PubMed  Google Scholar 

  6. Patat O, Pagin A, Siegfried A, Mitchell V, Chassaing N, Faguer S, et al. Truncating mutations in the adhesion G protein-coupled receptor G2 gene ADGRG2 cause an X-linked congenital bilateral absence of vas deferens. Am J Hum Genet. 2016;99(2):437–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Krausz C, Cioppi F, Riera-Escamilla A. Testing for genetic contributions to infertility: potential clinical impact. Expert Rev Mol Diagn. 2018;18(4):331–46.

    Article  CAS  PubMed  Google Scholar 

  8. Chiang HS, Wang YY, Lin YH, Wu YN. The role of SLC9A3 in Taiwanese patients with congenital bilateral absence of vas deferens (CBAVD). J Formos Med Assoc. 2019;118(12):1576–83.

    Article  CAS  PubMed  Google Scholar 

  9. Wedenoja S, Khamaysi A, Shimshilashvili L, Anbtawe-Jomaa S, Elomaa O, Toppari J, et al. A missense mutation in SLC26A3 is associated with human male subfertility and impaired activation of CFTR. Sci Rep. 2017;7(1):14208.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Shen Y, Yue HX, Li FP, Hu FY, Li XL, Wan Q, et al. SCNN1B and CA12 play vital roles in occurrence of congenital bilateral absence of vas deferens (CBAVD). Asian J Androl. 2019;21(5):525–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yuan P, Liang ZK, Liang H, Zheng LY, Li D, Li J, et al. Expanding the phenotypic and genetic spectrum of Chinese patients with congenital absence of vas deferens bearing CFTR and ADGRG2 alleles. Andrology. 2019;7(3):329–40.

    Article  CAS  PubMed  Google Scholar 

  12. Hamann J, Aust G, Arac D, Engel FB, Formstone C, Fredriksson R, et al. International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors. Pharmacol Rev. 2015;67(2):338–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yu J, Chen Z, Ni Y, Li Z. CFTR mutations in men with congenital bilateral absence of the vas deferens (CBAVD): a systemic review and meta-analysis. Hum Reprod. 2012;27(1):25–35.

    Article  CAS  PubMed  Google Scholar 

  14. Claustres M. Molecular pathology of the CFTR locus in male infertility. Reprod Biomed Online. 2005;10(1):14–41.

    Article  CAS  PubMed  Google Scholar 

  15. Jezequel P, Dubourg C, Le Lannou D, Odent S, Le Gall JY, Blayau M, et al. Molecular screening of the CFTR gene in men with anomalies of the vas deferens: identification of three novel mutations. Mol Hum Reprod. 2000;6(12):1063–7.

    Article  CAS  PubMed  Google Scholar 

  16. Taulan M, Girardet A, Guittard C, Altieri JP, Templin C, Beroud C, et al. Large genomic rearrangements in the CFTR gene contribute to CBAVD. BMC Med Genet. 2007;8:22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Amato F, Seia M, Giordano S, Elce A, Zarrilli F, Castaldo G, et al. Gene mutation in microRNA target sites of CFTR gene: a novel pathogenetic mechanism in cystic fibrosis? PLoS One. 2013;8(3):e60448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Li H, Wen Q, Li H, Zhao L, Zhang X, Wang J, et al. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens. J Cyst Fibros. 2012;11(4):316–23.

    Article  CAS  PubMed  Google Scholar 

  19. Oud MS, Ramos L, O’Bryan MK, McLachlan RI, Okutman Ö, Viville S, et al. Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia. Hum Mutat. 2017;38(11):1592–605.

    Article  CAS  PubMed  Google Scholar 

  20. Nakakuki M, Fujiki K, Yamamoto A, Ko SB, Yi L, Ishiguro M, et al. Detection of a large heterozygous deletion and a splicing defect in the CFTR transcripts from nasal swab of a Japanese case of cystic fibrosis. J Hum Genet. 2012;57(7):427–33.

    Article  CAS  PubMed  Google Scholar 

  21. Ratbi I, Legendre M, Niel F, Martin J, Soufir JC, Izard V, et al. Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Hum Reprod. 2007;22(5):1285–91.

    Article  CAS  PubMed  Google Scholar 

  22. Trujillano D, Ramos MD, Gonzalez J, Tornador C, Sotillo F, Escaramis G, et al. Next generation diagnostics of cystic fibrosis and CFTR-related disorders by targeted multiplex high-coverage resequencing of CFTR. J Med Genet. 2013;50(7):455–62.

    Article  CAS  PubMed  Google Scholar 

  23. Bai S, Du Q, Liu X, Tong Y, Wu B. The detection and significance of cystic fibrosis transmembrane conductance regulator gene promoter mutations in Chinese patients with congenital bilateral absence of the vas deferens. Gene. 2018;672:64–71.

    Article  CAS  PubMed  Google Scholar 

  24. Wu CC, Hsieh-Li HM, Lin YM, Chiang HS. Cystic fibrosis transmembrane conductance regulator gene screening and clinical correlation in Taiwanese males with congenital bilateral absence of the vas deferens. Hum Reprod. 2004;19(2):250–3.

    Article  CAS  PubMed  Google Scholar 

  25. Lissens W, Mahmoud KZ, El-Gindi E, Abdel-Sattar A, Seneca S, Van Steirteghem A, et al. Molecular analysis of the cystic fibrosis gene reveals a high frequency of the intron 8 splice variant 5T in Egyptian males with congenital bilateral absence of the vas deferens. Mol Hum Reprod. 1999;5(1):10–3.

    Article  CAS  PubMed  Google Scholar 

  26. de Souza D, Faucz FR, Pereira-Ferrari L, Sotomaior VS, Raskin S. Congenital bilateral absence of the vas deferens as an atypical form of cystic fibrosis: reproductive implications and genetic counseling. Andrology. 2018;6(1):127–35.

    Article  PubMed  CAS  Google Scholar 

  27. Jungwirth A, Diemer T, Kopa Z, Krause C, Tournaye H, Kelly B et al. EAU Guidelines on Male Infertility 2019[M]. 2019

  28. Li HR. Durbin, Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):1754–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lai Z, Markovets A, Ahdesmaki M, Chapman B, Hofmann O, McEwen R, et al. VarDict: a novel and versatile variant caller for next-generation sequencing in cancer research. Nucleic Acids Res. 2016;44(11):e108.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38(16):e164.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Thorvaldsdottir H, Robinson JT, Mesirov JP. Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform. 2013;14(2):178–92.

    Article  CAS  PubMed  Google Scholar 

  33. WHO, WHO manual for the standardized investigation and diagnosis of the infertile couple. 2000: Cambridge University Press: Cambridge.

  34. Petrova NV, Kashirskaya NY, Vasilyeva TA, Kondratyeva EI, Zhekaite EK, Voronkova AY et al. Analysis of CFTR mutation spectrum in ethnic Russian cystic fibrosis patients. Genes (Basel). 2020;11(5):554.

  35. Gajbhiye R, Kadam K, Khole A, Gaikwad A, Kadam S, Shah R, et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene abnormalities in Indian males with congenital bilateral absence of vas deferens & renal anomalies. Indian J Med Res. 2016;143(5):616.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wu C, Alper ÖM, Lu J, Wang S, Guo L, Chiang H, et al. Mutation spectrum of the CFTR gene in Taiwanese patients with congenital bilateral absence of the vas deferens. Hum Reprod. 2005;20(9):2470–5.

    Article  CAS  PubMed  Google Scholar 

  37. Shaoge L, Jiarong F, Yanan Z, Xiaojian Y, Gongchao M, Tengfei H et al. Mutation analysis of the cystic fibrosis transmembrane conductance regulator gene in Chinese congenital absence of vas deferens patients. Gene. 2021;765:145045.

  38. Tian X, Liu Y, Yang J, Wang H, Liu T, Xu W, et al. p.G970D is the most frequent CFTR mutation in Chinese patients with cystic fibrosis. Hum Genome Var. 2016;3:15063.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Ni WH, Jiang L, Fei QJ, Jin JY, Yang X, Huang XF. The CFTR polymorphisms poly-T, TG-repeats and M470V in Chinese males with congenital bilateral absence of the vas deferens. Asian J Androl. 2012;14(5):687–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Du Q, Li Z, Pan Y, Liu X, Pan B, Wu B. The CFTR M470V, Intron 8 poly-T, and 8 TG-repeats detection in Chinese males with congenital bilateral absence of the vas deferens. Biomed Res Int. 2014;2014:1–7.

    Google Scholar 

  41. Chillon M, Casals T, Mercier B, Bassas L, Lissens W, Silber S, et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med. 1995;332(22):1475–80.

    Article  CAS  PubMed  Google Scholar 

  42. Mak V, Jarvi KA, Zielenski J, Durie P, Tsui LC. Higher proportion of intact exon 9 CFTR mRNA in nasal epithelium compared with vas deferens. Hum Mol Genet. 1997;6(12):2099–107.

    Article  CAS  PubMed  Google Scholar 

  43. Lu S, Yang X, Cui Y, Li X, Zhang H, Liu J, et al. Different cystic fibrosis transmembrane conductance regulator mutations in Chinese men with congenital bilateral absence of vas deferens and other acquired obstructive azoospermia. Urology. 2013;82(4):824–8.

    Article  PubMed  Google Scholar 

  44. Lee JH, Choi JH, Namkung W, Hanrahan JW, Chang J, Song SY, et al. A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases. Hum Mol Genet. 2003;12(18):2321–32.

    Article  CAS  PubMed  Google Scholar 

  45. Schrijver I, Pique L, Graham S, Pearl M, Cherry A, Kharrazi M. The spectrum of CFTR variants in nonwhite cystic fibrosis patients: implications for molecular diagnostic testing. J Mol Diagn. 2016;18(1):39–50.

    Article  CAS  PubMed  Google Scholar 

  46. Bodian DL, Klein E, Iyer RK, Wong WS, Kothiyal P, Stauffer D, et al. Utility of whole-genome sequencing for detection of newborn screening disorders in a population cohort of 1,696 neonates. Genet Med. 2016;18(3):221–30.

    Article  PubMed  Google Scholar 

  47. Ni B, Lin Y, Sun L, Zhu M, Li Z, Wang H, et al. Low-frequency germline variants across 6p22.2–6p21.33 are associated with non-obstructive azoospermia in Han Chinese men. Hum Mol Genet. 2015;24(19):5628–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Marson F, Bertuzzo CS, Ribeiro JD. Classification of CFTR mutation classes. Lancet Respir Med. 2016;4(8):e37–8.

    Article  PubMed  Google Scholar 

  49. Wang Y, Wrennall JA, Cai Z, Li H, Sheppard DN. Understanding how cystic fibrosis mutations disrupt CFTR function: from single molecules to animal models. Int J Biochem Cell Biol. 2014;52:47–57.

    Article  CAS  PubMed  Google Scholar 

  50. Uzun S, Gokce S, Wagner K. Cystic fibrosis transmembrane conductance regulator gene mutations in infertile males with congenital bilateral absence of the vas deferens. Tohoku J Exp Med. 2005;207(4):279–85.

    Article  CAS  PubMed  Google Scholar 

  51. Xu WM, Chen J, Chen H, Diao RY, Fok KL, Dong JD, et al. Defective CFTR-dependent CREB activation results in impaired spermatogenesis and azoospermia. PLoS One. 2011;6(5):e19120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Yan C, Lang Q, Huijuan L, Jiang X, Ming Y, Huaqin S, et al. CFTR deletion in mouse testis induces VDAC1 mediated inflammatory pathway critical for spermatogenesis. PLoS One. 2016;11(8):e0158994.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Llabador MA, Pagin A, Lefebvre-Maunoury C, Marcelli F, Leroy-Martin B, Rigot JM, et al. Congenital bilateral absence of the vas deferens: the impact of spermatogenesis quality on intracytoplasmic sperm injection outcomes in 108 men. Andrology. 2015;3(3):473–80.

    Article  CAS  PubMed  Google Scholar 

  54. McBride JA, Kohn TP, Mazur DJ, Lipshultz LI, Coward RM. Sperm retrieval and intracytoplasmic sperm injection outcomes in men with cystic fibrosis disease versus congenital bilateral absence of the vas deferens. Asian J Androl. 2021;23(2):140–5.

    Article  CAS  PubMed  Google Scholar 

  55. Kamal A, Fahmy I, Mansour R, Serour G, Aboulghar M, Ramos L, et al. Does the outcome of ICSI in cases of obstructive azoospermia depend on the origin of the retrieved spermatozoa or the cause of obstruction? A comparative analysis. Fertil Steril. 2010;94(6):2135–40.

    Article  PubMed  Google Scholar 

  56. Chiang HS, Wu CC, Wu YN, Lu JF, Lin GH, Hwang JL. CFTR mutation analysis of a Caucasian father with congenital bilateral absence of vas deferens, a Taiwanese mother, and twins resulting from ICSI procedure. J Formos Med Assoc. 2008;107(9):736–40.

    Article  CAS  PubMed  Google Scholar 

  57. Gaikwad A, Khan S, Kadam S, Kadam K, Dighe V, Shah R, et al. The CFTR gene mild variants poly-T, TG repeats and M470V detection in Indian men with congenital bilateral absence of vas deferens. Andrologia. 2018;50(2):e12858.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors are deeply grateful for the participation of all the patients in this study. We thank Li Zhang from CarrierGene Biotechnologies Co., Ltd., for analyzing data. We also thank Charlesworth Author Services (www.cwauthors.com.cn) for editing the English text of the draft of this manuscript.

Funding

Suzhou Medical and Industrial Integration Collaborative Innovation Research Project (No. SLJ201906); Suzhou Medical and Industrial Cooperation Project (a new urine collection device study for ileal cystostomy).

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Authors and Affiliations

  1. Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, 215000, Jiangsu, China

    Hongbo Cheng & Jun Ouyang

  2. Center for Reproduction and Genetics, NHC Key Laboratory of Male Reproduction and Genetics, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China

    Hongbo Cheng, Shenmin Yang, Qingxia Meng, Bo Zheng, Yidong Gu, Luyun Wang, Gaigai Wang, Mutian Han, Liyan Shen, Jie Ding & Hong Li

  3. Department of Andrology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China

    Tao Song & Chunlu Xu

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  1. Hongbo Cheng
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  2. Shenmin Yang
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  13. Hong Li
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Correspondence to Hong Li or Jun Ouyang.

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This research was approved by the Ethics Review Committee of the Nanjing Medical University Affiliated Suzhou Hospital.

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Cheng, H., Yang, S., Meng, Q. et al. Genetic analysis and intracytoplasmic sperm injection outcomes of Chinese patients with congenital bilateral absence of vas deferens. J Assist Reprod Genet 39, 719–728 (2022). https://doi.org/10.1007/s10815-022-02417-z

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