Laboratory Medicine Online

Korean Society for Laboratory Medicine (대한진단검사의학회)
권호 표지
DOI QR코드

DOI QR Code

Genetic Screening for Chromosomal Abnormalities and Y Chromosome Microdeletions in 846 Infertile Korean Men

한국인 불임 남성 846명의 염색체 이상 및 Y 염색체 미세 결실에 대한 유전 스크리닝

  • 한성희 (바이오코아(주) 생명공학사업부) ;
  • 박정원 (원탑 비뇨기과) ;
  • 조현석 (바이오코아(주) 생명공학사업부) ;
  • 반가워 (바이오코아(주) 생명공학사업부) ;
  • 강점순 (바이오코아(주) 생명공학사업부) ;
  • 임환섭 ((재)서울의과학연구소) ;
  • 이경률 ((재)서울의과학연구소) ;
  • 황승용 (바이오코아(주) 생명공학사업부)
  • Received : 2018.01.05
  • Accepted : 2018.03.22
  • Published : 2018.10.01
⟨ Previous Next ⟩

Abstract

Background: Chromosomal abnormalities are confirmed as one of the frequent causes of male infertility. The microdeletion of the azoospermia factor (AZF) region in the Y chromosome was discovered as another frequent genetic cause associated with male infertility. The aim of this study was to evaluate the frequency and type of chromosomal abnormalities and Y chromosome microdeletions in Korean infertile men. Methods: A total of 846 infertile men with azoospermia and severe oligozoospermia were included for genetic screening. Cytogenetic analyses using G-banding and screening for Y chromosome microdeletions by multiplex PCR for AZF genes were performed. Results: Chromosomal abnormalities were detected in 112 infertile men (13.2%). Of these, Klinefelter's syndrome was the most common (55.4%, 62/112), followed by balanced translocation including translocation between sex chromosome and autosome (14.3%), Yq deletion (13.4%), X/XY mosaicism with Yq deletion (12.5%), and XX male (4.5%). The overall prevalence of Y chromosome microdeletions was 9.2% (78/846). Most microdeletions were in the AZFc region (51.3%) with a low incidence in AZFa (7.7%) and AZFb (6.4%). Combined deletions involving the AZFbc and AZFabc regions were detected in 26.9% and 7.7% of men, respectively. Among the infertile men with Y chromosome microdeletions, the incidence of chromosomal abnormality was 25.6% (20/78). Conclusions: There was a high incidence (20.1%) of chromosomal abnormalities and Y chromosome microdeletions in Korean infertile men. These findings strongly suggest that genetic screening for chromosomal abnormalities and Y chromosome microdeletions should be performed, and genetic counseling should be provided before starting assisted reproductive techniques.

배경: 염색체 이상은 남성 불임의 흔한 원인 중 하나이며, Y 염색체의 azoospermia factor (AZF) 부위의 미세 결실은 남성 불임과 연관된 또다른 유전적 원인으로 알려져 있다. 본 연구는 한국인 불임남성에서 염색체 이상 및 Y 염색체 미세 결실의 빈도와 유형을 알아보고자 하였다. 방법: 총 846명의 비 폐쇄성 무정자증 혹은 정자 부족증 국내 불임남성을 대상으로 염색체 이상 여부를 확인하기 위해 G-banding을 이용한 염색체 검사와 Y 염색체 미세 결실 검출을 위한 다중 PCR검사를 수행하였다. 결과: 염색체 이상은 112명(13.2%)의 불임 남성에서 발견되었는데, 클라인펠터 증후군(55.4%, 62/112)이 가장 흔하게 관찰되었고, 성염색체와 상염색체 간 전좌를 포함하는 균형 전좌(14.3%), Y 염색체 장완의 결실(13.4%), Y 염색체 장완의 결실을 동반하는 X/XY 모자이시즘(12.5%), XX남성(4.5%)의 순으로 관찰되었다. Y 염색체 미세 결실의 전체 유병률은 9.2% (78/846)였는데 대부분의 미세 결실은 AZFc 부위(51.3%)에서 관찰되었고 그 외 AZFa (7.7%)와 AZFb (6.4%) 부위에서 상대적으로 낮은 빈도로 관찰되었다. AZFbc와 AZFabc와 같은 중복 미세 결실은 각각 26.9%와 7.7%에서 관찰되었다. Y 염색체 미세 결실을 가진 불임 남성 중 25.6% (20/78)에서 염색체 이상을 같이 갖고 있었다. 결론: 한국인 불임남성에서 염색체 이상과 Y 염색체 미세결실은 20.1%로 높게 관찰되었으므로 염색체 이상과 Y 염색체 미세결실을 포함하는 유전 스크리닝은 반드시 수행되어야 하며, 보조 생식 시술 전에 스크리닝 결과에 대한 유전 상담이 제공되어야 한다.

Keywords

References

  1. De Kretser DM. Male infertility. Lancet 1997;349:787-90. https://doi.org/10.1016/S0140-6736(96)08341-9
  2. Dohle GR, Halley DJ, Van Hemel JO, van den Ouwel AM, Pieters MH, Weber RF, et al. Genetic risk factors in infertile men with severe oligozoospermia and azoospermia. Hum Reprod 2002;17:13-6. https://doi.org/10.1093/humrep/17.1.13
  3. Hamada A, Esteves SC, Agarwal A. The role of contemporary andrology in unraveling the mystery of unexplained male infertility. Open Reprod Sci J 2011;3:27-41. https://doi.org/10.2174/1874255601103010027
  4. Foresta C, Moro E, Ferlin A. Y chromosome microdeletions and alterations of spermatogenesis. Endocr Rev 2001;22:226-39.
  5. Vineeth VS and Malini SS. A journey on Y chromosomal genes and male infertility. Int J Hum Genet 2011;11:203-15. https://doi.org/10.1080/09723757.2011.11886144
  6. Behulova R, Strhakova L, Boronova I, Cibulkova A, Konecny M, Danisovic L, et al. DNA analysis of Y chromosomal AZF region in Slovak population with fertility disorders. Bratisl Lek Listy 2011;112:183-7.
  7. Akin H, Onay H, Turker E, Ozkinay F. Primary male infertility in Izmir/ Turkey: a cytogenetic and molecular study of 187 infertile Turkish patients. J Assist Reprod Genet 2011;28:419-23. https://doi.org/10.1007/s10815-011-9542-8
  8. Vijayalakshmi J, Venkatachalam P, Reddy S, Rani GU, Manjula G. Microdeletions of AZFc region in infertile men with azoospermia and oligoasthenoteratozoospermia. Int J Hum Genet 2013;13:183-7. https://doi.org/10.1080/09723757.2013.11886215
  9. Hopps CV, Mielnik A, Goldstein M, Palermo GD, Rosenwaks Z, Schlegel PN. Detection of sperm in men with Y chromosome microdeletions of the AZFa, AZFb and AZFc regions. Hum Reprod 2003;18:1660-5. https://doi.org/10.1093/humrep/deg348
  10. WHO. World Health Organization laboratory manual for the examination of human semen and sperm and sperm-cervical mucus interaction. UK: Cambridge University Press, 1999.
  11. McGowan-Jordan J, Simons A, et al. eds. ISCN 2016: An International System for Human Cytogenomic Nomenclature (2016). Basel: S. Kager AG, 2016.
  12. Krausz C, Hoefsloot L, Simoni M, Tuttelmann F; European Academy of Andrology; European Molecular Genetics Quality Network. EAA/EMQN best practice guidelines for molecular diagnosis of Y-chromosomal microdeletions: state-of-the-art 2013. Andrology 2014;2:5-19. https://doi.org/10.1111/j.2047-2927.2013.00173.x
  13. Ferlin A, Raicu F, Gatta V, Zuccarello D, Palka G, Foresta C. Male infertility: role of genetic background. Reprod Biomed Online 2007;14:734-45. https://doi.org/10.1016/S1472-6483(10)60677-3
  14. Hofherr SE, Wiktor AE, Kipp BR, Dawson DB, Van Dyke DL. Clinical diagnostic testing for the cytogenetic and molecular causes of male infertility: the Mayo Clinic experience. J Assist Reprod Genet 2011;28: 1091-8. https://doi.org/10.1007/s10815-011-9633-6
  15. Van Assche E, Bonduelle M, Tournaye H, Joris H, Verheyen G, Devroey P, et al. Cytogenetics of infertile men. Hum Reprod 1996;11 Suppl 4:1-26.
  16. Yang Y, Ma M, Xiao C, Li L, Li S, Zhang S. Massive deletion in AZFb/b+c and azoospermia with Sertoli cell only and/or maturation arrest. Int J Androl 2008;31:573-8. https://doi.org/10.1111/j.1365-2605.2007.00808.x
  17. Fu L, Xiong DK, Ding XP, Li C, Zhang LY, Ding M, et al. Genetic screening for chromosomal abnormalities and Y chromosome microdeletions in Chinese infertile men. J Assist Reprod Genet 2012;29:521-7. https://doi.org/10.1007/s10815-012-9741-y
  18. Martinez-Garza SG, Gallegos-Rivas MC, Vargas-Maciel M, Rubio-Rubio JM, de Los Monteros-Rodriguez ME, Gonzalez-Ortega C, et al. Genetic screening in infertile Mexican men: chromosomal abnormalities, Y chromosome deletions, and androgen receptor CAG repeat length. J Androl 2008;29:654-60. https://doi.org/10.2164/jandrol.107.004309
  19. Balkan M, Tekes S, Gedik A. Cytogenetic and Y chromosome microdeletion screening studies in infertile males with Oligozoospermia and Azoospermia in Southeast Turkey. J Assist Reprod Genet 2008; 25:559-65. https://doi.org/10.1007/s10815-008-9272-8
  20. Donker RB, Vloeberghs V, Groen H, Tournaye H, van Ravenswaaij-Arts CMA, Land JA. Chromosomal abnormalities in 1663 infertile men with azoospermia: the clinical consequences. Hum Reprod 2017;32:2574-80. https://doi.org/10.1093/humrep/dex307
  21. Brennan J and Capel B. One tissue, two fates: molecular genetic events that underlie testis versus ovary development. Nat Rev Genet 2004;5: 509-21.
  22. Margarit E, Soler A, Carrio A, Oliva R, Costa D, Vendrell T, et al. Molecular, cytogenetic, and clinical characterisation of six XX males including one prenatal diagnosis. J Med Genet 1998;35:727-30. https://doi.org/10.1136/jmg.35.9.727
  23. Carrell DT. Contributions of spermatozoa to embryogenesis: assays to evaluate their genetic and epigenetic fitness. Reprod Biomed Online 2008;16:474-84. https://doi.org/10.1016/S1472-6483(10)60454-3
  24. Elghezal H, Hidar S, Braham R, Denguezli W, Ajina M, Saad A. Chromosome abnormalities in one thousand infertile males with nonobstructive sperm disorders. Fertil Steril 2006;86:1792-5. https://doi.org/10.1016/j.fertnstert.2006.04.041
  25. Lian J, Zhang X, Tian H, Liang N, Wang Y, Liang C, et al. Altered microRNA expression in patients with non-obstructive azoospermia. Reprod Biol Endocrinol 2009;7:13. https://doi.org/10.1186/1477-7827-7-13
  26. Vogt PH, Edelmann A, Kirsch S, Henegariu O, Hirschmann P, Kiesewetter F, et al. Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet 1996;5:933-43. https://doi.org/10.1093/hmg/5.7.933
  27. Raicu F, Popa L, Apostol P, Cimponeriu D, Dan L, Ilinca E, et al. Screening for microdeletions in human Y chromosome--AZF candidate genes and male infertility. J Cell Mol Med 2003;7:43-8. https://doi.org/10.1111/j.1582-4934.2003.tb00201.x
  28. Kumtepe Y, Beyazyurek C, Cinar C, Ozbey I, Ozkan S, Cetinkaya K, et al. A genetic survey of 1935 Turkish men with severe male factor infertility. Reprod Biomed Online 2009;18:465-74. https://doi.org/10.1016/S1472-6483(10)60121-6
  29. Kim MJ, Choi HW, Park SY, Song IO, Seo JT, Lee HS. Molecular and cytogenetic studies of 101 infertile men with microdeletions of Y chromosome in 1,306 infertile Korean men. J Assist Reprod Genet 2012;29: 539-46. https://doi.org/10.1007/s10815-012-9748-4
  30. Wang RX, Fu C, Yang YP, Han RR, Dong Y, Dai RL, et al. Male infertility in China: laboratory finding for AZF microdeletions and chromosomal abnormalities in infertile men from Northeastern China. J Assist Reprod Genet 2010;27:391-6. https://doi.org/10.1007/s10815-010-9420-9
  31. Simoni M, Bakker E, Krausz C. EAA/EMQN best practice guidelines for molecular diagnosis of y-chromosomal microdeletions. State of the art 2004. Int J Androl 2004;27:240-9. https://doi.org/10.1111/j.1365-2605.2004.00495.x
  32. Yu XW, Wei ZT, Jiang YT, Zhang SL. Y chromosome azoospermia factor region microdeletions and transmission characteristics in azoospermic and severe oligozoospermic patients. Int J Clin Exp Med 2015;8: 14634-46.
  33. Ng PP, Tang MH, Lau ET, Ng LK, Ng EH, Tam PC, et al. Chromosomal anomalies and Y-microdeletions among Chinese subfertile men in Hong Kong. Hong Kong Med J 2009;15:31-8.
  34. Patrat C, Bienvenu T, Janny L, Faure AK, Fauque P, Aknin-Seifer I, et al. Clinical data and parenthood of 63 infertile and Y-microdeleted men. Fertil Steril 2010;93:822-32. https://doi.org/10.1016/j.fertnstert.2008.10.033
  35. Patsalis PC, Sismani C, Quintana-Murci L, Taleb-Bekkouche F, Krausz C, McElreavey K. Effects of transmission of Y chromosome AZFc deletions. Lancet 2002;360:1222-4. https://doi.org/10.1016/S0140-6736(02)11248-7
  36. Willis MJ, Bird LM, Dell'aquilla M, Jones MC. Natural history of prenatally diagnosed 46, X,isodicentric Y. Prenat Diagn 2006;26:134-7. https://doi.org/10.1002/pd.1352
  37. van Golde RJ, Wetzels AM, de Graaf R, Tuerlings JH, Braat DD, Kremer JA. Decreased fertilization rate and embryo quality after ICSI in oligozoospermic men with microdeletions in the azoospermia factor c region of the Y chromosome. Hum Reprod 2001;16:289-92. https://doi.org/10.1093/humrep/16.2.289
  38. Oates RD, Silber S, Brown LG, Page DC. Clinical characterization of 42 oligospermic or azoospermic men with microdeletion of the AZFc region of the Y chromosome, and of 18 children conceived via ICSI. Hum Reprod 2002;17:2813-24. https://doi.org/10.1093/humrep/17.11.2813
  39. Choi NM, Yang KM, Kang IS, Seo JT, Song IO, Park CW, et al. Effects of Y chromosome microdeletion on the outcome of in vitro fertilization. Korean J Fertil Steril 2007;34:41-8.
  40. Lee SH, Ahn SY, Lee KW, Kwack K, Jun HS, Cha KY. Intracytoplasmic sperm injection may lead to vertical transmission, expansion, and de novo occurrence of Y-chromosome microdeletions in male fetuses. Fertil Steril 2006;85:1512-5. https://doi.org/10.1016/j.fertnstert.2005.10.034