Journal of Reproduction & Infertility

Journal of Reproduction & Infertility

Apparent Homozygosity for a gr/gr AZFc Deletion in A 47,XYY Man with Oligozoospermia and Secondary Infertility

Authors
David J Bunyan 1
Mili Saran 2
James I Hobbs 3
David J Anderson 3
Philippa J Duncan-Flavell 3
Rachel J Howarth 3
Jonathan L.A Callaway 1
James N MacPherson 1
1 School of Medicine, University of Southampton, Southampton, UK; Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK
2 Complete Fertility Limited, Princess Anne Hospital, Southampton, UK
3 Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK
10.18502/jri.v23i4.10816
Abstract
Background: Approximately 1 in 1000 men have a 47,XYY karyotype. Previous publications have presented cases of infertile XYY men and have suggested that the additional Y chromosome may cause disrupted meiosis leading to sperm apoptosis. The purpose of the current study was to determine whether XYY men are over-represented in infertility cohorts. Methods: In this paper, an ongoing infertility cohort was evaluated for Y chromosome microdeletions using the MLPA technique and the data from the first 2000 referrals were recorded. Moreover, the MLPA technique detected 47,XYY karyotypes. Results: Four XYY individuals were identified within the cohort. One of the four XYY men was shown to have an apparent gr/gr partial AZFc deletion on both Y chromosomes while Sertoli cell only syndrome was detected in another case. The other two cases (out of 2000) might, therefore, represent an incidental finding. Conclusion: The gr/gr deletion is not detectable by the multiplex PCR method; therefore, there might be additional explanations for the fertility problems of infertile XYY men reported in previously published jri_articles. It seems that among other cases, their XYY karyotype may be coincidental, rather than causative of their fertility issues.
Keywords
Azoospermia
Chromosomal deletion
Infertility
Men
Sex chromosome disorders
XYY karyotype
Jacobs PA, Melville M, Ratcliffe S, Keay AJ, Syme J. A cytogenetic survey of 11,680 newborn infants. Ann Hum Genet. 1974;37(4):359-76.
Gekas J, Thepot F, Turleau C, Siffroi JP, Dadoune JP, Briault S, et al. Chromosomal factors of infertility in candidate couples for ICSI: an equal risk of constitutional aberrations in women and men. Hum Reprod. 2001;16(1):82-90.
Rives N, Milazzo JP, Miraux L, North MO, Sibert L, Macé B. From spermatocytes to spermatozoa in an infertile XYY male. Int J Androl. 2005;28(5):304-10.
Robinson DO, Jacobs PA. The origin of the extra Y chromosome in males with a 47,XYY karyotype. Hum Mol Genet. 1999;8(12):2205-9.
Moretti E, Anichini C, Sartini B, Collodel G. Sperm ultrastructure and meiotic segregation in an infertile 47,XYY man. Andrologia. 2007;39(6):229-34.
Wong EC, Ferguson KA, Chow V, Ma S. Sperm aneuploidy and meiotic sex chromosome configurations in an infertile XYY male. Hum Reprod. 2008;23(2):374-8.
El-Dahtory F, Elsheikha HM. Male infertility related to an aberrant karyotype, 47,XYY: four case reports. Cases J. 2009;2(1):28.
Zorrilla M, Yatsenko AN. The genetics of infertility: current status of the field. Curr Genet Med Rep. 2014;1(4):10.1007/s40142-013-0027-1.doi: 10.1007/s40142-013-0027-1
Blanco J, Rubio C, Simon C, Egozcue J, Vidal F. Increased incidence of disomic sperm nuclei in a 47,XYY male assessed by fluorescent in situ hybridization (FISH). Hum Genet. 1997;99(3):413-6.
Chevret E, Rousseaux S, Monteil M, Usson Y, Cozzi J, Pelletier R, et al. Meiotic behaviour of sex chromosomes investigated by three-colour FISH on 35,142 sperm nuclei from two 47,XYY males. Hum Genet. 1997;99(3):407-12.
Lim AS, Fong Y, Yu SL. Analysis of the sex chromosome constitution of sperm in men with a 47,XYY mosaic karyotype by fluorescence in situ hybridization. Fertil Steril. 1999;72(1):121-3.
Shi Q, Martin RH. Multicolor fluorescence in situ hybridization analysis of meiotic chromosome segregation in a 47,XYY male and a review of the literature. Am J Med Genet. 2000;93(1):40-6.
Blanco J, Egozcue J, Vidal F. Meiotic behaviour of the sex chromosomes in three patients with sex chromosome anomalies (47,XXY, mosaic 46,XY/47,XXY and 47,XYY) assessed by fluorescence in-situ hybridization. Hum Reprod. 2001;16(5):887-92.
Gonzalez-Merino E, Hans C, Abramowicz M, Englert Y, Emiliani S. Aneuploidy study in sperm and preimplantation embryos from nonmosaic 47,XYY men. Fertil Steril. 2007;88(3):600-6.
Kim IW, Khadilkar AC, Ko EY, Sabanegh Jr ES. 47,XYY syndrome and male infertility. Rev Urol. 2013;15(4):188-96.
Tiepolo L, Zuffardi O. Localization of factors controlling spermatogenesis in the nonfluorescent portion of the human Y chromosome long arm. Hum Genet. 1976;34(2):119-24.
Bianchi NO, Richard SM, Peltomäki P, Bianchi MS. Mosaic AZF deletions and susceptibility to testicular tumors. Mutat Res. 2002;503(1-2):51-62.
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(7):933-43.
Navarro-Costa P, Gonçalves J, Plancha CE. The AZFc region of the Y chromosome: at the crossroads between genetic diversity and male infertility. Hum Reprod Update. 2010;16(5):525-42.
Noordam MJ, Westerveld GH, Hovingh SE, van Daalen SK, Korver CM, van der Veen F, et al. Gene copy number reduction in the azoospermia factor c (AZFc) region and its effect on total motile sperm count. Hum Mol Genet. 2011;20(12):2457-63.
Foresta C, Moro E, Ferlin A. Y chromosome microdeletions and alterations of spermatogenesis. Endocr Rev. 2001;22(2):226-39.
Kuroda-Kawaguchi T, Skaletsky H, Brown LG, Minx PJ, Cordum HS, Waterston RH, et al. The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men. Nat Genet. 2001;29(3):279-86.
Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, Cordum HS, Hillier L, Brown LG, et al. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature. 2003;423(6942):825-37.
Reijo R, Lee TY, Salo P, Alagappan R, Brown LG, Rosenberg M, et al. Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat Genet. 1995;10(4):383-93.
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(11):2813-24.
Repping S, Skaletsky H, Lange J, Silber S, Van Der Veen F, Oates RD, et al. Recombination between palindromes P5 and P1 on the human Y chromosome causes massive deletions and spermatogenic failure. Am J Hum Genet. 2002;71(4):906-22.
Saxena R, de Vries JW, Repping S, Alagappan RK, Skaletsky H, Brown LG, et al. Four DAZ genes in two clusters found in the AZFc region of the human Y chromosome. Genomics. 2000;67(3):256-67.
Fernandes S, Huellen K, Goncalves J, Dukal H, Zeisler J, Rajpert De Meyts E, et al. High frequency of DAZ1/DAZ2 gene deletions in patients with severe oligozoospermia. Mol Hum Reprod. 2002;8(3):286-98.
Repping S, Skaletsky H, Brown L, van Daalen SK, Korver CM, Pyntikova T, et al. Polymorphism for a 1.6-Mb deletion of the human Y chromosome persists through balance between recurrent mutation and haploid selection. Nat Genet. 2003;35(3):247-51.
Repping S, van Daalen SK, Korver CM, Brown LG, Marszalek JD, Gianotten J, et al. A family of human Y chromosomes has dispersed throughout northern Eurasia despite a 1.8-Mb deletion in the azoospermia factor c region. Genomics. 2004;83(6):1046-52.
Fernandes S, Paracchini S, Meyer LH, Floridia G, Tyler-Smith C, Vogt PH. A large AZFc deletion removes DAZ3/DAZ4 and nearby genes from men in Y haplogroup N. Am J Hum Genet. 2004;74(1):180-7.
Moro E, Ferlin A, Yen PH, Franchi PG, Palka G, Foresta C. Male infertility caused by a de novo partial deletion of the DAZ cluster on the Y chromosome. J Clin Endocrinol Metab. 2000;85(11):4069-73.
Bienvenu T, Patrat C, McElreavey K, de Almeida M, Jouannet P. Reduction in the DAZ gene copy number in two infertile men with impaired spermatogenesis. Ann Genet. 2001;44(3):125-8.
Ferlin A, Moro E, Rossi A, Foresta C. A novel approach for the analysis of DAZ gene copy number in severely idiopathic infertile men. J Endocrinol Invest. 2002;25(1):RC1-3.
de Vries JW, Hoffer MJ, Repping S, Hoovers JM, Leschot NJ, van der Veen F. Reduced copy number of DAZ genes in subfertile and infertile men. Fertil Steril. 2002;77(1):68-75.
de Vries JW, Repping S, van Daalen SK, Korver CM, Leschot NJ, van der Veen F. Clinical relevance of partial AZFc deletions. Fertil Steril. 2002;78(6):1209-14.
Ferlin A, Bettella A, Tessari A, Salata E, Dallapiccola B, Foresta C. Analysis of the DAZ gene family in cryptorchidism and idiopathic male infertility. Fertil Steril. 2004;81(4):1013-8.
Ferlin A, Tessari A, Ganz F, Marchina E, Barlati S, Garolla A, et al. Association of partial AZFc region deletions with spermatogenic impairment and male infertility. J Med Genet. 2005;42(3):209-13.
Mitra A, Dada R, Kumar R, Gupta NP, Kucheria K, Gupta SK. Y chromosome microdeletions in azoospermic patients with Klinefelter's syndrome. Asian J Androl. 2006;8(1):81-8.
Cetinkaya M, Kaba M, Çetin ES, Candan S. Case report: Y chromosome microdeletion in an infertile patient with mosaic Klinefelter syndrome. Int J Hum Genet. 2015;15(3):145-8.
Li LX, Dai HY, Ding XP, Zhang YP, Zhang XH, Ren HY, et al. Investigation of AZF microdeletions in patients with Klinefelter syndrome. Genet Mol Res. 2015;14(4):15140-7.
Pan Y, Zhang HG, Xi QI, Zhang H, Wang RX, Li LL, et al. Molecular microdeletion analysis of infertile men with karyotypic Y chromosome abnormalities. J Int Med Res. 2018;46(1):307-15.
Aydemir H, Karkucak M, Cimen HI, Halis F, Kumsar S, Sonbahar AE, et al. A rare combination of 45, X/46, XY mosaicism and Y chromosome microdeletion in an infertile man with azoospermia. Genet Couns. 2016;27(1):95-8.
Kim JW, Park SY, Ryu HM, Lee DE, Lee BY, Kim SY, et al. Molecular and clinical characteristics of 26 cases with structural Y chromosome aberrations. Cytogenet Genome Res. 2012;136(4):270-7.
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(4):240-9.
Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 2002;30(12):e57.
Bunyan DJ, Callaway JLA, Laddach N. The detection of partial Y-chromosome AZFc deletions in infertile men using the Multiplex Ligation-dependent Probe Amplification assay. J Reprod Infertil. 2012;13(3):174-8.
Seabright M. A rapid banding technique for human chromosomes. Lancet. 1971;2(7731):971-2.
Rozen SG, Marszalek JD, Irenze K, Skaletsky H, Brown LG, Oates RD, et al. AZFc deletions and spermatogenic failure: A population-based survey of 20,000 Y chromosomes. Am J Hum Genet. 2012;91(5):890-6.
Krausz C, Hoefsloot L, Simoni M, Tüttelmann 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(1):5-19.
Mokanszki A, Ujfalusi A, Gombos É, Balogh I. Examination of Y-chromosomal microdeletions and partial microdeletions in idiopathic infertility in East Hungarian patients. J Hum Reprod Sci. 2018;11(4):329-36.
Jedidi I, Ouchari M, Yinb Q. Autosomal single-gene disorders involved in human infertility. Saudi J Biol Sci. 2018;25(5):881-7.
Stouffs K, Gheldof A, Tournaye H, Vandermaelen D, Bonduelle M, Lissens W, et al. Sertoli cell-only syndrome: behind the genetic scenes. Biomed Res Int. 2016;2016:6191307.
Journal of Reproduction & Infertility
Volume 23, Issue 4
Autumn 2022
Pages 296-302