To identify genomic imbalances and candidate loci in idiopathic male infertility.
Affymetrix CytoScan 750K Array was used to analyze genomic imbalances and candidate loci in 34 idiopathic infertile cases of different phenotypes (hypo-spermatogenesis, n = 8; maturation arrest, n = 7; and Sertoli cell-only syndrome, n = 13, severe oligozoospermia, n = 6, and 10 normozoospermic fertile men). Ten ethnically matched controls were screened for comparison.
The cytogenetic array analysis detected a genomic gain at the 19p13.3 region in 9 (26.47%) cases, with the highest frequency in patients with Sertoli cell-only syndrome (SCOS) (38%). Its complete absence in the control group suggests its likely pathogenic nature. In addition to Y-classical, micro, and partial deletions, the duplication in 19p13.3 could serve as a unique biomarker for evaluation of infertility risk. The common region across the individuals harboring the duplication identified STK11, ATP5D, MIDN, CIRBP, and EFNA2 genes which make them strong candidates for further investigations. The largest duplicated region identified in this study displayed a major network of 7 genes, viz., CIRBP, FSTL3, GPX4, GAMT, KISS1R, STK11, and PCSK4, associated with reproductive system development and function. The role of chance was ruled out by screening of ethnically matched controls.
The result clearly indicates the significance of 19p13.3 duplication in infertile men with severe testicular phenotypes. The present study underlines the utility and significance of whole genomic analysis in the cases of male infertility which goes undiagnosed due to limitations in the conventional cytogenetic techniques and for identifying genes that are essential for spermatogenesis.
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Holden CA, McLachlan RI, Pitts M, Cumming R, Wittert G, Agius PA, et al. Men in Australia Telephone Survey (MATeS): a national survey of the reproductive health and concerns of middle-aged and older Australian men. Lancet. 2005;366:218–24.
Matzuk MM, Lamb DJ. The biology of infertility: research advances and clinical challenges. Nat Med. 2008;14:1197–213.
Baker G, Barak S (2012) Clinical management of male infertility. wwwENDOTEXTorg Chapter 7: MDTEXT. COM. Inc, South Dartmouth, MA, USA.
Pastuszak AW, Lamb DJ. The genetics of male fertility—from basic science to clinical evaluation. J Androl. 2012;33:1075–84.
McLachlan RI, O’bryan MK. State of the art for genetic testing of infertile men. J Clin Endocrinol Metab. 2010;95:1013–24.
Diemer T, Desjardins C. Developmental and genetic disorders in spermatogenesis. Hum Reprod Update. 1999;5:120–40.
Yang L, Xu L, Zhou Y, Liu M, Wang L, Kijas JW, et al. Diversity of copy number variation in a worldwide population of sheep. Genomics. 2018;110:143–8.
Feuk L, Carson AR, Scherer SW. Structural variation in the human genome. Nat Rev Genet. 2006;7:85–97.
Jaillard S, Drunat S, Bendavid C, Aboura A, Etcheverry A, Journel H, et al. Identification of gene copy number variations in patients with mental retardation using array-CGH: novel syndromes in a large French series. Eur J Med Genet. 2010;53:66–75.
Kumaran M, Cass CE, Graham K, Mackey JR, Hubaux R, Lam W, et al. Germline copy number variations are associated with breast cancer risk and prognosis. Sci Rep. 2017;7:14621.
Marshall CR, Howrigan DP, Merico D, Thiruvahindrapuram B, Wu W, Greer DS, et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet. 2017;49:27–35.
Xie Y, Yuan H, Wang M, Zhong L, Zhou J, Song B, Yin Q, Sun X. Copy number variations independently induce autism spectrum disorder. Biosci Rep 2017;37:BSR20160570.
Eggers S, DeBoer KD, van den Bergen J, Gordon L, White SJ, Jamsai D, et al. Copy number variation associated with meiotic arrest in idiopathic male infertility. Fertil Steril. 2015;103:214–9.
Stouffs K, Vandermaelen D, Massart A, Menten B, Vergult S, Tournaye H, et al. Array comparative genomic hybridization in male infertility. Hum Reprod. 2012;27:921–9.
White S, Ohnesorg T, Notini A, Roeszler K, Hewitt J, Daggag H, et al. Copy number variation in patients with disorders of sex development due to 46, XY gonadal dysgenesis. PLoS One. 2011;6:e17793.
Jaiswal D, Singh V, Dwivedi US, Trivedi S, Singh K. Chromosome microarray analysis: a case report of infertile brothers with CATSPER gene deletion. Gene. 2014;542:263–5.
Vermeesch JR, Brady PD, Sanlaville D, Kok K, Hastings RJ. Genome-wide arrays: quality criteria and platforms to be used in routine diagnostics. Hum Mutat. 2012;33:906–15.
Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86:749–64.
Saeki H, Kitao H, Yoshinaga K, Nakanoko T, Kubo N, Kakeji Y, et al. Copy-neutral loss of heterozygosity at the p53 locus in carcinogenesis of esophageal squamous cell carcinomas associated with p53 mutations. Clin Cancer Res. 2011;17:1731–40.
Saare M, Soritsa D, Vaidla K, Palta P, Remm M, Laan M, et al. No evidence of somatic DNA copy number alterations in eutopic and ectopic endometrial tissue in endometriosis. Hum Reprod. 2012;27:1857–64.
Grimwood J, Gordon LA, Olsen A, Terry A, Schmutz J, Lamerdin J, et al. The DNA sequence and biology of human chromosome 19. Nature. 2004;428:529–35.
Ishikawa A, Enomoto K, Tominaga M, Saito T, Nagai J, Furuya N, et al. Pure duplication of 19p13. 3. Am J Med Genet A. 2013;161:2300–4.
Nevado J, Rosenfeld JA, Mena R, Palomares-Bralo M, Vallespín E, Mori MÁ, et al. PIAS4 is associated with macro/microcephaly in the novel interstitial 19p13. 3 microdeletion/microduplication syndrome. Eur J Hum Genet. 2015;23:1615.
Archer HL, Gupta S, Enoch S, Thompson P, Rowbottom A, Chua I, et al. Distinct phenotype associated with a cryptic subtelomeric deletion of 19p13. 3-pter. Am J Med Genet A. 2005;136:38–44.
Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HWG, Behre HM, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2010;16:231–45.
Singh V, Bansal SK, Singh R, Singh K. Autosomal genes in male infertility. In: Male infertility: understanding, causes treat. Springer; 2017. pp 231–252.
Jedidi I, Ouchari M, Yin Q. Autosomal single-gene disorders involved in human infertility. Saudi J Biol Sci. 2018;25:881–7.
Seidel MG, Duerr C, Woutsas S, Schwerin-Nagel A, Sadeghi K, Neesen J, et al. A novel immunodeficiency syndrome associated with partial trisomy 19p13. J Med Genet. 2014;51:254–63 jmedgenet-2013.
Xia Z, Zheng X, Zheng H, Liu X, Yang Z, Wang X. Cold-inducible RNA-binding protein (CIRP) regulates target mRNA stabilization in the mouse testis. FEBS Lett. 2012;586:3299–308.
Xia Y, Sidis Y, Schneyer A. Overexpression of follistatin-like 3 in gonads causes defects in gonadal development and function in transgenic mice. Mol Endocrinol. 2004;18:979–94.
Oldknow KJ, Seebacher J, Goswami T, Villen J, Pitsillides AA, O’shaughnessy PJ, et al. Follistatin-like 3 (FSTL3) mediated silencing of transforming growth factor β (TGFβ) signaling is essential for testicular aging and regulating testis size. Endocrinology. 2013;154:1310–20.
Schneider M, Förster H, Boersma A, Seiler A, Wehnes H, Sinowatz F, et al. Mitochondrial glutathione peroxidase 4 disruption causes male infertility. FASEB J. 2009;23:3233–42.
Schmidt A, Marescau B, Boehm EA, Renema WKJ, Peco R, Das A, et al. Severely altered guanidino compound levels, disturbed body weight homeostasis and impaired fertility in a mouse model of guanidinoacetate N-methyltransferase (GAMT) deficiency. Hum Mol Genet. 2004;13:905–21.
Clarke H, Dhillo WS, Jayasena CN. Comprehensive review on kisspeptin and its role in reproductive disorders. Endocrinol Metab. 2015;30:124–41.
Kong F, Wang M, Huang X, Yue Q, Wei X, Dou X, et al. Differential regulation of spermatogenic process by Lkb1 isoforms in mouse testis. Cell Death Dis. 2017;8:e3121.
Gyamera-Acheampong C, Tantibhedhyangkul J, Weerachatyanukul W, Tadros H, Xu H, van de Loo J-W, et al. Sperm from mice genetically deficient for the PCSK4 proteinase exhibit accelerated capacitation, precocious acrosome reaction, reduced binding to egg zona pellucida, and impaired fertilizing ability. Biol Reprod. 2006;74:666–73.
Mbikay M, Tadros H, Ishida N, Lerner CP, De Lamirande E, Chen A, et al. Impaired fertility in mice deficient for the testicular germ-cell protease PC4. Proc Natl Acad Sci. 1997;94:6842–6.
Johansson MM, Van Geystelen A, Larmuseau MHD, Djurovic S, Andreassen OA, Agartz I, et al. Microarray analysis of copy number variants on the human Y chromosome reveals novel and frequent duplications overrepresented in specific haplogroups. PLoS One. 2015;10:e0137223.
Connallon T, Clark AG. Gene duplication, gene conversion, and the evolution of the Y chromosome. Genetics. 2010;186:277–86.
The authors thank the patients for providing blood samples and their consent for genetic analysis. We would like to acknowledge the Interdisciplinary School of Life Sciences (ISLS), Banaras Hindu University for Affymetrix Microarray Facility. The first author thanks CSIR for the Senior Research Fellowship.
The study was funded by the Board of Research in Nuclear Sciences (BRNS), Govt. of India, with sanction number 2013/37B/27/BRNS.
This study was approved by the Institutional Human Ethics Committee of the Institute of Science, Banaras Hindu University, Varanasi, approved this study (Approval letter No. Dean/2011-12/119).
Informed consent was obtained from all individual participants included in the study.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee.
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Singh, V., Bala, R., Chakraborty, A. et al. Duplications in 19p13.3 are associated with male infertility. J Assist Reprod Genet 36, 2171–2179 (2019). https://doi.org/10.1007/s10815-019-01547-1
- Copy number variations
- Genomic imbalances
- Cytogenetic microarray