Skip to main content
SpringerLink
Log in

Genetic Analysis in Male Infertility

  • Living reference work entry
  • First Online:
Endocrinology of the Testis and Male Reproduction

Part of the book series: Endocrinology ((ENDOCR))

  • 144 Accesses

Abstract

Genetic factors are responsible for about 20–25% of severe male factor infertility and may affect both gametogenic and endocrine functions of the testis or may cause the congenital absence of vas deferens. Testing for chromosomal anomalies (karyotype and Y chromosome microdeletions) is performed in all patients affected by moderate or severe oligozoospermia and azoospermia, whereas mutation screening in candidate genes is indicated in specific disease conditions. All the abovementioned analyses aim at the identification of genetic factors showing a cause-effect relationship with the given phenotype, and they are part of the diagnostic work-up of infertile men. During the last 20 years, active research has been carried out in order to identify novel candidate genes and genetic risk factors for impaired sperm production. Despite efforts, the only genetic risk factor which is currently screened in selected populations is the Y-chromosome linked “gr/gr deletion.” With the recent advent of next-generation sequencing (NGS), the analysis of the entire exome has been applied also to male infertility. Although whole exome/genome data interpretation remains challenging, whole exome analysis seems to be a valid diagnostic tool for familial cases or for patients with consanguineous parents.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Aksglaede L, Juul A. Testicular function and fertility in men with Klinefelter syndrome: a review. Eur J Endocrinol. 2013;168:R67–76.

    Article  CAS  PubMed  Google Scholar 

  • Aksglaede L, Wikstrom AM, Rajpert-De ME, Dunkel L, Skakkebaek NE, Juul A. Natural history of seminiferous tubule degeneration in Klinefelter syndrome. Hum Reprod Update. 2006;12:39–48.

    Article  PubMed  Google Scholar 

  • Ayhan Ö, Balkan M, Guven A, Hazan R, Atar M, Tok A, Tolun A. Truncating mutations in TAF4B and ZMYND15 causing recessive azoospermia. J Med Genet. 2014;51:239–44.

    Article  CAS  PubMed  Google Scholar 

  • Bashamboo A, McElreavey K. Human sex-determination and disorders of sex-development (DSD). Semin Cell Dev Biol. 2015;45:77–83.

    Article  CAS  PubMed  Google Scholar 

  • Ben Khelifa M, Coutton C, Blum MGB, Abada F, Harbuz R, Zouari R, et al. Identification of a new recurrent aurora kinase C mutation in both European and African men with macrozoospermia. Hum Reprod. 2012;27(11):3337–46.

    Article  CAS  PubMed  Google Scholar 

  • Berthelsen JG, Skakkebaek N, Perboll O, et al. Electron microscopic demonstration of the extra Y chromosome in spermatocytes from human XYY males. In: Byskov AG, Peters H, editors. Development and function of reproductive organs. Amsterdam: Experta Medica; 1981. p. 328–37.

    Google Scholar 

  • Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L, Dwyer AA, Giacobini P, Hardelin JP, Juul A, Maghnie M, Pitteloud N, Prevot V, Raivio T, Tena-Sempere M, Quinton R, Young J. Expert consensus document: European consensus statement on congenital hypogonadotropic hypogonadism-pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2015;11(9):547–64.

    PubMed  Google Scholar 

  • Chandley AC, Edmond P, Christie S, Gowans L, Fletcher J, Frackiewicz A, Newton M. Cytogenetics and infertility in man. I. Karyotype and seminal analysis: results of a five-year survey of men attending a subfertility clinic. Ann Hum Genet. 1975;39:231–54.

    Article  CAS  PubMed  Google Scholar 

  • Chianese C, Fino MG, Riera Escamilla A, López Rodrigo O, Vinci S, Guarducci E, Daguin F, Muratori M, Tamburrino L, Lo Giacco D, Ars E, Bassas L, Costa M, Pisatauro V, Noci I, Coccia E, Provenzano A, Ruiz-Castañé E, Giglio S, Piomboni P, Krausz C. Comprehensive investigation in patients affected by sperm macrocephaly and globozoospermia. Andrology. 2015;3(2):203–12.

    Article  CAS  PubMed  Google Scholar 

  • Coutton C, Escoffier J, Martinez G, Arnoult C, Ray PF. Teratozoospermia: spotlight on the main genetic actors in the human. Hum Reprod Update. 2015;21(4):455–85.

    Article  PubMed  Google Scholar 

  • Cuppens H, Cassiman JJ. CFTR mutations and polymorphisms in male infertility. Int J Androl. 2004;27:251–6.

    Article  CAS  PubMed  Google Scholar 

  • Davis-Dao CA, Tuazon ED, Sokol RZ, Cortessis VK. Male infertility and variation in CAG repeat length in the androgen receptor gene: a meta-analysis. J Clin Endocrinol Metab. 2007;92:4319–2624.

    Article  CAS  PubMed  Google Scholar 

  • Davis-Dao C, Koh CJ, Hardy BE, Chang A, Kim SS, De Filippo R, et al. Shorter androgen receptor CAG repeat lengths associated with cryptorchidism risk among Hispanic white boys. J Clin Endocrinol Metab. 2012;97:E393–9.

    Article  CAS  PubMed  Google Scholar 

  • De Braekeleer M, Nguyen MH, Morel F, Perrin A. Genetic aspects of monomorphic teratozoospermia: a review. J Assist Reprod Genet. 2015;32(4):615–23.

    Article  PubMed  PubMed Central  Google Scholar 

  • Dieterich K, Soto Rifo R, Faure AK, Hennebicq S, Ben Amar B, Zahi M, et al. Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility. Nat Genet. 2007;39(5):661–5. Epub 2007 Apr 15.

    Article  CAS  PubMed  Google Scholar 

  • Dieterich K, Zouari R, Harbuz R, Vialard F, Martinez D, Bellayou H, et al. The Aurora Kinase C c.144delC mutation causes meiosis I arrest in men and is frequent in the North African population. Hum Mol Genet. 2009;18(7):1301–9. 16–19.

    Article  CAS  PubMed  Google Scholar 

  • Eggers S, Ohnesorg T, Sinclair A. Genetic regulation of mammalian gonad development. Nat Rev Endocrinol. 2014;10(11):673–83.

    Article  CAS  PubMed  Google Scholar 

  • Ferlin A, Vinanzi C, Garolla A, Selice R, et al. Male infertility and androgen receptor gene mutations: clinical features and identification of seven novel mutations. Clin Endocrinol. 2006;65:606–10.

    Article  CAS  Google Scholar 

  • Fullerton G, Hamilton M, Maheshwari A. Should non-mosaic Klinefelter syndrome men be labelled as infertile in 2009? Hum Reprod. 2010;25:588–97.

    Article  CAS  PubMed  Google Scholar 

  • Giachini C, Laface I, Guarducci E, Balercia G, et al. Partial AZFc deletions and duplications: clinical correlates in the Italian population. Hum Genet. 2008;124:399–410.

    Article  CAS  PubMed  Google Scholar 

  • Gies I, Oates R, de Schepper J, Tournaye H. Testicular biopsy and cryopreservation for fertility preservation of pre-pubertal boys with Klinefelter syndrome: a pro/con debate. Fertil Steril. 2016;105:249–55.

    Article  PubMed  Google Scholar 

  • Gottlieb B, Beitel LK, Nadarajah A, Palioura M, Trifiro M. The androgen receptor gene mutations database (ARDB): 2012 update. Human Mutation. 2012;33:887–94.

    Article  CAS  PubMed  Google Scholar 

  • Jaruzelska J, Korcz A, Wojda A, Jedrzejczak P, Bierla J, Surmacz T, Pawelczyk L, Page DC, Kotecki M. Mosaicism for 45,X cell line may accentuate the severity of spermatogenic defects in men with AZFc deletion. J Med Genet. 2001;38:798–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jungwirth A, Giwercman A, Tournaye H, Diemer T, Kopa Z, Dohle G, Krausz C. European association of urology working group on male infertility. European association of urology guidelines on male infertility: the 2012 update. Eur Urol. 2012;62(2):324–32.

    Article  PubMed  Google Scholar 

  • Kamischke A, Baumgardt A, Horst J, Nieschlag E. Clinical and diagnostic features of patients with suspected Klinefelter syndrome. J Androl. 2003;24:41–8.

    Article  PubMed  Google Scholar 

  • Kim JW, Park SY, Ryu HM, et al. Molecular and clinical characteristics of 26 cases with structural Y chromosome aberrations. Cytogenet Genome Res. 2012;136:270–7.

    Article  PubMed  Google Scholar 

  • Koscinski I, Elinati E, Fossard C, Redin C, Muller J, Velez de la Calle J, et al. DPY19L2 deletion as a major cause of globozoospermia. Am J Hum Genet. 2011;88(3):344–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krausz C. An encore for the repeats: new insights into an old genetic variant. J Clin Endocrinol Metab. 2012;97:764–7.

    Article  CAS  PubMed  Google Scholar 

  • Krausz C, Quintana-Murci L, McElreavey K. Prognostic value of Y deletion analysis: what is the clinical prognostic value of Y chromosome microdeletion analysis? Hum Reprod. 2000;15:1431–4.

    Article  CAS  PubMed  Google Scholar 

  • Krausz C, Degl’Innocenti S, Nuti F, et al. Natural transmission of USP9Y gene mutations: a new perspective on the role of AZFa genes in male fertility. Hum Mol Genet. 2006;15:2673–81.

    Article  CAS  PubMed  Google Scholar 

  • Krausz C, Giachini C, Lo Giacco D, Daguin F, Chianese C, Ars E, et al. High resolution X chromosome-specific array-CGH detects new CNVs in infertile males. PLoS One. 2012;7:e44887.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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;2:5–19.

    Article  CAS  PubMed  Google Scholar 

  • Krausz C, Escamilla AR, Chianese C. Genetics of male infertility: from research to clinic. Reproduction. 2015;150(5):R159–74.

    Article  CAS  PubMed  Google Scholar 

  • Lange J, Skaletsky H, van Daalen SK, et al. Isodicentric Y chromosomes and sex disorders as byproducts of homologous recombination that maintains palindromes. Cell. 2009;138:855–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lo Giacco D, Chianese C, Sánchez-Curbelo J, Bassas L, Ruiz P, Rajmil O, Sarquella J, Vives A, Ruiz-Castañé E, Oliva R, Ars E, Krausz C. Clinical relevance of Y-linked CNV screening in male infertility: new insights based on the 8-year experience of a diagnostic genetic laboratory. Eur J Hum Genet. 2014a;22(6):754–61.

    Article  PubMed  Google Scholar 

  • Lo Giacco D, Chianese C, Ars E, Ruiz-Castañé E, Forti G, Krausz C. Recurrent X chromosome-linked deletions: discovery of new genetic factors in male infertility. J Med Genet. 2014b;51:340–4.

    Article  CAS  PubMed  Google Scholar 

  • Lopes AM, Aston KI, Thompson E, Carvalho F, Gonçalves J, Huang N, et al. Human spermatogenic failure purges deleterious mutation load from the autosomes and both sex chromosomes, including the gene DMRT1. PLoS Genet. 2013;9:e1003349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu C, Zhang J, Li Y, Xia Y, et al. The b2/b3 subdeletion shows higher risk of spermatogenic failure and higher frequency of complete AZFc deletion than the gr/gr subdeletion in a Chinese population. Hum Mol Genet. 2009;18:1122–30.

    Article  CAS  PubMed  Google Scholar 

  • Molinari E, Mirabelli M, Raimondo S, Brussino A, Gennarelli G, Bongioanni F, et al. Sperm macrocephaly syndrome in a patient without AURKC mutations and with a history of recurrent miscarriage. Reprod BioMed Online. 2013;26(2):148–56.

    Article  PubMed  Google Scholar 

  • Mueller JL, Skaletsky H, Brown LG, Zaghlul S, Rock S, Graves T, et al. Independent specialization of the human and mouse X chromosomes for the male germ line. Nat Genet. 2013;45:1083–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nenonen H, Björk C, Skjaerpe P, Giwercmana RL, Svartberg J, et al. CAG repeat number is not inversely associated with androgen receptor activity in vitro. Mol Hum Reprod. 2010;16:153–7.

    Article  CAS  PubMed  Google Scholar 

  • Nenonen HA, Giwercman A, Hallengren E, Giwercman YL. Non-linear association between androgen receptor CAG repeat length and risk of male subfertility – a meta-analysis. Int J Androl. 2011;34:327–32.

    Article  CAS  PubMed  Google Scholar 

  • Nistal M, Paniagua R, Herruzo A. Multi-tailed spermatozoa in a case with asthenospermia and teratospermia. Virchows Arch B Cell Pathol. 1977;26(2):111–8.

    CAS  PubMed  Google Scholar 

  • O’Hara L, Smith LB. Androgen receptor roles in spermatogenesis and infertility. Best Pract Res Clin Endocrinol Metab. 2015;29:595–605.

    Article  PubMed  Google Scholar 

  • Oates RD, Amos JA. The genetic basis of congenital bilateral absence of the vas deferens and cystic fibrosis. J Androl. 1994;15:1–8.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Okutman O, Muller J, Baert Y, Serdarogullari M, Gultomruk M, Piton A, Rombaut C, Benkhalifa M, Teletin M, Skory V, Bakircioglu E, Goossens E, et al. Exome sequencing reveals a nonsense mutation in TEX15 causing spermatogenic failure in a Turkish family. Hum Mol Genet. 2015;24:5581–8.

    Article  CAS  PubMed  Google Scholar 

  • Patrizio P, Leonard DG. Mutations of the cystic fibrosis gene and congenital absence of the vas deferens. Results Probl Cell Differ. 2000;28:175–86.

    Article  CAS  PubMed  Google Scholar 

  • Pitteloud N, Quinton R, Pearce S, et al. Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J Clin Invest. 2007;117:457–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Plotton I, Giscard d’Estaing S, Cuzin B, et al. Preliminary results of a prospective study of testicular sperm extraction in young versus adult patients with non-mosaic 47,XXY Klinefelter syndrome. J Clin Endocrinol Metab. 2015;100:961–7.

    Article  CAS  PubMed  Google Scholar 

  • Raivio T, Falardeau J, Dwyer A, et al. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med. 2007;357:863–73.

    Article  CAS  PubMed  Google Scholar 

  • Rajender S, Singh L, Thangaraj K. Phenotypic heterogeneity of mutations in androgen receptor gene. Asian J Androl. 2007;9:147–79.

    Article  CAS  PubMed  Google Scholar 

  • Ramasamy R, Bakırcıoğlu ME, Cengiz C, Karaca E, Scovell J, Jhangiani SN, Akdemir ZC, Bainbridge M, Yu Y, Huff C, Gibbs RA, Lupski JR, et al. Whole-exome sequencing identifies novel homozygous mutation in NPAS2 in family with nonobstructive azoospermia. Fertil Steril. 2015;104:286–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Repping S, Skaletsky H, Brown L, van Daalen SK, 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;35:247–51.

    Article  CAS  PubMed  Google Scholar 

  • Ribeiro RS, Vieira TC, Abucham J. Reversible Kallmann syndrome: report of the first case with a KAL1 mutation and literature review. Eur J Endocrinol. 2007;156:285–90.

    Article  CAS  PubMed  Google Scholar 

  • Sinclair AH, Berta P, Palmer MS, Hawkins JR, Griffiths BL, Smith MJ, Foster JW, Frischauf AM, Lovell-Badge R, Goodfellow PN. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature. 1990;346:240–4.

    Article  CAS  PubMed  Google Scholar 

  • Skakkebaek NE, Zeuthen E, Nielsen J, Yde H. Abnormal spermatogenesis in XYY Males: a report on 4 cases ascertained through a population study. Fertil Steril. 1973;24:390–5.

    Article  CAS  PubMed  Google Scholar 

  • Staessen C, Tournaye H, Van Assche E, Michiels A, et al. PGD in 47,XXY Klinefelter’s syndrome patients. Hum Reprod Update. 2003;9:319–30.

    Article  CAS  PubMed  Google Scholar 

  • Tommiska J, Jørgensen N, Christiansen P, Juul A, Raivio T. A homozygous R262Q mutation in the gonadotropin-releasing hormone receptor presenting as reversal of hypogonadotropic hypogonadism and late-onset hypogonadism. Clin Endocrinol. 2013;78:316–7.

    Article  CAS  Google Scholar 

  • Tüttelmann F, Simoni M, Kliesch S, Ledig S, Dworniczak B, Wieacker P, et al. Copy number variants in patients with severe oligozoospermia and Sertoli-cell-only syndrome. PLoS One. 2011;6:e19426.

    Article  PubMed  PubMed Central  Google Scholar 

  • Tyler-Smith C, Krausz C. The will-o’-the-wisp of genetics – hunting for the azoospermia factor gene. N Engl J Med. 2009;360:925–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Van Saen D, Gies I, De Schepper J, Tournaye H, Goossens E. Can pubertal boys with Klinefelter syndrome benefit from spermatogonial stem cell banking? Hum Reprod. 2012;27:323–30.

    Article  CAS  PubMed  Google Scholar 

  • Vincent MC, Daudin M, De MP, Massat G, et al. Cytogenetic investigations of infertile men with low sperm counts: a 25-year experience. J Androl. 2002;23:18–22. discussion 44–15.

    Article  PubMed  Google Scholar 

  • Vogt PH, Edelmann A, Kirsch S, Henegariu O, Hirschmann P, Kiesewetter F, Köhn FM, Schill WB, Farah S, Ramos C, Hartmann M, Hartschuh W, Meschede D, Behre HM, Castel A, Nieschlag E, Weidner W, Gröne HJ, Jung A, Engel W, Haidl G. Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet. 1996;5:933–43.

    Article  CAS  PubMed  Google Scholar 

  • Vorona E, Zitzmann M, Gromoll J, Schüring AN, Nieschlag E. Clinical, endocrinological, and epigenetic features of the 46, XX male syndrome, compared with 47,XXY Klinefelter patients. J Clin Endocrinol Metab. 2007;92(9):3458–65. Epub 2007 June 19.

    Article  CAS  PubMed  Google Scholar 

  • Yang F, Silber S, Leu NA, et al. TEX11 is mutated in infertile men with azoospermia and regulates genome-wide recombination rates in mouse. EMBO Mol Med. 2015;7:1198–210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yassine S, Escoffier J, Martinez G, Coutton C, Karaouzene T, Zouari R, Ravanat JL, Metzler-Guillemain C, Lee HC, Fissore R, Hennebicq S, Ray PF, Arnoult C. Dpy19l2-deficient globozoospermic sperm display altered genome packaging and DNA damage that compromises the initiation of embryo development. Mol Hum Reprod. 2015;21:169–85.

    Article  PubMed  Google Scholar 

  • Yatsenko AN, Georgiadis AP, Röpke A, et al. X-linked TEX11 mutations, meiotic arrest, and azoospermia in infertile men. N Engl J Med. 2015;372:2097–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang F, Lu C, Li Z, Xie P, et al. Partial deletions are associated with an increased risk of complete deletion in AZFc: a new insight into the role of partial AZFc deletions in male infertility. J Med Genet. 2007;44:437–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zühlke C, Thies U, Braulke I, Reis A, Schirren C. Down syndrome and male fertility: PCR-derived fingerprinting, serological and andrological investigations. Clin Genet. 1994;46:324–6.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Pieraccini, 6, Florence, Italy

    Csilla Krausz

Authors
  1. Csilla Krausz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Csilla Krausz .

Editor information

Editors and Affiliations

  1. Dept. of Biomedicine, Metabolism and Neural Sciences, University of Modena and Reggio Emilia, Modena, Modena, Italy

    Manuela Simoni

  2. Dept. of Surgery and Cancer, Imperial College London, London, United Kingdom

    Ilpo Huhtaniemi

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this entry

Cite this entry

Krausz, C. (2017). Genetic Analysis in Male Infertility. In: Simoni, M., Huhtaniemi, I. (eds) Endocrinology of the Testis and Male Reproduction. Endocrinology. Springer, Cham. https://doi.org/10.1007/978-3-319-29456-8_17-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-29456-8_17-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-29456-8

  • Online ISBN: 978-3-319-29456-8

  • eBook Packages: Springer Reference MedicineReference Module Medicine

Publish with us

Policies and ethics

Search

Navigation