Journal of Assisted Reproduction and Genetics

, Volume 35, Issue 11, pp 1939–1951 | Cite as

Genetic evaluation of patients with non-syndromic male infertility

  • Ozlem Okutman
  • Maroua Ben Rhouma
  • Moncef Benkhalifa
  • Jean Muller
  • Stéphane VivilleEmail author



This review provides an update on the genetics of male infertility with emphasis on the current state of research, the genetic disorders that can lead to non-syndromic male infertility, and the genetic tests available for patients.


A comprehensive review of the scientific literature referenced in PubMed was conducted using keywords related to male infertility and genetics. The search included articles with English abstracts appearing online after 2000.


Mutations in 31 distinct genes have been identified as a cause of non-syndromic human male infertility, and the number is increasing constantly. Screening gene panels by high-throughput sequencing can be offered to patients in order to identify genes involved in various forms of human non-syndromic infertility. We propose a workflow for genetic tests which takes into account semen alterations.


The identification and characterization of the genetic basis of male infertility have broad implications not only for understanding the cause of infertility but also in determining the prognosis, selection of treatment options, and management of couples. Genetic diagnosis is essential for the success of ART techniques and for preserving future fertility as well as the prognosis for testicular sperm extraction (TESE) and adopted therapeutics.


Male infertility Non-syndromic Gene panel Whole exome sequencing Genetics 



We thank Robert Drillien for critical reading of the manuscript.

Funding information

The study was funded by Fondation Maladies Rares (“High-throughput sequencing and rare diseases”) and l’Agence de BioMédecine (“AMP, diagnostic prénatal et diagnostic génétique”).


  1. 1.
    Zegers-Hochschild F, Adamson GD, de Mouzon J, Ishihara O, Mansour R, Nygren K, et al. The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) Revised Glossary on ART Terminology. Hum Reprod. 2009;24:2683–7.CrossRefGoogle Scholar
  2. 2.
    Agarwal A, Mulgund A, Hamada A, Chyatte MR. A unique view on male infertility around the globe. Reprod Biol Endocrinol. 2015;13:37.CrossRefGoogle Scholar
  3. 3.
    Dimitriadis F, Adonakis G, Kaponis A, Mamoulakis C, Takenaka A, Sofikitis N. Pre-testicular, testicular, and post-testicular causes of male infertility. In: Simoni M, Huhtaniemi I, editors. Endocrinology of the testis and male reproduction. Endocrinology. Cham: Springer; 2017.Google Scholar
  4. 4.
    Sharma R, Biedenharn KR, Fedor JM, Agarwal A. Lifestyle factors and reproductive health: taking control of your fertility. Reprod Biol Endocrinol. 2013;11:66.CrossRefGoogle Scholar
  5. 5.
    Chianese C, Gunning AC, Giachini C, Daguin F, Balercia G, Ars E, et al. X chromosome-linked CNVs in male infertility: discovery of overall duplication load and recurrent, patient-specific gains with potential clinical relevance. PLoS One. 2014;9:e97746.CrossRefGoogle Scholar
  6. 6.
    Krausz C. Male infertility: pathogenesis and clinical diagnosis. Best Pract Res Clin Endocrinol Metab. 2011;25:271–85.CrossRefGoogle Scholar
  7. 7.
    Tiepolo L, Zuffardi O. Localization of factors controlling spermatogenesis in the nonfluorescent portion of the human Y chromosome long arm. Hum Genet. 1976;34:119–24.CrossRefGoogle Scholar
  8. 8.
    Harper J, Geraedts J, Borry P, Cornel MC, Dondorp WJ, Gianaroli L, et al. Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policy. Hum Reprod (Oxf Engl). 2014;29:1603–9.CrossRefGoogle Scholar
  9. 9.
    Harper JC, Aittomäki K, Borry P, Cornel MC, de Wert G, Dondorp W, et al. Recent developments in genetics and medically assisted reproduction: from research to clinical applications. Eur J Hum Genet. 2018;26:12–33.CrossRefGoogle Scholar
  10. 10.
    World Health Organization. WHO laboratory manual for the examination and processing of human semen. 5th ed. Geneva: World Health Organization; 2010. Google Scholar
  11. 11.
    Schultz N, Hamra FK, Garbers DL. A multitude of genes expressed solely in meiotic or postmeiotic spermatogenic cells offers a myriad of contraceptive targets. PNAS. 2003;100(21):12201–6.CrossRefGoogle Scholar
  12. 12.
    Bobadilla JL, Macek M, Fine JP, Farrell PM. Cystic fibrosis: a worldwide analysis of CFTR mutations correlation with incidence data and application to screening. Hum Mutat. 2002;19:575–606.CrossRefGoogle Scholar
  13. 13.
    Thauvin-Robinet C, Munck A, Huet F, Becdelièvre A, de Jimenez C, Lalau G, et al. CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders. J Med Genet. 2013;50:220–7.CrossRefGoogle Scholar
  14. 14.
    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.CrossRefGoogle Scholar
  15. 15.
    Mierla D, Jardan D, Stoian V. Chromosomal abnormality in men with impaired spermatogenesis. Int J Fertil Steril. 2014;8:35–42.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Ravel C, Berthaut I, Bresson JL, Siffroi JP, Genetics Commission of the French Federation of CECOS. Prevalence of chromosomal abnormalities in phenotypically normal and fertile adult males: large-scale survey of over 10,000 sperm donor karyotypes. Hum Reprod. 2006;21:1484–9.CrossRefGoogle Scholar
  17. 17.
    Răchian L, Niculae AS, Tintea I, Pop B, Militaru MS, Bizo A, et al. Association of fragile X syndrome, Robertsonian translocation (13, 22) and autism in a child. Clujul Medical. 2017;90:445–8.CrossRefGoogle Scholar
  18. 18.
    Jeong S, Kim BY, Yu JE. De novo pericentric inversion of chromosome 9 in congenital anomaly. Yonsei Med J. 2010;51:775–80.CrossRefGoogle Scholar
  19. 19.
    Rives N, Joly G, Machy A, Siméon N, Leclerc P, Macé B. Assessment of sex chromosome aneuploidy in sperm nuclei from 47,XXY and 46,XY/47,XXY males: comparison with fertile and infertile males with normal karyotype. Mol Hum Reprod. 2000;6:107–12.CrossRefGoogle Scholar
  20. 20.
    Walsh TJ, Pera RR, Turek PJ. The genetics of male infertility. Semin Reprod Med. 2009;27:124–36.CrossRefGoogle Scholar
  21. 21.
    Plotton I, Brosse A, Cuzin B, Lejeune H. Klinefelter syndrome and TESE-ICSI. Ann Endocrinol. 2014;75:118–25.CrossRefGoogle Scholar
  22. 22.
    Tachdjian G, Frydman N, Morichon-Delvallez N, Le Dû A, Fanchin R, Vekemans M, et al. Reproductive genetic counselling in non-mosaic 47,XXY patients: implications for preimplantation or prenatal diagnosis: case report and review. Hum Reprod. 2003;18(2):271–5.CrossRefGoogle Scholar
  23. 23.
    Greco E, Scarselli F, Minasi MG, Casciani V, Zavaglia D, Dente D, et al. Birth of 16 healthy children after ICSI in cases of nonmosaic Klinefelter syndrome. Hum Reprod. 2013;28:1155–60.CrossRefGoogle Scholar
  24. 24.
    Lele P, Dey M, Ptil D, Sharma R. Genetics and male infertility. WJPR. 2015;4(5):644–55.Google Scholar
  25. 25.
    Ma S, Ho Yuen B, Penaherrera M, Koehn D, Ness L, Robinson W. ICSI and the transmission of X-autosomal translocation: a three-generation evaluation of X; 20 translocation: case report. Hum Reprod. 2003;18:1377–82.CrossRefGoogle Scholar
  26. 26.
    Vozdova M, Oracova E, Kasikova K, Prinosilova P, Rybar R, Horinova V, et al. Balanced chromosomal translocations in men: relationships among semen parameters, chromatin integrity, sperm meiotic segregation and aneuploidy. J Assist Reprod Genet. 2013;30:391–405.CrossRefGoogle Scholar
  27. 27.
    Benet J, Oliver-Bonet M, Cifuentes P, Templado C, Navarro J. Segregation of chromosomes in sperm of reciprocal translocation carriers: a review. Cytogenet Genome Res. 2005;111:281–90.CrossRefGoogle Scholar
  28. 28.
    Morel F, Douet-Guilbert N, Le Bris MJ, Herry A, Amice V, Amice J, et al. Meiotic segregation of translocations during male gametogenesis. Int J Androl. 2004;27:200–12.CrossRefGoogle Scholar
  29. 29.
    Krausz C, Hoefsloot L, Simoni M, Tüttelmann F. EAA/EMQN best practice guidelines for molecular diagnosis of Y-chromosomal microdeletions: state-of-the-art 2013. Andrology. 2014;2:5–19.CrossRefGoogle Scholar
  30. 30.
    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.CrossRefGoogle Scholar
  31. 31.
    Longepied G, Saut N, Aknin-Seifer I, Levy R, Frances AM, Metzler-Guillemain C, et al. Complete deletion of the AZFb interval from the Y chromosome in an oligozoospermic man. Hum Reprod. 2010;25:2655–63.CrossRefGoogle Scholar
  32. 32.
    Kleiman SE, Yogev L, Lehavi O, Hauser R, Botchan A, Paz G, et al. The likelihood of finding mature sperm cells in men with AZFb or AZFb-c deletions: six new cases and a review of the literature (1994–2010). Fertil Steril. 2011;95:2005–12. 2012.e1–4.CrossRefGoogle Scholar
  33. 33.
    Soares AR, Costa P, Silva J, Sousa M, Barros A, Fernandes S. AZFb microdeletions and oligozoospermia–which mechanisms? Fertil Steril. 2012;97:858–63.CrossRefGoogle Scholar
  34. 34.
    Krausz C, Quintana-Murci L, McElreavey K. Prognostic value of Y deletion analysisWhat is the clinical prognostic value of Y chromosome microdeletion analysis? Hum Reprod. 2000;15:1431–4.CrossRefGoogle Scholar
  35. 35.
    Yang F, Silber S, Leu NA, Oates RD, Marszalek JD, Skaletsky H, 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.CrossRefGoogle Scholar
  36. 36.
    Yatsenko AN, Georgiadis AP, Röpke A, Berman AJ, Jaffe T, Olszewska M, et al. X-linked TEX11 mutations, meiotic arrest, and azoospermia in infertile men. N Engl J Med. 2015;372(22):2097–107.CrossRefGoogle Scholar
  37. 37.
    Karampetsou E, Morrogh D, Chitty L. Microarray technology for the diagnosis of fetal chromosomal aberrations: which platform should we use? J Clin Med. 2014;3:663–78.CrossRefGoogle Scholar
  38. 38.
    Majewski J, Schwartzentruber J, Lalonde E, Montpetit A, Jabado N. What can exome sequencing do for you? J Med Genet. 2011;48:580–9.CrossRefGoogle Scholar
  39. 39.
    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;39:661–5.CrossRefGoogle Scholar
  40. 40.
    Elinati E, Kuentz P, Redin C, Jaber S, Vanden Meerschaut F, Makarian J, et al. Globozoospermia is mainly due to DPY19L2 deletion via non-allelic homologous recombination involving two recombination hotspots. Hum Mol Genet. 2012;21:3695–702.CrossRefGoogle Scholar
  41. 41.
    Ghédir H, Ibala-Romdhane S, Okutman O, Viot G, Saad A, Viville S. Identification of a new DPY19L2 mutation and a better definition of DPY19L2 deletion breakpoints leading to globozoospermia. Mol Hum Reprod. 2016;22:35–45.CrossRefGoogle Scholar
  42. 42.
    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;88:344–50.CrossRefGoogle Scholar
  43. 43.
    Mou L, Xie N, Yang L, Liu Y, Diao R, Cai Z, et al. A novel mutation of DAX-1 associated with secretory azoospermia. PLoS One. 2015;10:e0133997.CrossRefGoogle Scholar
  44. 44.
    Okutman O, Muller J, Baert Y, Serdarogullari M, Gultomruk M, Piton A, et al. Exome sequencing reveals a nonsense mutation in TEX15 causing spermatogenic failure in a Turkish family. Hum Mol Genet. 2015;24:5581–8.CrossRefGoogle Scholar
  45. 45.
    Okutman O, Muller J, Skory V, Garnier JM, Gaucherot A, Baert Y, et al. A no-stop mutation in MAGEB4 is a possible cause of rare X-linked azoospermia and oligozoospermia in a consanguineous Turkish family. J Assist Reprod Genet. 2017:1–12.Google Scholar
  46. 46.
    Ayhan Ö, Balkan M, Guven A, Hazan R, Atar M, Tok A, et al. Truncating mutations in TAF4B and ZMYND15 causing recessive azoospermia. J Med Genet. 2014;51:239–44.CrossRefGoogle Scholar
  47. 47.
    Mou L, Wang Y, Li H, Huang Y, Jiang T, Huang W, et al. A dominant-negative mutation of HSF2 associated with idiopathic azoospermia. Hum Genet. 2013;132:159–65.CrossRefGoogle Scholar
  48. 48.
    Yatseenko AN, Roy A, Chen R, Ma L, Murthy LJ, Yan W, et al. Non-invasive genetic diagnosis of male infertility using spermatozoal RNA: KLHL10 mutations in oligozoospermic patients impair homodimerization. Hum Mol Genet. 2006;15:3411–9.CrossRefGoogle Scholar
  49. 49.
    Gershoni M, Hauser R, Yogev L, Lehavi O, Azem F, Yavetz H, et al. A familial study of azoospermic men identifies three novel causative mutations in three new human azoospermia genes. Genet Med. 2017;19:998–1006.CrossRefGoogle Scholar
  50. 50.
    Gou LT, Kang JY, Dai P, Wang X, Li F, Zhao S, et al. Ubiquitination-deficient mutations in human piwi cause male infertility by impairing histone-to-protamine exchange during spermiogenesis. Cell. 2017;169:1090–1104.e13.CrossRefGoogle Scholar
  51. 51.
    Kherraf ZE, Christou-Kent M, Karaouzene T, Amiri-Yekta A, Martinez G, Vargas AS, et al. SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes. EMBO Mol Med. 2017;9(8):1132–49.CrossRefGoogle Scholar
  52. 52.
    Choi Y, Jeon S, Choi M, Lee M, Park M, Lee DR, et al. Mutations in SOHLH1 gene associate with nonobstructive azoospermia. Hum Mutat. 2010;31:788–93.CrossRefGoogle Scholar
  53. 53.
    Ramasamy R, Bakırcıoğlu ME, Cengiz C, Karaca E, Scovell J, Jhangiani SN, et al. Whole-exome sequencing identifies novel homozygous mutation in NPAS2 in family with nonobstructive azoospermia. Fertil Steril. 2015;104:286–91.CrossRefGoogle Scholar
  54. 54.
    Arafat M, Har-Vardi I, Harlev A, Levitas E, Zeadna A, Abofoul-Azab M, et al. Mutation in TDRD9 causes non-obstructive azoospermia in infertile men. J Med Genet. 2017;54:633–9.CrossRefGoogle Scholar
  55. 55.
    Kusz-Zamelczyk K, Sajek M, Spik A, Glazar R, Jędrzejczak P, Latos-Bieleńska A, et al. Mutations of NANOS1, a human homologue of the Drosophila morphogen, are associated with a lack of germ cells in testes or severe oligo-astheno-teratozoospermia. J Med Genet. 2013;50:187–93.CrossRefGoogle Scholar
  56. 56.
    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.CrossRefGoogle Scholar
  57. 57.
    Karki R, Pandya D, Elston RC, Ferlini C. Defining “mutation” and “polymorphism” in the era of personal genomics. BMC Med Genet. 2015;8.Google Scholar
  58. 58.
    Dam AH, Koscinski I, Kremer JA, Moutou C, Jaeger AS, Oudakker AR, et al. Homozygous mutation in SPATA16 is associated with male infertility in human globozoospermia. AJHG. 2007;81:813–20.CrossRefGoogle Scholar
  59. 59.
    Ben Khelifa M, Coutton C, Zouari R, Karaouzène T, Rendu J, Bidart M, et al. Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella. Am J Hum Genet. 2014;94:95–104.CrossRefGoogle Scholar
  60. 60.
    Kuo PL, Chiang HS, Wang YY, Kuo YC, Chen MF, Yu IS, et al. SEPT12-microtubule complexes are required for sperm head and tail formation. Int J Mol Sci. 2013;14:22102–16.CrossRefGoogle Scholar
  61. 61.
    Tang S, Wang X, Li W, Yang X, Li Z, Liu W, et al. Biallelic mutations in CFAP43 and CFAP44 cause male infertility with multiple morphological abnormalities of the sperm flagella. Am J Hum Genet. 2017;100:854–64.CrossRefGoogle Scholar
  62. 62.
    Li L, Sha Y, Wang X, Li P, Wang J, Kee K, et al. Whole-exome sequencing identified a homozygous BRDT mutation in a patient with acephalic spermatozoa. Oncotarget. 2017;8:19914–22.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Zhu F, Wang F, Yang X, Zhang J, Wu H, Zhang Z, et al. Biallelic SUN5 mutations cause autosomal-recessive acephalic spermatozoa syndrome. Am J Hum Genet. 2016;99:942–9.CrossRefGoogle Scholar
  64. 64.
    Avenarius MR, Hildebrand MS, Zhang Y, Meyer NC, Smith LL, Kahrizi K, et al. Human male infertility caused by mutations in the CATSPER1 channel protein. Am J Hum Genet. 2009;84:505–10.CrossRefGoogle Scholar
  65. 65.
    Takasaki N, Tachibana K, Ogasawara S, Matsuzaki H, Hagiuda J, Ishikawa H, et al. A heterozygous mutation of GALNTL5 affects male infertility with impairment of sperm motility. Proc Natl Acad Sci U S A. 2014;111:1120–5.CrossRefGoogle Scholar
  66. 66.
    Dirami T, Rode B, Jollivet M, Da Silva N, Escalier D, Gaitch N, et al. Missense mutations in SLC26A8, encoding a sperm-specific activator of CFTR, are associated with human asthenozoospermia. Am J Hum Genet. 2013;92:760–6.CrossRefGoogle Scholar
  67. 67.
    Xu X, Sha YW, Mei LB, Ji ZY, Qiu PP, Ji H, et al. A familial study of twins with severe asthenozoospermia identified a homozygous SPAG17 mutation by whole-exome sequencing. Clin Genet. 2017;93:345–9. Scholar
  68. 68.
    Escoffier J, Lee HC, Yassine S, Zouari R, Martinez G, Karaouzène T, et al. Homozygous mutation of PLCZ1 leads to defective human oocyte activation and infertility that is not rescued by the WW-binding protein PAWP. Hum Mol Genet. 2016;25:878–91.CrossRefGoogle Scholar
  69. 69.
    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 (Oxf Engl). 2012;27:25–35.CrossRefGoogle Scholar
  70. 70.
    Ray PF, Toure A, Metzler-Guillemain C, Mitchell MJ, Arnoult C, Coutton C. Genetic abnormalities leading to qualitative defects of sperm morphology or function. Clin Genet. 2017;91:217–32.CrossRefGoogle Scholar
  71. 71.
    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 (Oxf Engl). 2012;27:3337–46.CrossRefGoogle Scholar
  72. 72.
    ElInati E, Fossard C, Okutman O, Ghédir H, Ibala-Romdhane S, Ray PF, et al. A new mutation identified in SPATA16 in two globozoospermic patients. J Assist Reprod Genet. 2016;33:815–20.CrossRefGoogle Scholar
  73. 73.
    Kuentz P, Vanden Meerschaut F, Elinati E, Nasr-Esfahani MH, Gurgan T, Iqbal N, et al. Assisted oocyte activation overcomes fertilization failure in globozoospermic patients regardless of the DPY19L2 status. Hum Reprod (Oxf Engl). 2013;28:1054–61.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institut de Parasitologie et Pathologie Tropicale, EA 7292, Fédération de Médecine Translationelle (IPPTS)Université de StrasbourgStrasbourgFrance
  2. 2.Laboratoire de Diagnostic Génétique, UF3472-génétique de l’infertilitéHôpitaux Universitaires de StrasbourgStrasbourgFrance
  3. 3.Médecine de la Reproduction et Cytogénétique Médicale CHU et Faculté de MédecineUniversité de Picardie Jules VerneAmiensFrance
  4. 4.Laboratoire de Diagnostic GénétiqueHôpitaux Universitaires de StrasbourgStrasbourgFrance
  5. 5.Laboratoire de Génétique Médicale, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS)Université de StrasbourgStrasbourgFrance

Personalised recommendations