Top

Journal of Assisted Reproduction and Genetics

Published in:

01-11-2018 | Review

Genetic evaluation of patients with non-syndromic male infertility

Authors: Ozlem Okutman, Maroua Ben Rhouma, Moncef Benkhalifa, Jean Muller, Stéphane Viville

Published in: Journal of Assisted Reproduction and Genetics | Issue 11/2018

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

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.CrossRef

Agarwal A, Mulgund A, Hamada A, Chyatte MR. A unique view on male infertility around the globe. Reprod Biol Endocrinol. 2015;13:37.CrossRef

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.

Sharma R, Biedenharn KR, Fedor JM, Agarwal A. Lifestyle factors and reproductive health: taking control of your fertility. Reprod Biol Endocrinol. 2013;11:66.CrossRef

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.CrossRef

Krausz C. Male infertility: pathogenesis and clinical diagnosis. Best Pract Res Clin Endocrinol Metab. 2011;25:271–85.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

10.

World Health Organization. WHO laboratory manual for the examination and processing of human semen. 5th ed. Geneva: World Health Organization; 2010. http://www.who.int/iris/handle/10665/44261

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

15.

Mierla D, Jardan D, Stoian V. Chromosomal abnormality in men with impaired spermatogenesis. Int J Fertil Steril. 2014;8:35–42.PubMedPubMedCentral

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.CrossRef

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.CrossRef

18.

Jeong S, Kim BY, Yu JE. De novo pericentric inversion of chromosome 9 in congenital anomaly. Yonsei Med J. 2010;51:775–80.CrossRef

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.CrossRef

20.

Walsh TJ, Pera RR, Turek PJ. The genetics of male infertility. Semin Reprod Med. 2009;27:124–36.CrossRef

21.

Plotton I, Brosse A, Cuzin B, Lejeune H. Klinefelter syndrome and TESE-ICSI. Ann Endocrinol. 2014;75:118–25.CrossRef

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.CrossRef

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.CrossRef

24.

Lele P, Dey M, Ptil D, Sharma R. Genetics and male infertility. WJPR. 2015;4(5):644–55.

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

57.

Karki R, Pandya D, Elston RC, Ferlini C. Defining “mutation” and “polymorphism” in the era of personal genomics. BMC Med Genet. 2015;8.

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.PubMedPubMedCentral

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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. https://doi.org/10.1111/cge.13059.CrossRefPubMed

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.CrossRef

Title: Genetic evaluation of patients with non-syndromic male infertility
Authors: Ozlem Okutman
Maroua Ben Rhouma
Moncef Benkhalifa
Jean Muller
Stéphane Viville
Publication date: 01-11-2018
Publisher: Springer US
Published in: Journal of Assisted Reproduction and Genetics / Issue 11/2018
Print ISSN: 1058-0468
Electronic ISSN: 1573-7330
DOI: https://doi.org/10.1007/s10815-018-1301-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Genetic evaluation of patients with non-syndromic male infertility

Abstract

Purpose

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 11/2018

Comparison of perinatal outcomes following frozen embryo transfer cycles using autologous versus donor oocytes in women 40 to 43 years old: analysis of SART CORS data

Perinatal follow-up of children born after preimplantation genetic diagnosis between 1995 and 2014

Preimplantation genetic diagnosis versus prenatal diagnosis—decision-making among pregnant FMR1 premutation carriers

Oocyte retrieval after heterotopic transplantation of ovarian tissue cryopreserved by closed vitrification protocol

Response from the authors re: Letter to the Editor for our manuscript “The cost of a euploid embryo identified from preimplantation genetic testing for aneuploidy (PGT-A): a counseling tool”

Chromosome positioning and male infertility: it comes with the territory