Genetic Disorders of Human Infertility


Diagnostic identification of human genetic disorders causing male or female infertility is of paramount interest in each infertility clinic dealing with the term ‘idiopathic infertility’, which means ‘no reason found for observed infertility pathology’. In such cases, if there is a genetic disorder behind (in about 30%), there is usually a high risk of transfer of this genetic lesion to the offspring by the applied fertilisation protocol. Such genetic‐based infertility disorders can be unbalanced chromosome aberrations including aneuploidies and/or specific gene mutations, respectively. As comparative genomic hybridisation (CGH) and next‐generation sequencing (NGS) tools have now shown that the normal human genome can have a highly variable sequence composition, thus also in men and women with normal fertility, it has become a major challenge for the clinicians to then identify only those genome/gene mutations which may indeed cause the observed infertility pathology.

Key Concepts

  • Genetic disorders can cause about 30% male and female infertility.
  • Analysis of chromosome aberrations (aneuploidies) is mandatory before ART application in ‘idiopathic’ male and female infertility.
  • Artificial insemination protocols such as ICSI can increase genetic disorders causing infertility in offspring.
  • Genes causing male or female infertility can have pleiotropic somatic genetic disorders such as cystic fibrosis.
  • Genes on the Y chromosome causing male infertility (AZF genes) are inherited by ICSI to male offsprings with 100%.

Keywords: idiopathic male and female sterility; chromosome aberrations and aneuploidies; CFTR and CBAVD; azoospermia factors on Y chromosome; POI/POF syndrome; DSD females with 46,XY and tumour risk; CAIS and PAIS; mitochondrial lesions and infertility

Figure 1. Multiple genetic loci for the maintenance and progression of human folliculogenesis are located on the X chromosome. According to the OMIM database they are summarised under POF1 (OMIM: #311360) with FMR1 as the most prominent POF candidate gene (because most frequently mutated), POF2 (OMIM: #300511 and #300604) and POF4 (OMIM: #300247). Associated POF candidate genes, that is genes known to be expressed during human folliculogenesis, of which some were already found with mutations in women with POI/POF syndrome, are listed at the right. For further description see the text.
Figure 2. Schematic view of the CFTR exon structure with polymorphic (T)n tract at the intron 8 acceptor splice site (n = 5–9). In men with CBAVD, there is an increased frequency of the 5T variant causing most often (<90%) skipping of CFTR exon 9, which results in translation of the nonfunctional CFTR protein.
Figure 3. Schematic view of AZF gene content on the long arm of the human Y chromosome in Yq11. The pink coloured blocks mark the X–Y homologous sequence blocks. It includes also the AZFa deletion interval. Homologous blocks in the ampliconic repetitive sequence structure in distal Yq11 encompassing AZFb and AZFc deletion intervals are marked by the same colour code as designated by Kuroda‐Kawaguchi et al. . The 19 protein encoding Y genes mapped in Yq11 and expressed in the male germ line are distinguished by specific colours and represented by arrows with the corresponding 5′–3′ polarity (modified from Vogt et al., ).


Aittomaki K, Lucena JL, Pakarinen P, et al. (1995) Mutation in the follicle‐stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 82: 959–968.

Beau I, Touraine P, Meduri G, et al. (1998) A novel phenotype related to partial loss of function mutations of the follicle stimulating hormone receptor. Journal of Clinical Investigation 102: 1352–1359.

Bilgin EM and Kovanci E (2015) Genetics of premature ovarian failure. Current Opinion in Obstetrics and Gynecology 27: 167–174.

Bione S, Sala C, Manzini C, et al. (1998) A human homologue of the Drosophila melanogaster diaphanous gene is disrupted in a patient with premature ovarian failure: evidence for conserved function in oogenesis and implications for human sterility. American Journal of Human Genetics 62: 533–541.

Bunyan DJ, Callaway LA and Laddal N (2012) Detection of partial deletions of Y‐chromosome AZFc in infertile men using the multiplex ligation‐dependent probe amplification assay. Journal of Reproduction & Infertility 13: 174–178.

Conway GS, Payne NN, Webb J, Murray A and Jacobs PA (1998) Fragile X premutation screening in women with premature ovarian failure. Human Reproduction 13: 1184–1187.

Cooper AR, Baker VL, Sterlin EW, et al. (2011) The time is now for a new approach to primary ovarian insufficiency. Fertility and Sterility 95: 1890–1897.

Corona G, Pizzocaro A, Lanfranco F, et al. (2017) Sperm recovery and ICSI outcomes in Klinefelter syndrome: a systematic review and meta‐analysis. Human Reproduction Update 23: 265–275.

Davison RM, Fox M and Conway GS (2000) Mapping of the POF1 locus and identification of putative genes for premature ovarian failure. Molecular Human Reproduction 6: 314–318.

Demain L, Conway GS and Newman WG (2017) Genetics of mitochondrial dysfunction and infertility. Clinical Genetics 91: 199–207.

Eggers S, Sadedin S, van den Bergen JA, et al. (2016) Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort. Genome Biology 17: 243. DOI: 10.1186/s13059-016-1105-y.

Elzaiat M, Todeschini AL, Caburet S, et al. (2017) The genetic make‐up of ovarian development and function: the focus on the transcription factor FOXL2. Clinical Genetics 91: 173–182.

Estivill X (1996) Complexity in a monogenic disease. Nature Genetics 12: 348–350.

Faraut T, Mermet M‐A, Demongeot J and Cohen O (2000) Cooperation of selection and meiotic mechanisms in the production of imbalances in reciprocal translocations. Cytogenetics and Cell Genetics 88: 15–21.

Fassnacht W, Mempel A, Strowitzki T and Vogt PH (2006) Premature Ovarian Failure (POF) Syndrome: towards the molecular clinical analysis of its genetic complexity. Current Medicinal Chemistry 13: 1397–1410.

Finkelstein S, Mukamel E, Yavetz H, Paz G and Avivi L (1998) Increased rate of nondisjunction in sex cells derived from low‐quality semen. Human Genetics 102: 129–137.

Gleicher N, Weghofer A and Barad DH (2008) A pilot study of premature ovarian senescence: I. Correlation of triple CGG repeats on the FMR1 gene to ovarian reserve parameters FSH and anti‐Müllerian hormone. Fertility and Sterility 91: 1700–1706.

Gleicher N and Barad DH (2010) The FMR1 gene as regulator of ovarian recruitment and ovarian reserve. Obstetrics & Gynecology Survey 9: 523–530.

Gleicher N, Kushnir VA, Weghofer A and Barad DH (2014) How the FMR1 gene became relevant to female fertility and reproductive medicine. Frontiers in Genetics 5: 284. DOI: 10.3389/fgene.2014.00284.

Gonzalez‐Merino MS, Abramowicz HC, Englert Y and Emiliani S (2007) Aneuploidy study in sperm and preimplantation embryos from nonmosaic 47,XYY men. Fertility and Sterility 88: 600–606.

Goswami D and Conway G (2005) Premature ovarian failure. Human Reproduction Update 4: 391–410.

Guo Y, Sun J and Lai D (2017) Role of microRNAs in premature ovarian insufficiency. Reproductive Biology and Endocrinology 15: 38. DOI: 10.1186/s12958-0170256-3.

Hassold T, Sherman S and Hunt P (2000) Counting cross‐overs: characterizing meiotic recombination in mammals. Human Molecular Genetics 9: 2409–2419.

Hermus R, van Bever Y, Wolffenbuttel KP, et al. (2017) The biology of germ cell tumors in disorders of sex development. Clinical Genetics 91: 292–301.

Hughes IA, Houk C, Ahmed SF, Lee PA and Lawson Wilkins Pediatric Endocrine Society/European Society for Paediatric Endocrinology Consensus Group (2006) Consensus statement on management of intersex disorders. Journal of Pediatric Urology 2: 148–162.

Kao SH, Chao HT and Wei YH (1995) Mitochondrialdeoxyribonuclei acid 4,977‐bp deletion is associated with diminished fertility and motility of human sperm. Biology of Reproduction 52: 729–736.

Keymolen K, van Berkel K, Vorsselmans A, Staessen C and Liebaers I (2011) Pregnancy outcome in carriers of Robertsonian translocations. American Journal of Medical Genetics 155: 2381–2385.

Kohn TP, Clavijo R, Ramasamy R, et al. (2015) Reproductive outcomes in men with karyotype abnormalities: case report and review of literature. Canadian Urology Association Journal 9: E667–E670.

Krausz C, Hoefsloot L, Simoni M and Tüttelmann F (2014) EAA/EMQN best practice guidelines for molecular diagnosis of Y chromosomal microdeletions: state of the art 2013. Andrology 2: 5–19.

Kuroda‐Kawaguchi T, Skaletsky H, Brown LG, et al. (2001) The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men. Nature Genetics 29: 279–286.

Layman LC, Lee EJ, Peak DB, et al. (1997) Delayed puberty and hypogonadism caused by mutations in the follicle‐stimulating hormone beta‐subunit gene. New England Journal of Medicine 337: 607–611.

Mallepaly R, Butler P, Herati AS and Lamb DJ (2017) Genetic basis of male and female infertility. In: Vogt PH, Basel S and Karger AG (eds.) Genetics of Human Infertility, Monographs in Human Genetics, vol. 21, pp. 57–73. Basel: Karger.

Martin RH (2008) Cytogenetic determinants of male fertility. Human Reproduction Update 14: 379–390.

Matthews CH, Borgato S, Beck‐Peccoz P, et al. (1993) Primary amenorrhoea and infertility due to a mutation in the beta‐subunit of follicle‐stimulating hormone. Nature Genetics 5: 83–86.

Modi DN, Sane S and Bhartiya D (2003) Accelerated germ cell apoptosis in sex chromosome aneuploidfetal human gonads. Molecular Human Reproduction 9: 219–225.

Morita Y and Tilly JL (1999) Oocyte apoptosis: like sand through an hourglass. Developmental Biology 213: 1–17.

Mroz K, Carrel L and Hunt P (1999) Germ cell development in the XXY mouse: evidence that X chromosome reactivation is independent of sexual differentiation. Developmental Biology 207: 229–238.

Nelson LM, Anasti JN and Kimzey LM (1994) Development of luteinized graafian follicles in patients with karyotypically normal spontaneous premature ovarian failure. Journal of Clinical Endocrinology & Metabolism 79: 1470–1475.

Nudell D, Castillo M, Turek P and Reijo‐Pera R (2000) Increased frequency of mutations in DNA from infertile men with meiotic arrest. Human Reproduction 15: 1289–1294.

Pieters MH, Geraedts JP, Meyer H, et al. (1990) Human games and zygotes studied by nonradioactive in situ hybridization. Cytogenetics and Cell Genetics 53: 15–19.

Prueitt RL, Ross JL and Zinn AR (2000) Physical mapping of nine Xq translocation breakpoints and identification of XPNPEP2 as a premature ovarian failure gene. Cytogenetics and Cell Genetics 89: 44–50.

Qin Y, Jiao X, Simpson JL, et al. (2015) Genetics of primary ovarian insufficiency: new developments and opportunities. Human Reproduction Update 21: 287–808.

Qin Y, Simpson JL and Chen Z‐J (2017) Genetics of premature ovarian failure: new developments in etiology. In: Vogt PH, Basel S and Karger AG (eds.) Genetics of Human Infertility, Monographs in Human Genetics, vol. 21, pp. 17–39. Basel: Karger.

Rao L, Babu A, Padmalatha V, et al. (2005) Novel X‐chromosomal defect associated with abnormal ovarian function. Journal of Obstetrics & Gynecology Research 1: 12–15.

Rizzolio F, Bione S, Sala C, et al. (2006) Chromosomal rearrangements in Xq and premature ovarian failure: mapping of 25 new cases and review of the literature. Human Reproduction 21: 1477–1483.

Ruiz‐Pesini E, Lapena A, Diez‐Sanchez C, et al. (2000) Human mitochondrial DNA haplogroups associated with high or reduced spermatozoa motility. American Journal of Human Genetics 67: 682–696.

Sciurano RB, Luna Hisano CV, Rahn MI, et al. (2009) Focal spermatogenesis originates in euploid germ cells in classical Klinefelter patients. Human Reproduction 24: 2352–2360.

Simpson JL and Rajkovic A (1999) Ovarian differentiation and gonadal failure. American Journal of Medical Genetics 89: 186–200.

Stenchever MA, Macintyre MN, Jarvis JA and Hempel JM (1969) Cytogenetic studies of 32 infertile couples. Obstetrics and Gynecology 33: 380–382.

Tempest HG (2011) Meiotic recombination errors, the origin of sperm aneuploidy and clinical recommendations. Systems Biology in Reproductive Medicine 57: 93–101.

Toniolo D and Rizzolio F (2006) X chromosome and ovarian failure. Current Opinion in Genetics & Development 16: 293–300.

Toure A (2017) Genetics and pathophysiology of the cystic fibrosis transmembrane conductance regulator in male reproduction: new evidence of a direct effect on the male germline. In: Vogt PH, Basel S and Karger AG (eds.) Genetics of Human Infertility, Monographs in Human Genetics, vol. 21, pp. 74–85. Basel: Karger.

Trofimova T, Lizneva D, Suturina L, et al. (2017) Genetic basis of eugonadal and hypogonadal female reproductive disorders. Best Practice & Research. Clinical Obstetrics & Gynaecology. 10.1016/j.bpobgyn.2017.05.003.

Tyler‐Smith C and Krausz C (2009) The will‐o'‐the‐wisp of genetics – hunting for the azoospermia factor gene. New England Journal of Medicine 360: 925–992.

Van Assche E, Bonduelle M, Tournaye H, et al. (1996) Cytogenetics of infertile men. Human Reproduction 11: 1–24.

Verlinsky Y and Evsikov S (1999) Karyotyping of human oocytes by chromosomal analysis of the second polar bodies. Molecular Human Reproduction 5: 89–95.

Vogt PH, Edelmann A, Hirschmann P and Köhler MR (1995) Theazoospermia factor (AZF) of the human Y chromosome in Yq11: function and analysis in spermatogenesis. Reproduction, Fertility, and Development 7: 685–693.

Vogt PH, Edelmann A, Kirsch S, et al. (1996) Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Human Molecular Genetics 5: 933–943.

Vogt PH (2005) Azoospermia factor (AZF) in Yq11: towards a molecular understanding of its function for human male fertility and spermatogenesis. Reproductive BioMedicine Online 10: 81–93.

Vogt PH, Falcao CL, Hanstein R and Zimmer J (2008) The AZF proteins. Journal of andrology 31: 383–394.

Vogt PH and Bender U (2013) Human Y chromosome microdeletion analysis by PCR multiplex protocols identifying only clinically relevant AZF microdeletions. Methods in Molecular Biology 927: 187–204.

Vogt PH, Bender U, Zimmer J and Strowitzki T (2017) Human Y chromosome and male infertility: forward and back from azoospermia factor chromatin structure to Azoospermia Factor gene function. In: Vogt PH, Basel S and Karger AG (eds.) Genetics of Human Infertility, Monographs in Human Genetics, vol. 21, pp. 57–73. Basel: Karger.

Welt CK (2008) Primary ovarian insufficiency: a more accurate term for premature ovarian failure. Clinical Endocrinology 68: 499–509.

Yatsenko AN, Yatsenko SA, Weedin JW, et al. (2010) Comprehensive 5‐year study of cytogenetic aberrations in 668 infertile men. Journal of Urology 183: 1636–1642.

Yu J, Chen Z, Ni Y, et al. (2012) CFTR mutations in men with congenital bilateral absence of the vas deferens (CBAVD): a systemic review and meta‐analysis. Human Reproduction Update 27: 25–35.

Zühlke C, This U, Braulke I, et al. (1994) Down syndrome and male fertility: PCR‐derived fingerprinting, serological and andrological investigations. Clinical Genetics 46: 324–326.

Further Reading

Chen H, Ruan YC, Xu WM, Chen J and Chan HC (2012) Regulation of male fertility by CFTR and implications in male infertility. Human Reproduction Update 18: 703–713.

Craig JR, Jenkins TG, Carrell DT and Hotaling JM (2017) Obesity, male infertility, and the sperm epigenome. Fertilty and Sterility 107: 848–859.

Das L, Parbin S, Pradhan N, Kausar C and Patra SK (2017) Epigenetics of reproductive infertility. Frontiers in Bioscience (Scholar Edition) 9: 509–535.

Gleicher N, Kushnir VA and Barad DH (2014) How the FMR1 gene became relevant to female fertility and reproductive medicine. Frontiers in Genetics 29 (5): 284. DOI: 10.3389/fgene.2014.00284.

Guo Y, Junyan S and Lai D (2017) Role of microRNAs in premature ovarian insufficiency. Reproductive Biology and Endocrinology 15: 38. DOI: 10.1186/s12958-017-0256-3.

Komsky‐Elbaz A, Raziel A, Ben‐Ami I, et al. (2015) Ploidy of spermatogenic cells of men with non‐mosaic Klinefelter's syndrome as measured by a computerized cell scanning system. Journal of Assisted Reproduction and Genetics 32: 1113–1121.

Krausz C and Casamonti E (2017) Spermatogenic failure and the Y chromosome. Human Genetics 136: 637–655.

Shamsi MB, Simon L and Carrell DT (2017) The Epigenetics of Sperm Chromatin. In: Vogt PH, Basel S and Karger AG (eds.) Genetics of Human Infertility, Monographs in Human Genetics, vol. 21, pp. 116–127. Basel: Karger.

Sinha A, Singh V and Yadav S (2017) Multi‐omics and male infertility: status, integration and future prospects. Frontiers in Bioscience (Scholar Edition) 9: 375–394.

Vogt PH (2017) Genetics of Human Infertility. In: Vogt PH, Basel S and Karger AG (eds.) Monographs in Human Genetics, vol. 21.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Vogt, Peter H(Dec 2017) Genetic Disorders of Human Infertility. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005520.pub2]