Infertility: Genetic Disorders


Identification of genetic disorders causing human male or female infertility is of paramount importance in each infertility clinic that has to consider the possible risk of transfer of a specified genetic abnormality (i.e. a distinct chromosomal aberration and/or a specific gene mutation) to the offspring created by the applied artificial fertilization protocol. This is useful especially for those men and women where no obstructions of the germ line can be observed and who are therefore diagnosed in the clinic as having idiopathic infertility.

Keywords: idiopathic sterility; chromosome aberrations; azoospermia factors; CBAVD; primary amenorrhea; POF syndrome

Figure 1.

X‐chromosome G banding pattern. Multiple genetic loci for the maintenance of folliculogenesis are located on the human X chromosome. Deletions in the primary amenorrhea (PRIMAM) locus in Xp21.1–22.2 cause primary ovarian failure (POF), before puberty. Deletions in POF1 locus (Xq26.1–28) and POF2 (Xq13.3–21.1) cause premature ovarian failure during the reproductive cycle of the female, that is, after puberty. Putative POF candidate genes are listed at the right. See text for further descriptions.

Figure 2.

Increased frequency of 5T variant in the splice acceptor site of CFTR intron 8 in men with congenital bilateral absence of the vas deferens (CBAVD). Reduction of the T nucleotides to five causes most often skipping of CFTR exon 9, which results in the translation of nonfunctional CFTR protein (<90%).



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.

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

Fernandes S, Huellen K, Goncalves J, et al. (2002) High frequency of DAZ1/DAZ2 gene deletions in patients with severe oligozoospermia. Molecular Human Reproduction 8: 286–298.

Gabriel‐Robez O and Rumpler Y (1996) The meiotic pairing behaviour in human spermatocytes carrier of chromosome anomalies and their repercussions on reproductive fitness. II. Robertsonian and reciprocal translocations. A European collaborative study. Journal Annual Genetics 39: 17–25.

Gottlieb B, Pinskky L, Beitel LK and Trifiro M (1999) Androgen insensitivity. American Journal of Medical Genetics 89: 210–217.

Greenhouse S, Rankin T and Dean J (1998) Genetic causes of female infertility: targeted mutagenesis in mice. American Journal of Human Genetics 62: 1282–1287.

Kamp C, Hirschmann P, Voss H, Huellen K and Vogt PH (2000) Two long homologous retroviral sequence blocks in proximal Yq11 cause AZFa microdeletions as a result of intrachromosomal recombination events. Human Molecular Genetics 9: 2563–2572.

Kao SH, Chao HT and Wei YH (1998) Multiple deletions of mitochondrial DNA are associated with the decline of motility and fertility of human spermatozoa. Molecular Human Reproduction 4: 657–666.

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.

Lewis‐Jones I, Seshadri S, Douglas A and Howard P (2003) Sperm chromosomal abnormalities are linked to sperm morphologic deformities. Fertility and Sterility 79: 212–215.

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

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.

Ong YC, Kolatkar PR and Yong EL (2002) Androgen receptor mutations causing human androgen insensitivity syndromes show a key role of residue M807 in helix 8–helix 10 interactions and in receptor ligand‐binding domain stability. Molecular Human Reproduction 8: 101–108.

Pellestor F (1991) Frequency and distribution of aneuploidy in human female gametes. Human Genetics 86: 283–288.

Pfeffer J, Pang M‐G, Hoegerman SF, et al. (1999) Aneuploidy frequencies in semen fractions from ten oligoasthenoteratozoospermic patients donating sperm for intracytoplasmatic sperm injection. Fertility and Sterility 72: 472–478.

Repping S, Skaletsky H, Lange J, et al. (2002) Recombination between palindromes P5 and P1 on the human Y chromosome causes massive deletions and spermatogenic failure. American Journal of Human Genetics 71: 906–922.

Rovio AT, Marchington DR, Donat S, et al. (2001) Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility. Nature Genetics 29: 261–262.

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.

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

Sun C, Skaletsky H, Birren B, et al. (1999) An azoospermic man with a de novo point mutation in the Y‐chromosome gene USP9Y. Nature Genetics 23: 429–432.

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

Vegetti W, Tibiletti MG, Testa G, et al. (1998) Inheritance in idiopathic premature ovarian failure: analysis of 71 cases. Human Reproduction 13: 1796–1800.

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.

World Health Organization (1987) Towards more objectivity in diagnosis and management of male infertility. International Journal of Andrology 7: 1–35.

Further Reading

Cummins J, Jequier AM and Kann R (1994) Molecular biology of human male infertility: links with aging mitochondrial genetics, and oxidative stress? Molecular Reproductive Development 37: 345–362.

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.

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.

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

Marozzi A, Manfredini E, Tibiletti MG, et al. (2000) Molecular definition of Xq common‐deleted region in patients affected by premature ovarian failure. Human Genetics 107: 304–311.

Matias PM, Donner P, Coelho R, et al. (2000) Structural evidence for ligand binding specificity in the binding domain of the human androgen receptor: implications for pathogenic gene mutations. Journal of Biological Chemistry 275: 26164–26171.

Mumm S, Herrera L, Waeltz PW, et al. (2001) X/autosomal translocations in the Xq critical region associated with premature ovarian failure fall within and outside genes. Genomics 76: 30–36.

Nature supplement on fertility

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

Rajpert‐DeMeyts E, Leffers H, Petersen JH, et al. (2002) CAG repeat length in androgen‐receptor gene and reproductive variables of fertile and infertile men. Lancet 359: 44–46.

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

Vogt PH (1996) Human Y chromosome function in male germ cell development. Advances in Developmental Biology 4: 191–257.

Vogt PH (1998) Human chromosome deletions in Yq11, AZF candidate genes and male infertility: history and update. Molecular Human Reproduction 4: 739–744.

Vogt PH, Affara N, Davey P, et al. (1997) Report on the third international workshop on Y chromosome mapping 1997. Cytogenetics and Cell Genetics 79: 1–20.

Web Links

AR mutations database http//

Cystic Fibrosis Mutation Data Base

Downs syndrome. Mendelian Inheritance of man Online (OMIM) website: reference number: 190685

Human Y AZF (Azoospermia Factor) candidate spermatogenesis genes http://humangenetik.uni‐

Cystic fibrosis transmembrane conductance regulator, ATP‐binding cassette (sub‐family C, member 7) (CFTR); LocusID: 1080. LocusLink:

Diaphanous homolog 2 (Drosophila) (DIAPH2). LocusID: 1730. LocusLink:

Forkhead transcription factor (FOXL2 on chromosome 3; 3q23) LocusID: 668. LocusLink:

Heparan sulfate 6‐O‐sulfotransferase 1 (HS6ST1); LocusID: 9394. LocusLink:

Premature ovarian failure, X‐linked (POF); LocusID: 5421. LocusLink:

X‐prolyl aminopeptidase (aminopeptidase P) 2, membrane‐bound (XPNPEP2). LocusID: 7512. LocusLink:

Azoospermia factor 1(AZF1); MIM number: 415000. OMIM:‐post/Omim/dispmim?415000

Blepharophimosis, ptosis, and epicanthus inversus (BPES); MIM number: 110100. OMIM:‐post/Omim/dispmim?110100

Cystic fibrosis transmembrane conductance regulator, ATP‐binding cassette (sub‐family C, member 7) (CFTR); MIM number: 602421. OMIM:‐post/Omim/dispmim?602421

Diaphanous homolog 2 (Drosophila) (DIAPH2). MIM number: 300108. OMIM:‐post/Omim/dispmim?300108

Heparan sulfate 6‐O‐sulfotransferase 1 (HS6ST1); MIM number: 604846. OMIM:‐post/Omim/dispmim?604846

Infertile male syndrome. MIM number: 308370. OMIM:‐post/Omim/dispmim?308370

Premature ovarian failure, X‐linked (POF); MIM number: 311360.http OMIM:‐post/Omim/dispmim?311360

X‐prolyl aminopeptidase (aminopeptidase P) 2, membrane‐bound (XPNPEP2). MIM number: 300145. OMIM:‐post/Omim/dispmim?300145

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Vogt, Peter H(Jan 2006) Infertility: Genetic Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0005520]