Molecular Genetics of Spermatogenic Disturbances


A large proportion of male infertility is predicted to be related to genetic factors. These factors may act directly at the testicular level or through the endocrine regulation of the testis. A number of new causative mutations have been identified in hypogonadotrophic hypogonadism allowing a genetic diagnosis in approximately 30–40% of cases. However, search for causative mutations in Y‐chromosome, autosomal and X‐linked genes with predicted spermatogenic function have been substantially unsuccessful with some rare exceptions. Up to now, only Y‐chromosome rearrangements such as AZoospermia Factor (AZF) deletions and gr/gr deletion have been confirmed as molecular genetic causes of primitive testicular failure.

Key concepts:

  • Spermatogenic failure can be caused by genetic factors acting at the pre‐testicular or directly at the testicular level.

  • Mutation in genes involved in the hormonal regulation of the testis (pre‐testicular level) is associated with hypogonadotrophic hypogonadism.

  • Genetic factors involved in primitive testicular failure can be divided in chromosomal abnormalities and monogenic mutations.

  • Microdeletions in specific regions of the long arm of the Y‐chromosome (AZF regions) represent the most frequent molecular genetic cause of primitive testicular failure. The diagnosis of AZF deletions is clinically relevant since it provides the aethiology of infertility, has a prognostic value for testicular sperm retrieval and the deletion will be obligatory transmitted to the male offspring. gr/gr deletion of the AZFc region is the only significant risk factor for impaired sperm production identified to date.

  • Search for X‐linked and autosomal gene mutations/polymorphisms has been largely unsuccessful.

  • Given the polygenic nature of male infertility a major advancement will likely be achieved from future studies based on whole genome analyses in large study populations.

Keywords: genetics; male infertility; spermatogenesis; polymorphisms

Figure 1.

(a) Schematic representation of the Y‐chromosome with the indication of the AZoospermia Factor (AZF) regions and genotype/phenotype correlations of different types of AZF deletions. AZFb deletions (two subtypes) overlap with the AZFc region. (b) The AZFc region is presented in detail. This region contains a number of repeated sequences with the same orientation (narrow with the same motives) which through intrachromosomal recombination may lead to deletions. Genes are listed inside the repeated sequences. The clinically relevant complete AZFc and ‘gr/gr’ deletions are shown. The breakpoint of gr/gr deletion may vary, whereas the complete AZFc deletion is always between b2 and b4. Yq, long arm of the Y‐chromosome; Yp, short arm of the Y‐chromosome; PAR, pseudoautosomal region; SCOS, sertoli cell only syndrome; SGA, spermatogenic arrest; OAT, oligoasthenoteratozoospermia and NZ, normozoospermia.



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Further Reading

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Web Links

MSY breakpoint mapper of the Y chromosome

The Androgen Receptor Gene Mutations Database World Wide Web Server (web:

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Krausz, Csilla(Dec 2009) Molecular Genetics of Spermatogenic Disturbances. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021694]