ReviewGenetic causes of male infertility
Introduction
Infertility affects about 15% of couples trying to conceive in Western countries [1], and genetic causes may be identified in a large proportion of infertile couples. In about 15% of male and 10% of female infertile subject genetic abnormalities could be present, including chromosome aberrations and single gene mutations. Intracytoplasmic sperm injection, the injection of a single sperm into a single egg, is one of the leading methods of treatment for male factor infertility. However, patients affected by some forms of genetic abnormalities (for example chromosomal alterations and Y chromosome microdeletions) produce a higher frequency of sperm with aneuploidies. Sperm aneuploidies are the direct result of the constitutional genetic abnormality or are caused by meiotic errors induced by the altered testicular environment that these men present. The risk of transmission concerns also the use of standard in vitro fertilization (IVF) and intrauterine insemination (IUI), since also normozoospermic infertile men could have some genetic defect (for example 47,XYY males). Natural selection prevents the transmission of mutations causing infertility, while this protective mechanism is overcome by the assisted reproduction techniques. Consequently the risk consists in the increase of the genetic causes of infertility in the future, and thus, the identification of genetic factors has become good practice for appropriate management of the infertile couple.
Recently, we prepared guidelines for the appropriate use of genetic tests in the infertile couple [2]. These guidelines have been prepared not to include all the genetic causes of infertility, but only those clinically relevant, both in terms of prevalence in male and female infertility and risk of transmission to offspring.
In this review we will report and discuss the genetic causes of male infertility know up to date, and finally, we will analyse genetic polymorphisms possibly associated with male infertility (Table 1).
Section snippets
Chromosomal abnormalities
The prevalence of chromosome abnormalities is higher in infertile men, this figure being inversely related to the sperm count. Based on the largest published series it could be estimated that the overall incidence of a chromosomal factor in infertile males ranges between 2% and 8%, with a mean value of 5%. This value is increasing to about 15% in azoospermic males, being largely contributed by patients with 47,XXY aneuploidy. Sex chromosomes abnormalities are predominating, but a wide range of
Y chromosome microdeletions
From the initial observation in 1976 [14] a number of studies ascertained that microdeletions in the Y chromosome (Yq) represent the most frequent molecular genetic cause of severe infertility, observed with a prevalence of 10–15% in non-obstuctive azoospermia and severe oligozoospermia [15]. Three regions, referred to as “azoospermia factors” (AZFa, b and c from proximal to distal) has been defined as spermatogenesis loci [16]. The genetic pathways and mechanisms of spermatogenic impairment in
Gene mutations
Several hundreds of genes are necessary for normal sexual development, testis determination, testis descent, and spermatogenesis. However, only few of them have routine clinical importance. These include the CFTR gene, whose mutations cause cystic fibrosis and absence of vas deferens, the androgen receptor gene, whose mutations cause the androgen insensitivity syndrome and spermatogenic damage, and the INSL3-LGR8 genes, whose mutations have been associated with abnormalities in testis descent
Gene polymorphisms and male infertility
The analysis of polymorphisms in genes involved in spermatogenesis represents one of the most exciting area of research in genetics of male infertility. Polymorphisms or genetic variants in these genes are considered potential risk factors which may contribute to the severity of spermatogenic failure. Several polymorphic variants have been described in association with male infertility. However, these association studies often do not report unique results. This is mainly due to different
Acknowledgements
Supported by grants of the University of Padova to AF and AB, and of the Italian Ministry of University and Research to CF.
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