Journées Klotz 2014Genetic causes of male infertilityCauses génétiques d’infertilité masculine
Introduction
Infertility is affecting 10–15% of couples with a desire to have children. In about half of these couples, a male factor can be assigned as the underlying cause [1], [2]. Male infertility can be either acquired or of congenital origin. Despite all major efforts during the last decennia to clarify the exact nature of male infertility, a large number of men are diagnosed as having an ‘idiopathic male infertility’. Presumably, part of these cases can be explained by genetic causes. In this review, we will first give an overview of the current knowledge on genetic causes of male infertility. We will especially focus on those cases where male infertility due to an altered spermatogenesis is the only phenotypic abnormality. In a second part of this review, the focus will be on new technologies such as array comparative genomic hybridisation or next generation sequencing that allow the investigation of the whole exome/genome at once.
Section snippets
Chromosomal aberrations and Yq microdeletions.
The two most frequently observed genetic causes of male infertility are chromosomal aberrations and Yq microdeletions. In an infertile patient group, Yq microdeletions are detected in ∼7.4% of patients while karyotype abnormalities are detected in ∼5% [3]. For both aberrations, this prevalence increases when only considering men with azoospermia, to > 10% or >13% for respectively Yq microdeletions or chromosomal aberrations [4], [5].
The most common chromosomal abnormality detected in male
Mutation analysis of individual genes
During the past decade, many genes have been analysed through Sanger sequencing in order to find mutations that are possibly linked to the observed fertility problem. Only a small number of disease causing mutations have been detected, mostly in patients whose sperm showed an abnormal morphology (f.i. AURKc, DPY19L2,…. reviewed in Massart et al., 2012 [3]). Moreover, some potential associations have been investigated. Nevertheless, sequencing gene after gene is time-consuming. Therefore, new
Array comparative genomic hybridisation and single nucleotide polymorphism arrays
Through array CGH and SNP arrays, deletions or gain in copy numbers – also referred to as copy number variations (CNVs) – can be detected in the whole genome of patients with spermatogenesis defects (and controls). In addition, SNP arrays can be used to define SNPs that are potentially associated with male infertility. Currently, few studies have been published in order to detect CNVs that are linked to male infertility [17], [18], [19]. In none of the studies, CNVs in known infertility genes
Next generation sequencing technologies
Next generation sequencing (NGS) technologies are a group of promising techniques allowing to investigate the complete exome/genome/epigenome/… of patients (and controls). Moreover, (small) RNA sequencing of transcripts in testicular tissues from patients with different testicular pathologies (f.i. Sertoli cell-only syndrome, maturation arrest of spermatogenesis, normal spermatogenesis) will allow to identify genes and transcripts that are essential for each stage of spermatogenesis [22], [23].
Conclusions
Besides two well-known causes of spermatogenesis defects, the chromosomal anomalies and Yq microdeletions, only a few causal mutations have been identified in the past decennia. However, a new era has started and massive parallel sequencing technologies are promising tools for identifying genes essential for spermatogenesis and mutations involved in spermatogenesis failure.
Acknowledgements
This work was supported by Wetenschappelijk Fonds Willy Gepts of the UZ Brussel and the Methusalem grant of the Research Council of the Vrije Universiteit Brussel.
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