Journées Klotz 2014
Genetic causes of male infertilityCauses génétiques d’infertilité masculine

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Abstract

Male infertility, affecting around half of the couples with a problem to get pregnant, is a very heterogeneous condition. Part of patients are having a defect in spermatogenesis of which the underlying causes (including genetic ones) remain largely unknown. The only genetic tests routinely used in the diagnosis of male infertility are the analyses for the presence of Yq microdeletions and/or chromosomal abnormalities. Various other single gene or polygenic defects have been proposed to be involved in male fertility. Yet, their causative effect often remains to be proven. The recent evolution in the development of whole genome-based techniques may help in clarifying the role of genes and other genetic factors involved in spermatogenesis and spermatogenesis defects.

Résumé

L’infertilité masculine, qui touche environ la moitié des couples infertiles, correspond à une situation très hétérogène. Un certain nombre de patient présente un défaut de spermatogénèse dont les causes (y compris les causes génétiques) demeurent largement inconnues. Les seuls tests génétiques pratiqués en routine correspondent à la recherche de micro-délétions Yq et/ou d’anomalies chromosomiques. Différentes atteintes monogéniques ou des défauts polygéniques ont également été impliqués dans la fertilité masculine. Cependant, leur implication causale restent souvent à démontrer. L’évolution et le développement récent des techniques de séquençage du génome entier peuvent aider à clarifier le rôle de ces gènes et d’autres facteurs génétiques impliqués dans la spermatogénèse.

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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