Endocrine Abstracts

Infertility affects 10–15% of couples and the causes of couple infertility are equally attributed to male and female (co-)factors. Male infertility is a genetically and clinically highly heterogeneous disease with a multitude of up to 1,500 genes supposedly involved in spermatogenesis. Thus, unravelling the underlying causes and the pathophysiology is challenging and candidate gene approaches, e.g. picking one or several genes known to cause infertility in mice, did not identify novel genetic causes of infertility in men.

The sex chromosomes are enriched for genes required for fertility and the Y-chromosomal AZF-microdeletions have been known for a long time to cause azoo- or severe oligozoospermia. However, X-chromosomal microdeletions and mutations in X-linked genes have only been analysed recently by utilising novel methods of genome-wide analyses. These have greatly expanded the toolbox for genetic studies and broadened the scope beyond single gene analyses. The power of such approaches is demonstrated by genome-wide array-Comparative Genomic Hybridisation (array-CGH) in groups of clinically well-characterised oligo- and azoospermic men. We were the first to report an excess of Copy Number Variations (CNVs) in infertile males especially on the sex-chromosomes. X-linked CNVs have also been proposed as recurrent cause for male infertility by others - comparable to the Y-chromosomal AZF-deletions.

Very recently, by using high-resolution array-CGH, we identified exon-deletions and nucleotide mutations in TEX11 as the first common X-linked cause for meiotic arrest in about 15% of men with this phenotype. This breakthrough relied on phenotyping by testicular histology allowing specific selection of study subjects. Hemizygous mutations in TEX11 were confirmed as an important cause for meiotic arrest already in another study.

Taken together, comprehensive screening for small deletions and sequencing of X-chromosomal genes will likely result in fast identification of novel genetic causes for male infertility.