Endocrine Abstracts

Infertility affects 10–15% of couples. In about half of them, a descriptive cause can be established in the male partner, mostly reduced sperm output, of which azoospermia, the complete lack of spermatozoa in the ejaculate, is the most severe form. Non-obstructive azoospermia (NOA) comprises several subforms of spermatogenic failure, such as meiotic arrest (MeiA) and Sertoli-Cell-Only syndrome (SCOS). Most of these phenotypes are suspected to be of genetic origin. However, aside from chromosomal aberrations and Y-chromosomal AZF deletions, monogenic causes are poorly understood. Still, a number of candidate genes have been proposed to be associated with NOA, but for the majority functional analyses and validation in independent studies are lacking. Like in many other diseases, genome-wide analyses comprising arrays to detect Copy Number Variants (CNVs) and whole-exome sequencing (WES) to detect nucleotide variation are now utilised in several large scale studies to promote validation of proposed candidate genes and identification of novel genes. Candidate genes for NOA and male infertility will be reviewed and put into perspective of novel findings from the recent WES results. The importance of functional assessment especially of missense variants causing amino acid substitutions will be highlighted. Indeed, we could recently increase causal genetic diagnoses in non-obstructive azoospermic men from ~20% to ~30% by WES together with in silico/in vitro analyses. Identifying the causal mutations in an infertile men has direct implications on treatment, especially decisions on performing a testicular biopsy and counselling about risks for offspring.