Finding novel genes relevant for male infertility is a challenging task. Over 2000 genes are moderately to highly, and over 800 genes are exclusively expressed in the testis, with the majority of these genes being presumably involved in spermatogenesis - the process of sperm differentiation. Nevertheless, only very few new genes associated with male infertility have been identified by the analysis of individual candidate genes, underlining the necessity of a more systematic and unbiased genome-wide approach.
Attempting to accomplish the aim of finding further genetic causes of infertility, we are currently working on the establishment of such a systematic approach. Whole-exome sequencing was performed in our cohort of more than 900 male patients, mainly including azoospermic men without any spermatids in the ejaculate. Another large part within the cohort was descriptively diagnosed with oligoasthenoteratozoospermia, refering to spermatids decreased in number, impaired in motility or with abnormal morphology. In order to efficiently process such broad genetic data, we have developed a variant filter tool called Haystack in cooperation with colleagues from the Institute of Medical Informatics. With this tool, thousands of genetic variants can be filtered according to specific criteria, their expression in the testis can be analysed and genes where presumable loss-of-function variants have also been found in control individuals with intact spermatogenesis can be excluded.
Even after such an intensive filtering process, still several hundred genes remain. The usage of other programmes available online provides further options to characterise interesting genes more deeply. Subsequently, a literature research is conducted in order to gather as much background information as possible for each individual candidate. As an example, it is checked whether there are already promising publications on reproduction-related issues, such as an already existing gene-specific animal model that comes with restrictions in fertility. Using the described approaches, we are currently working on some novel and highly interesting candidate genes for azoospermia, which we plan to publish soon!