O-154 Genetic screening in male infertility: time for new guidelines?

Abstract

Abstract Approximately 1 in 7 couples wishing to conceive fail to do so after one year of trying. About half of the cases can be assigned to male factors. Currently, genetic causes explain approximately 4-9% of all cases of male infertility, with strong variation among the different subtypes of infertility. Presently a majority of all infertile males (60-70%) remain without a clear diagnosis, despite the expectation that genetic causes explain a substantial fraction of these patients. Without a genetic diagnosis, it is impossible for a clinician to accurately provide counseling to couples with questions about the causes of their infertility, possible co-morbidities, the potential success of ART treatment and the reproductive health of their offspring. Hence, knowing and understanding the genetic causes of infertility is of enormous value to patients and clinicians. Already for more than 25 years, genetic testing is recommended for patients with severe oligozoospermia or azoospermia. These tests typically include karyotyping, azoospermia factor (AZF) deletion screening and/or CFTR mutation testing (in case of CBAVD). For a long time, further genetic testing was time-consuming and expensive, resulting in slow progress to unveil novel causes of male infertility in both research and clinic. The uptake of next-generation sequencing (NGS) methods has revolutionized genetic testing for a plethora of disorders, allowing for cost-effective screening of variants in limited gene panels, all coding parts of genes (exome), or the entire genome. NGS is now routinely used by many laboratories for genetic testing in diagnostics and research. Using these new technologies, we and others have identified numerous novel causal variants in genes indispensable for human fertility. Although the use of NGS in male infertility research is skyrocketing in recent years, it has not yet broadly found its way into diagnostics. This means that 1) numerous patients with over a hundred newly discovered monogenic causes of male infertility are presently left undiagnosed and 2) large groups of patients with phenotypes such as globozoospermia or multiple morphological abnormalities of the sperm flagellum do not routinely receive genetic testing, even though diagnostic yields of up to 60% can be expected. The field of genetics of male infertility is rapidly evolving and it is time for patients to benefit from these advances. This talk will cover the steps we and others are taking towards bringing NGS methods such as whole exome sequencing to the clinic for male infertility and will show the first results on the validation of our whole exome sequencing-based test for male infertility.