O-176 Genetics of teratozoospermia

Male infertility, affecting over 20 million men worldwide, is a significant health concern with a strong yet underexplored genetic basis. Recent advances in genetic sequencing, particularly the use of whole-exome sequencing (WES), have enabled the identification of many genetic causes of teratozoospermia, including AURKC mutations in macrozoospermia, DPY19L2 defects in globozoospermia, and DNAH1 mutations in patients with flagellar abnormalities, collectively termed multiple morphological abnormalities of the flagella (MMAF). A comprehensive literature review on human genetics, experimental models, and teratozoospermia physiopathology confirmed that DPY19L2 deletions account for over 90% of globozoospermia cases, while two recurrent AURKC mutations explain 70% of macrozoospermia cases. Notably, an AURKC diagnosis indicates that intracytoplasmic sperm injection (ICSI) cannot be successful, while DPY19L2 mutations are associated with very low fertilization rates, which can be improved through artificial oocyte activation (AOA) using calcium ionophore. Over 50 genes have now been linked with the MMAF phenotype, allowing a diagnosis efficiency of approximately 50%. Data from human and animal models shows that MMAF primarily arises from defects in the axoneme, a microtubule-based structure that serves as the backbone and enables the movement of sperm flagella and motile cilia. As a result, in addition to their primary infertility, a proportion of MMAF patients develop a primary ciliary dyskinesia (PCD) suggesting that a pulmonary functional test should be proposed to all. These insights, driven by advances in genetic sequencing, enhance our understanding of teratozoospermia, improve diagnostic strategies, guide genetic counseling and pave the way for preventive medicine and potential personalized treatments targeting defective gene products.