O-153 Unravelling the causes of male infertility: the role of genetics

Abstract

Abstract Infertility is a common multifactorial disease and global health problem affecting 10-15% of couples. It can often be overcome by medically assisted reproduction (MAR), offering couples that fail to conceive naturally the chance for parenthood. In half of the couples, the infertility is due to male-factors. Despite advances in the past decade, in the majority of infertile men, the underlying genetic, molecular, cellular, and/or organ defect(s) still remain ill-defined or unknown altogether. Thereby, evidence-based treatment decisions for testicular sperm extraction (TESE) and MAR, estimating and counselling as to risks for both the men and their offspring, and potential preventive measures are largely precluded. However, in recent years, the number of male infertility cases “solved” by genetic analyses, most importantly exome sequencing, increases continuously. We and others have contributed significantly to 1) identifying novel genes and causal variants (mutations), 2) functionally scrutinising them, and 3) translating findings into the clinic. Most attention is currently focussed on azoospermia, supposedly affecting up to 1% of the male population, and specific sperm defects clinically detected as morphological aberrations or decreased/completely lacking motility. Crypto- and azoospermia (very few/no sperm in the semen) are main contributors to male factor infertility. Genetic causes for spermatogenic failure (SPGF) include Klinefelter syndrome (47,XXY) and Y-chromosomal AZF microdeletions, and CFTR mutations for obstructive azoospermia (OA). However, the majority of cases remain unexplained because monogenic causes are not analysed. The clinical distinction between azoospermia due to SPGF (non-obstructive azoospermia, NOA) and obstructive azoospermia (OA) is challenging but critical for counselling patients prior to surgical sperm retrieval procedures: men with OA have high success rates for TESE and subsequent intracytoplasmic sperm injection (ICSI), while rates for NOA patients range from virtually zero up to ∼50% depending on the genotype. One focus of the talk will be the recent results of our four years prospective exome sequencing study in crypto-/azoospermic men and the impact for predicting TESE and MAR success based on identified mutations. Another focus will be the genetic makeup of morphologically abnormal sperm and the consequences for MAR/ICSI. Lastly, a previously underestimated cause for infertility and IVF failure will be reviewed.