Endocrine Abstracts

Background: Non-obstructive azoospermia affects about 1% of men and has a multifactorial etiology with heterogeneous testicular histology. Pure spermatogenic maturation arrest (MA) is a relatively rare NOA phenotype but its clinical relevance is high, since patients affected by MA should not undergo invasive testis surgery. A clear-cut distinction between MA and other spermatogenic disturbances leading to azoospermia is not possible with the currently available clinical tools. Consequently, testis biopsy (TESE), is offered to all NOA patients as the only treatment option to recover spermatozoa for subsequent in vitro fertilization. MA is of polygenic nature and in >60% of cases the etiology remains unknown.

Methods: We aimed to identify the underlying genetic cause of MA in 17 patients using whole exome analysis.

Results: Rare or novel LoF mutations (homozygous or compound heterozygous) were identified in 5 novel genes (TERB1, MSH4, ADAD2, SHOC1 and RAD21L1) for which mouse KO models are concordant with the human phenotype. Our meiotic studies in the testis biopsy of the mutation carriers provided detailed characterization of the functional consequences of the variants, supporting their causative role in MA. In addition, 8 patients carried pathogenic variants in 7 previously reported genes - TEX11, TEX14, MEIOB, MEI1, DMRT1, STAG3 and SYCE1. Thanks to our study, the clinical significance of these genes can now be upgraded to strong or definitive level, therefore they can be proposed for diagnostic purposes. In four cases, infertile or fertile brothers were available, and the recessive genotype segregated with azoospermia. Interestingly, both of our patients with variants in MSH4 and SYCE1 had at least one infertile sister with suspected premature ovarian insufficiency (POI).

Conclusions: The diagnostic yield of our exome analysis was 76%. This data is unique in this field and have implications for the understanding of human meiosis and its defects. In addition, we report novel genetic links between azoospermia and POI and propose three novel MA genes (ADAD2, RAD21L1 and TERB1) as potential candidates for POI. Since the reported gene defects were all associated with pure MA (no mature spermatozoa found in the testis), our study contributes substantially to the development of a pre-testis biopsy gene panel with prognostic value for sperm retrieval.