Monogenic causes of non-obstructive azoospermia: challenges, established knowledge, limitations and perspectives

AbstractIt is estimated that one in 100 men have azoospermia, the complete lack of sperm in the ejaculate. Currently,  ~ 20% of azoospermia cases remain idiopathic. Non-obstructive azoospermia (NOA) is mostly explained by congenital factors leading to spermatogenic failure, such as chromosome abnormalities. The knowledge of the monogenic causes of NOA is very limited. High genetic heterogeneity due to the compl exity of spermatogenesis and testicular function, lack of non-consanguineous familial cases and confirmatory studies challenge the field. The reported monogenic defects cause syndromic NOA phenotypes presenting also additional congenital problems and isolated NOA cases, explained by spermatogenic de fects. The established and recently reported NOA genes (n = 38) represent essential guardians of meiosis, transcriptional and endocrine regulators of reproduction. Despite the list being short, 92% of these loci are predicted to functionally interact with each other (STRING analysis: average 5.21 connections/gene, enrichmentP <  10–16). Notably,  ~ 50% of NOA genes have also been implicated in primary ovarian insufficiency, amenorrhea and female genital anomalies, referring to overlapping mechanisms. Considering the knowledge from respective female phenotypes and animal models, exploring the scenarios of di/oligogenic and de novo mutati ons represent perspective directions in the genetic research of NOA. Knowing the exact genetic cause in each patient i...
Source: Human Genetics - Category: Genetics & Stem Cells Source Type: research