Purpose:
Azoospermia affects 1% of men and it can be the consequence of spermatogenic maturation arrest (MA). Although the etiology of MA is likely to be of genetic origin, only 13 genes have been reported as recurrent potential causes of MA.
Methods:
Exome sequencing in 147 selected MA patients (discovery cohort and two validation cohorts).
Results:
We found strong evidence for 5 novel genes likely responsible for MA (
ADAD2
,
TERB1
,
SHOC1
,
MSH4
, and
RAD21L1
), for which mouse knockout (KO) models are concordant with the human phenotype. Four of them were validated in the two independent MA cohorts. In addition, 9 patients carried pathogenic variants in 7 previously reported genes -
TEX14
,
DMRT1
,
TEX11
,
SYCE1
,
MEIOB
,
MEI1
and
STAG3
- allowing to upgrade the clinical significance of these genes for diagnostic purposes. Our meiotic studies provide novel insight into the functional consequences of the variants, supporting their pathogenic role.
Conclusions:
Our findings contribute substantially to the development of a pre-TESE prognostic gene panel. If properly validated, the genetic diagnosis of complete MA prior to surgical interventions is clinically relevant. Wider implications include the understanding of potential genetic links between NOA and cancer predisposition, and between NOA and premature ovarian failure.
Current patterns of presentation of RMs are consistent with the decreasing trends in age and clinical or pathologic size and increasing incidental diagnosis. Patients exhibit a considerable basal comorbidity and presence of risk factors for RCC. Half of the cases are treated by a nephron-sparing modality with an increase in the penetration of NSS techniques in the contemporary urologic practice.
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