Ontology highlight
ABSTRACT: 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 five 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, nine patients carried pathogenic variants in seven 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.Conclusion
Our findings contribute substantially to the development of a pre-testicular sperm extraction (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 nonobstructive azoospermia (NOA) and cancer predisposition, and between NOA and premature ovarian failure.
SUBMITTER: Krausz C
PROVIDER: S-EPMC7710580 | biostudies-literature | 2020 Dec
REPOSITORIES: biostudies-literature
Krausz Csilla C Riera-Escamilla Antoni A Moreno-Mendoza Daniel D Holleman Kaylee K Cioppi Francesca F Algaba Ferran F Pybus Marc M Friedrich Corinna C Wyrwoll Margot J MJ Casamonti Elena E Pietroforte Sara S Nagirnaja Liina L Lopes Alexandra M AM Kliesch Sabine S Pilatz Adrian A Carrell Douglas T DT Conrad Donald F DF Ars Elisabet E Ruiz-Castañé Eduard E Aston Kenneth I KI Baarends Willy M WM Tüttelmann Frank F
Genetics in medicine : official journal of the American College of Medical Genetics 20200803 12
<h4>Purpose</h4>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.<h4>Methods</h4>Exome sequencing in 147 selected MA patients (discovery cohort and two validation cohorts).<h4>Results</h4>We found strong evidence for five novel genes likely responsible for MA (ADAD2, TERB1, SHOC1, MSH4, and RAD21L1), for which mous ...[more]