Dataset Information

Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men.

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

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Publications

Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men.

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]

PMID: 32741963

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Project description:STUDY QUESTION:Given the relevant role of the extracellular microenvironment in regulating tissue homeostasis, is testicular bacterial microbiome (BM) associated with germ cell aplasia in idiopathic non-obstructive azoospermia (iNOA)? SUMMARY ANSWER:A steady increase of dysbiosis was observed among testis with normal spermatogenesis vs. iNOA with positive sperm retrieval and iNOA with complete germ cell aplasia. WHAT IS KNOWN ALREADY:Tissue-associated BM has been reported to be a biologically important extracellular microenvironment component for numerous body habitats, but not yet for the human testis. STUDY DESIGN, SIZE, DURATION:Cross-sectional study, investigating tissue-associated BM in the testis of (i) five men with iNOA and negative sperm retrieval at microdissection testicular sperm extraction (microTESE); (ii) five men with iNOA and positive sperm retrieval at microTESE; and (iii) five normozoospermic men upon orchiectomy. Every testicular specimen was histologically classified and analyzed in terms of bacterial community. PARTICIPANTS/MATERIALS, SETTING, METHODS:Massive ultra-deep pyrosequencing was applied to investigate testis microbiome. Metagenome was analyzed using Quantitative Insights Into Microbial Ecology (QIIME). Tissue-associated bacterial load was quantified by digital droplet PCR. MAIN RESULTS AND THE ROLE OF CHANCE:Normozoospermic men showed small amounts of bacteria in the testis, with Actinobacteria, Bacteroidetes, Firmicutes Proteobacteria as the dominating phyla; iNOA individuals had increased amounts of bacterial DNA (P = 0.02), associated with decreased taxa richness due to the lack of Bacteroidetes and Proteobacteria (P = 2 × 10-5). Specimens with negative sperm retrieval at microTESE depicted complete germ cell aplasia and a further decrease in terms of Firmicutes and Clostridia (P < 0.05), a complete lack of Peptoniphilus asaccharolyticus, but increased amount of Actinobacteria. LIMITATIONS, REASONS FOR CAUTION:The limited number of specimens analyzed in this preliminary study deserves external validation. The paraneoplastic microenvironment could have an impact on the residential bacterial flora. WIDER IMPLICATION OF THE FINDINGS:Human testicular microenvironment is not microbiologically sterile, containing low amounts of Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria. A dysbiotic bacterial community was associated with iNOA and complete germ cell aplasia. Novel findings on testicular BM could support future translational therapies of male-factor infertility. STUDY FUNDING/COMPETING INTEREST(S):This work was supported by URI-Urological Research Institute free funds. Authors declared no conflict of interest. TRIAL REGISTRATION NUMBER:N/A.

Dataset Information

Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men.

Purpose

Methods

Results

Conclusion

Publications

Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men.

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