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.

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Fig. 1: Investigation of patient 10–200 carrying the TERB1 variant.
Fig. 2: Investigation of patient 11–272 carrying the SHOC1 variant.
Fig. 3: Investigation of patient 11–127 carrying the MSH4 variant.
Fig. 4: Investigation of patient 07–359 carrying the RAD21L1 variant.

Change history

  • 07 August 2020

    The original online PDF version of the Article contained figures in monochrome. They now appear in colour in the PDF and HTML versions of the Article.

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Acknowledgements

The authors thank the patients participating in the study for their important contribution. A special acknowledgment is dedicated to Esperança Martí (President of the Fundació Puigvert). Esther Sleddens-Linkels, Jochen Wistuba, and Jutta Salzig are gratefully acknowledged for their help with testicular histological evaluation. We thank Christian Ruckert, Jochen Seggewiß, and Marius Wöste for their support in bioinformatics and the long-range seq, respectively. The study was supported by Spanish Ministry of Health Instituto Carlos III-FIS (grant number FIS/FEDER-PI14/01250; PI17/01822to C.K. and A.R.-E.), the European Commission, Reproductive Biology Early Research Training (REPROTRAIN, project number 289880, awarded to C.K. and A.R.-E.), the German Research Foundation Clinical Research Unit “Male Germ Cells: from Genes to Function” (DFG CRU326, grants to F.T.), and by the National Institutes of Health (R01HD078641, awarded to D.F.C., L.N., K.I.A., and D.T.C.).

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Correspondence to Csilla Krausz MD, PhD.

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Krausz, C., Riera-Escamilla, A., Moreno-Mendoza, D. et al. Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men. Genet Med (2020). https://doi.org/10.1038/s41436-020-0907-1

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Key words

  • male infertility
  • azoospermia
  • genetics
  • spermatogenesis
  • meiosis

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