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

Csilla Krausz, Antoni Riera-Escamilla, Daniel Moreno-Mendoza, Kaylee Holleman, Francesca Cioppi, Ferran Algaba, Marc Pybus, Corinna Friedrich, Margot J. Wyrwoll, Elena Casamonti, Sara Pietroforte, Liina Nagirnaja, Alexandra M. Lopes, Sabine Kliesch, Adrian Pilatz, Douglas T. Carrell, Donald F. Conrad, Elisabet Ars, Eduard Ruiz-Castañé, Kenneth I. AstonWilly M. Baarends, Frank Tüttelmann

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1956-1966
Number of pages11
JournalGenetics in Medicine
Issue number12
StatePublished - Dec 2020


  • azoospermia
  • genetics
  • male infertility
  • meiosis
  • spermatogenesis

ASJC Scopus subject areas

  • Genetics(clinical)


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