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

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

  • Genet Med. 2020 Dec;22(12):1956-1966. doi: 10.1038/s41436-020-0907-1.
Csilla Krausz # 1 2,  Antoni Riera-Escamilla # 3 4,  Daniel Moreno-Mendoza 3,  Kaylee Holleman 5,  Francesca Cioppi 6,  Ferran Algaba 7,  Marc Pybus 4,  Corinna Friedrich 8,  Margot J Wyrwoll 8,  Elena Casamonti 6,  Sara Pietroforte 6 4,  Liina Nagirnaja 9,  Alexandra M Lopes 10 11,  Sabine Kliesch 12,  Adrian Pilatz 13,  Douglas T Carrell 14 15,  Donald F Conrad 9 16,  Elisabet Ars 4,  Eduard Ruiz-Castañé 3,  Kenneth I Aston 14,  Willy M Baarends # 5,  Frank Tüttelmann # 8
Affiliations

Affiliations

  • 1 Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Florence, Florence, Italy. [email protected].
  • 2 Andrology Department, Fundació Puigvert, Universitat Autònoma de Barcelona, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Barcelona, Catalonia, Spain. [email protected].
  • 3 Andrology Department, Fundació Puigvert, Universitat Autònoma de Barcelona, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Barcelona, Catalonia, Spain.
  • 4 Molecular Biology Laboratory, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.
  • 5 Department of Developmental Biology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands.
  • 6 Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Florence, Florence, Italy.
  • 7 Pathology Section, Fundació Puigvert, Universitat Autonoma de Barcelona, Barcelona, Catalonia, Spain.
  • 8 Institute of Human Genetics, University of Münster, Münster, Germany.
  • 9 Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA.
  • 10 Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal-IPATIMUP, Porto, Portugal.
  • 11 Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
  • 12 Centre of Reproductive Medicine and Andrology, Department of Clinical and Surgical Andrology, University Hospital Münster, Münster, Germany.
  • 13 Clinic for Urology, Pediatric Urology and Andrology, Justus Liebig University, Gießen, Germany.
  • 14 Andrology and IVF Laboratories, Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • 15 Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • 16 Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
  • # Contributed equally.
PMID: 32741963 DOI: 10.1038/s41436-020-0907-1
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.

Keywords

azoospermia; genetics; male infertility; meiosis; spermatogenesis.

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