Diverse monogenic subforms of human spermatogenic failure

Liina Nagirnaja, Alexandra M. Lopes, Wu-Lin Charng, Brian Miller, Rytis Stakaitis, Ieva Golubickaite, Alexandra Stendahl, Tianpengcheng Luan, Corinna Friedrich, Eisa Mahyari, Eloise Fadial, Laura Kasak, Katinka Vigh-Conrad, Manon S. Oud, Miguel J. Xavier, Samuel R. Cheers, Emma R. James, Jingtao Guo, Timothy G. Jenkins, Antoni Riera-Escamilla, Alberto Barros, Filipa Carvalho, Susana Fernandes, João Gonçalves, Christina A. Gurnett, Niels Jørgensen, Davor Jezek, Emily S. Jungheim, Sabine Kliesch, Robert I. McLachlan, Kenan R. Omurtag, Adrian Pilatz, Jay I. Sandlow, James Smith, Michael L. Eisenberg, James M. Hotaling, Keith A. Jarvi, Margus Punab, Ewa Rajpert- De Meyts, Douglas T. Carrell, Csilla Krausz, Maris Laan, Moira K. O’Bryan, Peter N. Schlegel, Frank Tüttelmann, Joris A. Veltman, Kristian Almstrup, Kenneth I. Aston and Donald F. Conrad ()
Additional contact information
Liina Nagirnaja: Oregon Health & Science University
Alexandra M. Lopes: University of Porto
Wu-Lin Charng: Washington University
Brian Miller: Oregon Health & Science University
Rytis Stakaitis: Copenhagen University Hospital - Rigshospitalet
Ieva Golubickaite: Copenhagen University Hospital - Rigshospitalet
Alexandra Stendahl: Oregon Health & Science University
Tianpengcheng Luan: The University of Melbourne
Corinna Friedrich: University of Münster
Eisa Mahyari: Oregon Health & Science University
Eloise Fadial: Oregon Health & Science University
Laura Kasak: University of Tartu
Katinka Vigh-Conrad: Oregon Health & Science University
Manon S. Oud: Radboud University Medical Centre
Miguel J. Xavier: Newcastle University
Samuel R. Cheers: The University of Melbourne
Emma R. James: University of Utah School of Medicine
Jingtao Guo: University of Utah School of Medicine
Timothy G. Jenkins: University of Utah School of Medicine
Antoni Riera-Escamilla: Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau)
Alberto Barros: University of Porto
Filipa Carvalho: University of Porto
Susana Fernandes: University of Porto
João Gonçalves: Instituto Nacional de Saúde Dr. Ricardo Jorge
Christina A. Gurnett: Washington University
Niels Jørgensen: Copenhagen University Hospital - Rigshospitalet
Davor Jezek: University of Zagreb School of Medicine
Emily S. Jungheim: Division of Reproductive Endocrinology
Sabine Kliesch: University Hospital Münster
Robert I. McLachlan: Monash University
Kenan R. Omurtag: Division of Reproductive Endocrinology
Adrian Pilatz: Justus Liebig University
Jay I. Sandlow: Medical College of Wisconsin
James Smith: University California San Francisco
Michael L. Eisenberg: Stanford University School of Medicine
James M. Hotaling: University of Utah School of Medicine
Keith A. Jarvi: University of Toronto
Margus Punab: Tartu University Hospital
Ewa Rajpert- De Meyts: Copenhagen University Hospital - Rigshospitalet
Douglas T. Carrell: University of Utah School of Medicine
Csilla Krausz: University of Florence
Maris Laan: University of Tartu
Moira K. O’Bryan: The University of Melbourne
Peter N. Schlegel: Weill Cornell Medicine
Frank Tüttelmann: University of Münster
Joris A. Veltman: Newcastle University
Kristian Almstrup: Copenhagen University Hospital - Rigshospitalet
Kenneth I. Aston: University of Utah School of Medicine
Donald F. Conrad: Oregon Health & Science University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the most advanced classification of NOA subforms is not based on genetics, but simple description of testis histology. In this study, we exome-sequenced over 1000 clinically diagnosed NOA cases and identified a plausible recessive Mendelian cause in 20%. We find further support for 21 genes in a 2-stage burden test with 2072 cases and 11,587 fertile controls. The disrupted genes are primarily on the autosomes, enriched for undescribed human “knockouts”, and, for the most part, have yet to be linked to a Mendelian trait. Integration with single-cell RNA sequencing data shows that azoospermia genes can be grouped into molecular subforms with synchronized expression patterns, and analogs of these subforms exist in mice. This analysis framework identifies groups of genes with known roles in spermatogenesis but also reveals unrecognized subforms, such as a set of genes expressed across mitotic divisions of differentiating spermatogonia. Our findings highlight NOA as an understudied Mendelian disorder and provide a conceptual structure for organizing the complex genetics of male infertility, which may provide a rational basis for disease classification.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35661-z

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DOI: 10.1038/s41467-022-35661-z

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