Diverse monogenic subforms of human spermatogenic failure
Nagirnaja, Liina (Oregon Health & Science University)
Lopes, Alexandra M. (IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto)
Charng, Wu-Lin (Washington University)
Miller, Brian (Oregon Health & Science University)
Stakaitis, Rytis (Lithuanian University of Health Sciences)
Golubickaite, Ieva (Lithuanian University of Health Sciences)
Stendahl, Alexandra (Oregon Health & Science University)
Luan, Tianpengcheng (The University of Melbourne)
Friedrich, Corinna (University of Münster)
Mahyari, Eisa (Oregon Health & Science University)
Fadial, Eloise (Oregon Health & Science University)
Kasak, Laura (University of Tartu)
Vigh-Conrad, Katinka (Oregon Health & Science University)
Oud, Manon S. (Radboud University Medical Centre)
Xavier, Miguel (Newcastle University)
Cheers, Samuel R. (The University of Melbourne)
James, Emma R. (University of Utah School of Medicine)
Guo, Jingtao (University of Utah School of Medicine)
Jenkins, Timothy G. (University of Utah School of Medicine)
Riera-Escamilla, Antoni (Institut d'Investigació Biomèdica Sant Pau)
Barros, Alberto (Faculdade de Medicina da Universidade do Porto)
Carvalho, Filipa (Faculdade de Medicina da Universidade do Porto)
Fernandes, Susana (Faculdade de Medicina da Universidade do Porto)
Gonçalves, João (Nova Medical School)
Gurnett, Christina A. (Washington University.)
Jørgensen, Niels (Copenhagen University Hospital - Rigshospitalet)
Jezek, Davor (University of Zagreb School of Medicine)
Jungheim, Emily S. (Division of Reproductive Endocrinology)
Kliesch, Sabine (University Hospital of Münster (Alemanya))
McLachlan, Robert I. (Monash University)
Omurtag, Kenan R. (Division of Reproductive Endocrinology)
Pilatz, Adrian (Justus Liebig University)
Sandlow, Jay I. (Medical College of Wisconsin)
Smith, James (University California San Francisco)
Eisenberg, Michael L. (Stanford University School of Medicine)
Hotaling, James M. (University of Utah School of Medicine)
Jarvi, Keith A. (University of Toronto)
Punab, Margus (University of Tartu)
Rajpert-De Meyts, Ewa (Copenhagen University Hospital - Rigshospitalet)
Carrell, Douglas T. (University of Utah School of Medicine)
Krausz, Csilla (University of Florence)
Laan, Maris (University of Tartu)
O'Bryan, Moira Kathleen (Monash University)
Schlegel, Peter N. (Weill Cornell Medicine)
Tüttelmann, Frank (University of Münster)
Veltman, Joris A. (Newcastle University)
Almstrup, Kristian (Copenhagen University Hospital - Rigshospitalet)
Aston, Kenneth I. (University of Utah School of Medicine)
Conrad, Donald F. (Oregon Health & Science University)
Universitat Autònoma de Barcelona

Fecha:	2022
Resumen:	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. The GEMINI consortium sequenced 1,000 cases of idiopathic male infertility and identified a plausible Mendelian cause in 20% of cases. The infertility genes can be grouped by expression pattern, facilitating their interpretation and follow-up.
Ayudas:	Instituto de Salud Carlos III PI20/01562
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Genetics research ; Infertility ; Medical genomics
Publicado en:	Nature communications, Vol. 13 (december 2022) , ISSN 2041-1723

DOI: 10.1038/s41467-022-35661-z
PMID: 36572685

18 p, 4.7 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut de Recerca Sant Pau
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