Diverse monogenic subforms of human spermatogenic failure
Por:
Nagirnaja, L, Lopes, AM, Charng, WL, Miller, B, Stakaitis, R, Golubickaite, I, Stendahl, A, Luan, TPC, Friedrich, C, Mahyari, E, Fadial, E, Kasak, L, Vigh-Conrad, K, Oud, MS, Xavier, MJ, Cheers, SR, James, ER, Guo, JT, Jenkins, TG, Riera-Escamilla, A, Barros, A, Carvalho, F, Fernandes, S, Goncalves, J, Gurnett, CA, Jorgensen, N, Jezek, D, Jungheim, ES, Kliesch, S, McLachlan, RI, Omurtag, KR, Pilatz, A, Sandlow, J, Smith, J, Eisenberg, ML, Hotaling, JM, Jarvi, KA, Punab, M, Rajpert-De Meyts, E, Carrell, DT, Krausz, C, Laan, M, O'Bryan, MK, Schlegel, PN, Tuttelmann, F, Veltman, JA, Almstrup, K, Aston, KI, Conrad, DF
Publicada:
26 dic 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.
Filiaciones:
Nagirnaja, L:
Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Genet, Beaverton, OR 97006 USA
Lopes, AM:
Univ Porto, I3S Inst Invest & Inovacao Saude, Porto, Portugal
Univ Porto, IPATIMUP Inst Patol & Imunol Mol, Porto, Portugal
Charng, WL:
Washington Univ, Dept Neurol, St Louis, MO 63110 USA
Miller, B:
Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Genet, Beaverton, OR 97006 USA
Stakaitis, R:
Copenhagen Univ Hosp, Rigshosp, Dept Growth & Reprod, Copenhagen, Denmark
Copenhagen Univ Hosp, Rigshosp, Int Ctr Res & Res Training Endocrine Disrupt Male, Copenhagen, Denmark
Lithuanian Univ Hlth Sci, Neurosci Inst, Lab Mol Neurooncol, Kaunas, Lithuania
Golubickaite, I:
Copenhagen Univ Hosp, Rigshosp, Dept Growth & Reprod, Copenhagen, Denmark
Copenhagen Univ Hosp, Rigshosp, Int Ctr Res & Res Training Endocrine Disrupt Male, Copenhagen, Denmark
Lithuanian Univ Hlth Sci, Dept Genet & Mol Med, Kaunas, Lithuania
Stendahl, A:
Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Genet, Beaverton, OR 97006 USA
Luan, TPC:
Univ Melbourne, Fac Sci, Sch BioSci, Parkville, Vic, Australia
Friedrich, C:
Univ Munster, Inst Reprod Genet, Munster, Germany
Mahyari, E:
Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Genet, Beaverton, OR 97006 USA
Fadial, E:
Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Genet, Beaverton, OR 97006 USA
Kasak, L:
Univ Tartu, Inst Biomed & Translat Med, Tartu, Estonia
Vigh-Conrad, K:
Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Genet, Beaverton, OR 97006 USA
Oud, MS:
Radboud Univ Nijmegen Med Ctr, Dept Human Genet, Nijmegen, Netherlands
Xavier, MJ:
Newcastle Univ, Fac Med Sci, Biosci Inst, Newcastle Upon Tyne, Tyne & Wear, England
Cheers, SR:
Univ Melbourne, Fac Sci, Sch BioSci, Parkville, Vic, Australia
James, ER:
Univ Utah, Sch Med, Dept Surg Urol, Androl & IVF Lab, Salt Lake City, UT USA
Univ Utah, Sch Med, Dept Human Genet, Salt Lake City, UT 84132 USA
Guo, JT:
Univ Utah, Sch Med, Dept Surg Urol, Androl & IVF Lab, Salt Lake City, UT USA
Jenkins, TG:
Univ Utah, Sch Med, Dept Surg Urol, Androl & IVF Lab, Salt Lake City, UT USA
Riera-Escamilla, A:
Univ Autonoma Barcelona, Androl Dept, Fundacio Puigvert, Inst Invest Biomed St Pau IIB St Pau, Barcelona, Catalonia, Spain
Univ Autonoma Barcelona, Inst Invest Biomed St Pau MB St Pau, Mol Biol Lab, Fundacio Puigvert, Barcelona 08025, Catalonia, Spain
Barros, A:
Univ Porto, I3S Inst Invest & Inovacao Saude, Porto, Portugal
Univ Porto, Dept Patol, Serv Genet, Fac Med, Porto, Portugal
Carvalho, F:
Univ Porto, I3S Inst Invest & Inovacao Saude, Porto, Portugal
Univ Porto, Dept Patol, Serv Genet, Fac Med, Porto, Portugal
Fernandes, S:
Univ Porto, I3S Inst Invest & Inovacao Saude, Porto, Portugal
Univ Porto, Dept Patol, Serv Genet, Fac Med, Porto, Portugal
Goncalves, J:
Inst Nacl Saude Dr Ricardo Jorge, Dept Genet Humana, Lisbon, Portugal
Nova Med Sch, Ctr Toxicogen & Human Hlth, Lisbon, Portugal
Gurnett, CA:
Washington Univ, Dept Neurol, St Louis, MO 63110 USA
Jorgensen, N:
Copenhagen Univ Hosp, Rigshosp, Dept Growth & Reprod, Copenhagen, Denmark
Copenhagen Univ Hosp, Rigshosp, Int Ctr Res & Res Training Endocrine Disrupt Male, Copenhagen, Denmark
Jezek, D:
Univ Zagreb, Dept Histol & Embryol, Sch Med, Zagreb, Croatia
Jungheim, ES:
Northwestern Univ, Div Reprod Endocrinol, Dept Obstet & Gynecol, Chicago, IL 60611 USA
Kliesch, S:
Univ Hosp Munster, Ctr Reprod Med & Androl, Dept Clin & Surg Androl, Munster, Germany
McLachlan, RI:
Monash Univ, Hudson Inst Med Res, Clayton, Vic, Australia
Monash Univ, Dept Obstet & Gynecol, Clayton, Vic, Australia
Omurtag, KR:
Washington Univ, Div Reprod Endocrinol, Dept Obstet & Gynecol, St Louis, MO 63110 USA
Pilatz, A:
Justus Liebig Univ, Clin Urol Pediat Urol & Androl, Giessen, Germany
Sandlow, J:
Med Coll Wisconsin, Dept Urol, Milwaukee, WI 53226 USA
Smith, J:
Univ Calif San Francisco, Dept Urol, San Francisco, CA USA
Eisenberg, ML:
Stanford Univ, Dept Urol, Sch Med, Stanford, CA 94305 USA
Hotaling, JM:
Univ Utah, Sch Med, Dept Surg Urol, Androl & IVF Lab, Salt Lake City, UT USA
Jarvi, KA:
Univ Toronto, Mt Sinai Hosp, Dept Surg, Div Urol, Toronto, ON, Canada
Punab, M:
Tartu Univ Hosp, Androl Ctr, Tartu, Estonia
Univ Tartu, Inst Clin Med, Tartu, Estonia
Rajpert-De Meyts, E:
Copenhagen Univ Hosp, Rigshosp, Dept Growth & Reprod, Copenhagen, Denmark
Copenhagen Univ Hosp, Rigshosp, Int Ctr Res & Res Training Endocrine Disrupt Male, Copenhagen, Denmark
Carrell, DT:
Univ Utah, Sch Med, Dept Surg Urol, Androl & IVF Lab, Salt Lake City, UT USA
Krausz, C:
Univ Florence, Dept Expt & Clin Biomed Sci, Florence, Italy
Laan, M:
Univ Tartu, Inst Biomed & Translat Med, Tartu, Estonia
O'Bryan, MK:
Univ Melbourne, Fac Sci, Sch BioSci, Parkville, Vic, Australia
Monash Univ, Sch Biol Sci, Clayton, Vic, Australia
Schlegel, PN:
Weill Cornell Med, Dept Urol, New York, NY USA
Tuttelmann, F:
Univ Munster, Inst Reprod Genet, Munster, Germany
Veltman, JA:
Newcastle Univ, Fac Med Sci, Biosci Inst, Newcastle Upon Tyne, Tyne & Wear, England
Almstrup, K:
Copenhagen Univ Hosp, Rigshosp, Dept Growth & Reprod, Copenhagen, Denmark
Copenhagen Univ Hosp, Rigshosp, Int Ctr Res & Res Training Endocrine Disrupt Male, Copenhagen, Denmark
Aston, KI:
Univ Utah, Sch Med, Dept Surg Urol, Androl & IVF Lab, Salt Lake City, UT USA
Conrad, DF:
Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Genet, Beaverton, OR 97006 USA
Green Published, gold, Green Submitted
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