Diverse monogenic subforms of human spermatogenic failure

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, w...

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Detalles Bibliográficos
Autores: 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
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p15442
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=15442
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85144638273&doi=10.1038%2fs41467-022-35661-z&partnerID=40&md5=1298387d6c807cdd3cf9785378f63e66
Access Level:acceso abierto
Palabra clave:gene expression
genetic analysis
genetics
histology
infertility
RNA
animal
azoospermia
human
male
male infertility
mouse
pathology
spermatogenesis
testis
Animals
Azoospermia
Humans
Infertility, Male
Male
Mice
Spermatogenesis
Testis
Descripción
Sumario: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.

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