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Diverse monogenic subforms of human spermatogenic failure

Lookup NU author(s): Dr Miguel Garcia Dos Santos XavierORCiD, Professor Joris VeltmanORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2022, The Author(s).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.

Publication metadata

Author(s): Nagirnaja L, Lopes AM, Charng W-L, Miller B, Stakaitis R, Golubickaite I, Stendahl A, Luan T, Friedrich C, Mahyari E, Fadial E, Kasak L, Vigh-Conrad K, Oud MS, Xavier MJ, Cheers SR, James ER, Guo J, 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 JI, 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

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2022

Volume: 13

Issue: 1

Online publication date: 26/12/2022

Acceptance date: 16/12/2022

Date deposited: 12/01/2023

ISSN (electronic): 2041-1723

Publisher: Nature Research


DOI: 10.1038/s41467-022-35661-z

PubMed id: 36572685


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Funder referenceFunder name
Wellcome Trust