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Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure

Lookup NU author(s): Professor Joris VeltmanORCiD


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Copyright © 2022. Published by Elsevier Inc. Although the evolutionary history of the X chromosome indicates its specialization in male fitness, its role in spermatogenesis has largely been unexplored. Currently only three X chromosome genes are considered of moderate-definitive diagnostic value. We aimed to provide a comprehensive analysis of all X chromosome-linked protein-coding genes in 2,354 azoospermic/cryptozoospermic men from four independent cohorts. Genomic data were analyzed and compared with data in normozoospermic control individuals and gnomAD. While updating the clinical significance of known genes, we propose 21 recurrently mutated genes strongly associated with and 34 moderately associated with azoospermia/cryptozoospermia not previously linked to male infertility (novel). The most frequently affected prioritized gene, RBBP7, was found mutated in ten men across all cohorts, and our functional studies in Drosophila support its role in germ stem cell maintenance. Collectively, our study represents a significant step towards the definition of the missing genetic etiology in idiopathic severe spermatogenic failure and significantly reduces the knowledge gap of X-linked genetic causes of azoospermia/cryptozoospermia contributing to the development of future diagnostic gene panels.

Publication metadata

Author(s): Riera-Escamilla A, Vockel M, Nagirnaja L, Xavier MJ, Carbonell A, Moreno-Mendoza D, Pybus M, Farnetani G, Rosta V, Cioppi F, Friedrich C, Oud MS, van der Heijden GW, Soave A, Diemer T, Ars E, Sanchez-Curbelo J, Kliesch S, O'Bryan MK, Ruiz-Castane E, Azorin F, Veltman JA, Aston KI, Conrad DF, Tuttelmann F, Krausz C

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2022

Volume: 109

Issue: 8

Pages: 1458-1471

Print publication date: 04/08/2022

Online publication date: 08/07/2022

Acceptance date: 13/06/2022

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2022.06.007

PubMed id: 35809576


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