Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure.
RBBP7
X chromosome
azoospermia
cryptozoospermia
genes
genetics
genomics
male infertility
next-generation sequencing
spermatogenesis
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
04 08 2022
04 08 2022
Historique:
received:
24
03
2022
accepted:
13
06
2022
pubmed:
10
7
2022
medline:
10
8
2022
entrez:
9
7
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35809576
pii: S0002-9297(22)00260-9
doi: 10.1016/j.ajhg.2022.06.007
pmc: PMC9388793
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1458-1471Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 209451/Z/17/Z
Pays : United Kingdom
Organisme : NICHD NIH HHS
ID : R01 HD078641
Pays : United States
Organisme : Wellcome Trust
ID : 209451
Pays : United Kingdom
Informations de copyright
Copyright © 2022. Published by Elsevier Inc.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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