Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men.
azoospermia
genetics
male infertility
meiosis
spermatogenesis
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
29
01
2020
accepted:
07
07
2020
revised:
06
07
2020
pubmed:
4
8
2020
medline:
28
4
2021
entrez:
4
8
2020
Statut:
ppublish
Résumé
Azoospermia affects 1% of men and it can be the consequence of spermatogenic maturation arrest (MA). Although the etiology of MA is likely to be of genetic origin, only 13 genes have been reported as recurrent potential causes of MA. Exome sequencing in 147 selected MA patients (discovery cohort and two validation cohorts). We found strong evidence for five novel genes likely responsible for MA (ADAD2, TERB1, SHOC1, MSH4, and RAD21L1), for which mouse knockout (KO) models are concordant with the human phenotype. Four of them were validated in the two independent MA cohorts. In addition, nine patients carried pathogenic variants in seven previously reported genes-TEX14, DMRT1, TEX11, SYCE1, MEIOB, MEI1, and STAG3-allowing to upgrade the clinical significance of these genes for diagnostic purposes. Our meiotic studies provide novel insight into the functional consequences of the variants, supporting their pathogenic role. Our findings contribute substantially to the development of a pre-testicular sperm extraction (TESE) prognostic gene panel. If properly validated, the genetic diagnosis of complete MA prior to surgical interventions is clinically relevant. Wider implications include the understanding of potential genetic links between nonobstructive azoospermia (NOA) and cancer predisposition, and between NOA and premature ovarian failure.
Identifiants
pubmed: 32741963
doi: 10.1038/s41436-020-0907-1
pii: S1098-3600(21)00804-2
pmc: PMC7710580
mid: NIHMS1619687
doi:
Substances chimiques
Cell Cycle Proteins
0
DNA-Binding Proteins
0
MEIOB protein, human
0
STAG3 protein, human
0
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
1956-1966Subventions
Organisme : NICHD NIH HHS
ID : P50 HD096723
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD078641
Pays : United States
Organisme : NIH HHS
ID : R01HD078641
Pays : United States
Organisme : Marie Curie
ID : 289880
Pays : United Kingdom
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