A higher mutational burden in females supports a "female protective model" in neurodevelopmental disorders.

Détails

ID Serval
serval:BIB_0ECCA4248136
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
A higher mutational burden in females supports a "female protective model" in neurodevelopmental disorders.
Périodique
American Journal of Human Genetics
Auteur(s)
Jacquemont S., Coe B.P., Hersch M., Duyzend M.H., Krumm N., Bergmann S., Beckmann J.S., Rosenfeld J.A., Eichler E.E.
ISSN
1537-6605 (Electronic)
ISSN-L
0002-9297
Statut éditorial
Publié
Date de publication
2014
Peer-reviewed
Oui
Volume
94
Numéro
3
Pages
415-425
Langue
anglais
Notes
Publication types: Journal Article
Résumé
Increased male prevalence has been repeatedly reported in several neurodevelopmental disorders (NDs), leading to the concept of a "female protective model." We investigated the molecular basis of this sex-based difference in liability and demonstrated an excess of deleterious autosomal copy-number variants (CNVs) in females compared to males (odds ratio [OR] = 1.46, p = 8 × 10(-10)) in a cohort of 15,585 probands ascertained for NDs. In an independent autism spectrum disorder (ASD) cohort of 762 families, we found a 3-fold increase in deleterious autosomal CNVs (p = 7 × 10(-4)) and an excess of private deleterious single-nucleotide variants (SNVs) in female compared to male probands (OR = 1.34, p = 0.03). We also showed that the deleteriousness of autosomal SNVs was significantly higher in female probands (p = 0.0006). A similar bias was observed in parents of probands ascertained for NDs. Deleterious CNVs (>400 kb) were maternally inherited more often (up to 64%, p = 10(-15)) than small CNVs < 400 kb (OR = 1.45, p = 0.0003). In the ASD cohort, increased maternal transmission was also observed for deleterious CNVs and SNVs. Although ASD females showed higher mutational burden and lower cognition, the excess mutational burden remained, even after adjustment for those cognitive differences. These results strongly suggest that females have an increased etiological burden unlinked to rare deleterious variants on the X chromosome. Carefully phenotyped and genotyped cohorts will be required for identifying the symptoms, which show gender-specific liability to mutational burden.
Pubmed
Web of science
Open Access
Oui
Création de la notice
11/04/2014 17:40
Dernière modification de la notice
20/08/2019 12:35
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