De novo mutations in congenital heart disease with neurodevelopmental and other birth defects
File(s)
Accepted version
Supporting information
Author(s)
Type
Journal Article
Abstract
Congenital heart disease (CHD) patients have increased prevalence of extra-cardiac congenital anomalies (CA) and risk of neurodevelopmental disabilities (NDD). Exome sequencing of 1,213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD and CA but only 2% with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, an mRNA splice regulator. Genes mutated in other cohorts ascertained for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.
Date Issued
2015-12-04
Date Acceptance
2015-10-16
Citation
Science, 2015, 350 (6265), pp.1262-1266
ISSN
0036-8075
Publisher
American Association for the Advancement of Science
Start Page
1262
End Page
1266
Journal / Book Title
Science
Volume
350
Issue
6265
Copyright Statement
© 2015. Authors retain copyright of their work. Exclusive publication licence granted to American Association for the Advancement of Science
Sponsor
Wellcome Trust
Identifier
https://science.sciencemag.org/content/350/6265/1262
Grant Number
107469/Z/15/Z
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
INTELLECTUAL DISABILITY
AUTISM
SPECTRUM
GENES
OUTCOMES
Brain
Child
Congenital Abnormalities
Exome
Heart Defects, Congenital
Humans
Mutation
Nervous System Malformations
Neurogenesis
Prognosis
RNA Splicing
RNA Splicing Factors
RNA, Messenger
RNA-Binding Proteins
Repressor Proteins
Transcription, Genetic
Brain
Humans
Nervous System Malformations
Heart Defects, Congenital
RNA-Binding Proteins
Repressor Proteins
RNA, Messenger
Prognosis
Transcription, Genetic
RNA Splicing
Mutation
Child
Congenital Abnormalities
Neurogenesis
Exome
RNA Splicing Factors
General Science & Technology
Publication Status
Published
Date Publish Online
2015-12-04