De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies
Top Cited Papers
- 4 December 2015
- journal article
- other
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 350 (6265), 1262-1266
- https://doi.org/10.1126/science.aac9396
Abstract
Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator of mRNA splicing. Genes mutated in other cohorts examined 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.Keywords
Funding Information
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute
- Simons Foundation for Autism Research
- Wellcome Trust
- Harvard Medical School
- Heart and Stroke Foundation of Ontario
- British Heart Foundation
- Arthritis Research UK
- Academy of Medical Sciences
- Imperial College London
- Leducq Foundation
- National Human Genome Research Institute of the National Institutes of Health (NIH)
- National Research Science Award
- NIHR Cardiovascular Biomedical Research Unit at Royal Brompton
- Harefield NHS Foundation Trust
- Ted Roger Centre for Heart Research
- Kostin Family Innovation Fund
- Aaron Stern Professorship at the University of Michigan
- Braylon’s Gift of Hope Fund
This publication has 28 references indexed in Scilit:
- Interpreting de novo Variation in Human Disease Using denovolyzeRCurrent Protocols in Human Genetics, 2015
- Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studiesHuman Molecular Genetics, 2014
- The contribution of de novo coding mutations to autism spectrum disorderNature, 2014
- Increased Frequency of De Novo Copy Number Variants in Congenital Heart Disease by Integrative Analysis of Single Nucleotide Polymorphism Array and Exome Sequence DataCirculation Research, 2014
- A framework for the interpretation of de novo mutation in human diseaseNature Genetics, 2014
- dbNSFP v2.0: A Database of Human Non-synonymous SNVs and Their Functional Predictions and AnnotationsHuman Mutation, 2013
- De novo mutations in histone-modifying genes in congenital heart diseaseNature, 2013
- Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing studyThe Lancet, 2012
- De novo mutations revealed by whole-exome sequencing are strongly associated with autismNature, 2012
- Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutationsNature Genetics, 2011