De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies

Science. 2015 Dec 4;350(6265):1262-6. doi: 10.1126/science.aac9396.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / abnormalities
  • Brain / metabolism
  • Child
  • Congenital Abnormalities / genetics
  • Exome / genetics
  • Heart Defects, Congenital / diagnosis*
  • Heart Defects, Congenital / genetics*
  • Humans
  • Mutation
  • Nervous System Malformations / genetics*
  • Neurogenesis / genetics*
  • Prognosis
  • RNA Splicing / genetics
  • RNA Splicing Factors
  • RNA, Messenger / genetics
  • RNA-Binding Proteins / genetics
  • Repressor Proteins / genetics
  • Transcription, Genetic


  • RBFOX2 protein, human
  • RNA Splicing Factors
  • RNA, Messenger
  • RNA-Binding Proteins
  • Repressor Proteins