De novo mutations in congenital heart disease and neurodevelopmental anomalies

In a study, published Dec. 4, 2015 in the journal Science, investigators from the Bench to Bassinet Program’s Pediatric Cardiac Genomics Consortium used exome sequencing to genetically evaluate 1,213 family trios composed of a child with congenital heart disease and the mother and father. Through this technique, which examines only the protein-coding regions of DNA, they found that children with moderate-to-severe congenital heart disease had a substantial number of "de novo" gene mutations. De novo mutations occur within egg, sperm, and fertilized cells, but are not part of the genetic makeup of the mother or father.

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 Congenital heart disease (CHD), neurodevelopmental disabilities (NDDs), and extracardiac congenital anomalies (CAs) 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.

These findings have implications for basic research and clinical medicine. Further analyses of these mutated genes, would help uncover new pathways that are critical for the development of the heart, brain, and other organs.

If the relationship between the de novo mutations and neurodevelopmental abnormalities in children continues to hold, clinical genetic tests could be created for newborns with moderate-to- severe congenital heart abnormalities. The patients found to carry the gene mutations could then be targeted for greater surveillance and early interventions that might address and limit developmental delays and improve their outcomes.

Congenital heart disease in which there are structural defects in the heart is the most common type of birth defect in the United States, and one of the leading causes of infant death. Nearly 40,000 children are born with congenital heart disease each year, and experts estimate that approximately 1 to 2 million adults and 800,000 children in the U.S. currently live with the disease.Surgery is often performed early in life to repair heart defects,but once children reach school age, many exhibit various attention deficits, including attention deficit hyperactivity disorder, and other neurobehavioral problems.

Citation:

Homsy J, Zaidi S, Shen Y, et al. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science. 2015; doi:10.1126/science.aac9396.

Bench to Bassinet Program’s Pediatric Cardiac Genomics Consortium