Ten percent of babies born with congenital heart disease have genetic mutations that occurred while they were in the womb, i.e. they did not inherited the genetic mutations from their parents, researchers reported in the May 12th issue of the journal Nature.

Thousands of children are born annually with severely malformed hearts. These disorders are collectively referred to as "congenital heart disease" or congenital heart defects. Congenital means you are born with it. Congenital does not necessarily mean it is inherited; congenital heart disease, for example, may be inherited, could be due to genetic abnormalities that occur after conception, components in the intrauterine environment, or other factors.

The defect associated with congenital heart disease either obstructs the flow of blood in the heart or nearby vessels, or causes blood to flow through the heart abnormally. Congenital heart disease is a common birth defect and a major cause of death associated with birth defects.

Many congenital heart defects can be repaired with surgery. However, experts cannot fully explain what causes them, or how to prevent them. According to new research, approximately 10% of congenital heart defects are caused by genetic abnormalities which are not present in the infant's parents.

Spontaneous mutations behind some cases of congenital heart disease

A large number of babies born with heart defects have parents and siblings with healthy hearts. This suggests that diseases are also caused by new genetic mutations that occur spontaneously, i.e. after conception. They are sometimes referred to as de novo mutations - mutations that neither parent possessed nor transmitted.

"The mutations in patients with congenital heart disease were found much more frequently in genes that are highly expressed in the developing heart."
Christine E. Seidman
Howard Hughes Medical Institute (HHMI) investigator, Richard Lifton, who is also at Yale School of Medicine, said "Until recently, we simply didn't have the technology to test for this possibility." The research team also included Christine Seidman, an HHMI researcher at Brigham and Women's Hospital, Boston, as well as scientists from Columbia, Mt. Sinai and the University of Pennsylvania. They collaborated to study congenital heart disease through the Pediatric Cardiac Genomics Consortium (part of the National Heart Lung and Blood Institute).

The team used robust sequencing technologies to compare the protein-coding genome regions in infants and young children with congenital heart disease and healthy children and their parents. They found that approximately 10% of severe cases of congenital heart diseases were caused by de novo mutations.

Many mutations found in the epigenome

Lifton explained that severe congenital heart defects were caused by mutations in many hundreds of different genes - they were concentrated in a pathway that regulates key developmental genes. These genes affect a system of chemical tags that alters gene expression - the epigenome.

The investigators started off gathering and analyzing genomic data from 362 families where both parents were "healthy" with no family history of heart problems, but had a child with severe congenital heart disease. After comparing genomes within these families, they were able to detect where the DNA mutations which were only present in the child (but not his/her parents). They also recruited 264 families whose parents and offspring had no heart problems, to compare de novo mutations of healthy children.

The scientists concentrated their gene-mutation search on the "exome". The exome consists of all the genome's exons, which are the coding portions of genes - this is where disease-causing mutations usually occur.

All the children (with and without congenital heart disease) had more-or-less the same number of de novo mutations - slightly less than one protein-altering mutation each. However, there was a clear difference in where these mutations were located. Seidman said "The mutations in patients with congenital heart disease were found much more frequently in genes that are highly expressed in the developing heart."

Seidman explained that infants with severe congenital heart disease were 7.5 times more likely to have a harmful mutation in genes expressed in the developing heart.

Mutations were found in a range of genes in the children. However, one particular pathway was clearly enriched in infants with heart defects. This pathway helps regulate gene activity by regulating how DNA is packaged inside cells. Our DNA is wrapped around histones (types of proteins), chemical tags called methyl groups are added to histones to control which genes are turned off and on.

In the infants with congenital heart disease, the authors detected excess mutations in genes that affect histone methylation at two locations that regulate key developmental genes.

Overall, Lifton, Seidman and team found that de novo mutations cause 10% of severe congenital heart diseases. Lifton explained that approximately one third of this contribution comes from the histone-methylation pathway. A mutation in just one copy of a gene in this pathway may be enough to considerably increase the risk of a heart abnormality.

Hunting down de novo mutations by using direct sequencing of protein-coding regions in the human genome has only been done with one other relatively major congenital condition - autism. In that analysis, Lifton and team detected mutations in some of the same genes mutated in patients with congenital heart disease. The same pathway appears to be involved in autism as well. The authors believe "this pathway may be perturbed in a variety of congenital disorders".

Identifying mutations may not help prevent heart diseases from developing in the first place, but knowing they are present might help doctors provide more effective and prompt treatment.

Seidman said "After we repair the hearts of these children, some children do great and some do poorly."

Experts have long suspected that some congenital heart problems are probably due to de novo mutations.

According to researchers from the University of East Anglia, the origins of congenital heart defect could be traced right back to the first stages of embryonic development.

Written by Christian Nordqvist