Due to advances in modern medicine and surgery, children diagnosed or treated for congenital heart disease have a much better survival rate today. However, certain recovering infants show delays in cognitive skills, such as language and social functioning. These impairments can significantly affect their overall performance in schools and at the workplace, compromising their quality of life.

But why does this phenomenon occur? The Pediatric Cardiovascular Genetics Consortium, led by a team of Harvard Medical School scientists, has finally answered this question. By analyzing exome sequences of over 1,200 children and their parents, the researchers reported that children suffering from congenital heart disease and subsequent neurodevelopmental delays shared a particular genetic mutation that hindered normal development of the heart and brain.

Finding The Answer: Congenital Heart Disease In Children

Epidemiological studies revealed that the risk of developing neurodevelopmental delays is tenfold higher for children with moderate to severe congenital heart disease as compared to other children. However, the exact reason was not clear. Several possibilities were considered – rigors of open-heart surgery soon after birth, limitation of nutrients and oxygen due to heart defects, spontaneous genetic mutations were among some of the theories proposed.

To determine the actual reason, co-authors Kaitlin Samocha and Mark Daly of the Analytical and Translational Genetics Unit at Massachusetts General Hospital created a mathematical model for analyzing those mutations in the protein-coding portion of genomes of children with congenital heart disease that were absent in their parents’ genomes. The analysis revealed that the children had more of these de novo mutations in genes that were significantly involved in heart development.

Genetic Link Is The Key

The de novo mutations discovered were observed to be more common in children who, along with congenital heart disease, had another birth defect, such as neurodevelopmental delay or a more-subtle abnormality of finger or ear shape. These findings reinforce the idea of shared genetic causes of cardiac and extra-cardiac abnormalities instead of surgeries or environmental factors.

“We’re closing in on a set of genes that have shown multiple roles in different tissues during the development of heart tissue, brain tissue, limb tissue and various other developing organs,” stated co-lead author of the Science paper Jason Homsy, an HMS LaDue Fellow who trained at Mass General. “Our study shows a mutual genetic link for the development of these diseases”.

Explaining The Mutations Discovered

We can very accurately tell parents of children with congenital heart disease the prognosis after their heart surgery, but a bigger question always remains unclear: “Will my kid learn well in school?”, explained Christine Seidman, the HMS Thomas W. Smith Professor of Genetics and Medicine at Brigham and Women’s Hospital and a Howard Hughes Medical Institute investigator. “If we could identify high-risk populations of children, in terms of neurodevelopmental delays, they could be given increased surveillance and earlier interventions for a better outcome”.

The mutations basically affected genes involved in morphogenesis, chromatin modification and transcriptional regulation. A slight alteration in any one of these processes during a critical developmental stage could result in malformation of the heart and various other developmental defects, including a severed connection within the brain.

“These genes are not only involved in shaping the heart, but they are also major regulators of organ development”.

One of the mutated genes – RBFOX2 – encodes a molecule involved in regulating RNA splicing. This gene has not been implicated in congenital heart disease previously, but de novo mutations in RBFOX2 were found in many affected children.

What The Future Holds

“There are still multiple questions that remain unanswered, such as why does the same mutation cause extremely different clinical manifestations in certain children”, Seidman said. One possibility is the existence of additional genetic variants in the multiple layers of transcriptional regulation that compensate for some of the mutations, but worsen the consequences of others.

But for now, the researchers state that these findings could lead to early testing and identification of newborns with congenital heart disease at a higher risk of neurodevelopmental difficulties.

“We’d like to believe that if we know the steps via which these mutations disturbed the regulation of genetic expression, we might even be able to effectively treat it”, concluded Seidman.