Genetic factors linked with neurodevelopmental delays in children with congenital heart disease

brain geneticsAs survival has improved dramatically for children with even the most serious forms of heart disease, neurodevelopmental disabilities have been increasingly recognized. These can affect not only school performance, but also future employment, quality of life and social relationships.

“We’ve known for a while that children with congenital heart disease (CHD) have a higher risk of developmental delays,” says Amy Roberts, MD, a genetic cardiologist at the Boston Children’s Hospital Heart Center. “There are multiple hypotheses as to why that might be, and they’re not mutually exclusive.”

The side effects of surgery, such as oxygen deprivation during bypass, are commonly thought to be to blame. Others suspect problems with the in utero environment. But these factors are not the whole story.

“Even in studies that have measured every known risk factor, only one third of neurodevelopmental disabilities in children with CHD can be explained by factors related to the child’s heart disease, medical history or family factors,” notes Jane Newburger, MD, MPH, director of the Cardiac Neurodevelopment Program at Boston Children’s.

Perhaps there is a genetic component?

In a recent study published in Science, a team of researchers from seven hospitals (Boston Children’s, Brigham and Women’s Hospital, Children’s Hospital of Philadelphia, Columbia, Mount Sinai, Yale and University of California Los Angeles), examined the whole genomes of 1,213 patients with complex CHD, looking for genetic indicators that a child will have developmental delays alongside his or her CHD.

Clues in the codes

The group focused on “de novo” mutations, or mutations that are not inherited. Their question: Is there a difference in the rate of de novo variants in patients with and without CHD?

To find out, the researchers looked at de novo variants in genes that contribute to heart and brain development. These genes are referred to as “high heart” and “high brain” genes. Roberts also calls them “master regulators,” because they have widespread effects on the body’s most vital organs.

CHD patients with de novo variants in these genes exhibited more developmental delays than CHD patients without those variants.

Roberts emphasizes that genetic factors may not only contribute to neurodevelopmental disabilities by affecting brain structure and microstructure, but also may influence the body’s response to the stresses of heart disease. For instance, there might be genetic variants that make children better or less able to tolerate oxygen deprivation or anesthesia.

“We can’t yet tell individual patients whether or not they will suffer developmental delays based on genetic factors,” says Roberts. “But in the future, we’d like to be able to tell parents if their child is in the low, medium or high risk group.”

What’s next?

In the next stage of this research, a subgroup of patients who took part in the first study, and thus have had their genome sequenced, will be evaluated by MRI and specific tests for cognitive function. The results will be analyzed to uncover any patterns that point to potential genetic indicators for developmental issues. Newburger is the national co-chair for this study.

“This is a very exciting time,” Roberts says. “We’re using a much more advanced approach than before. It’s a genome-wide analysis, so the research is looking at all of a patient’s genes, not just a few. And it’s a large group of subjects; patient data are compiled from five-partner institutions across the country. We’re in the beginning stages of some very ambitious research.”

The published study was supported by the National Heart, Lung and Blood Institute (NHLBI) and, in Boston, by the Kostin Family Innovation Fund (other centers had other grant sources). The ongoing work is supported by the NHLBI and the National Institute of Child Health and Human Development and, in Boston, by the Kostin Family Innovation Fund.

Learn more about the Cardiovascular Genetics Program