New research examines why some children born with heart defects also have developmental disabilities. [Image courtesy of Mark L. Riccio

An NIH-funded study led by scientists at Harvard Medical School that were part of the Pediatric Cardiovascular Genetics Consortium have found a link for a set of gene mutations in the development of congenital heart disease and various neurodevelopmental abnormalities in children—include cognitive, motor, social, and language impairments.

“We're homing in on a set of genes that have multiple different roles in multiple different tissues during development: heart tissue, brain tissue, other developing organs, limb tissue,” said co-lead author Jason Homsy, M.D., a Harvard Medical School fellow. “Our study shows a common genetic link for the development of these diseases.”

The investigators utilized whole exome sequencing from more than 1,200 children and their parents, to show that children with both congenital heart disease and neurodevelopmental delays share certain genetic mutations that thwart the normal development of both the heart and the brain.

“The risk of developing neurodevelopmental disabilities is so high when these particular gene mutations are present that we might consider testing for them in all patients with congenital heart disease,” explained co-author Jonathan Kaltman, M.D., a study investigator and program administrator of the National Heart, Lung, and Blood Institute’s (NHLBI) Bench to Bassinet Program, which funded the current study.

The findings from this study were published recently in Science through an article entitled “De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.”

After sequencing, the researchers employed the use of a mathematical model to analyze mutations in the protein-coding portion of the genomes from children with congenital heart disease that were not present in their parents' genomes. Moreover, the researchers found that these children have more of these de novo mutations in genes that are highly expressed in the developing heart, compared to a control cohort of children without congenital heart disease.

The authors noted that the de novo mutations were also found to be more frequent in children with congenital heart disease plus another birth defect, either neurodevelopmental delay or more subtle abnormalities of finger or ear shape—supporting the hypothesis for shared genetic causes of the cardiac and extra-cardiac abnormalities rather than surgeries or environmental factors.

“This finding was especially high in patients who had congenital heart disease and another structural birth defect and/or a neurodevelopmental abnormality,” noted Howard Hughes Medical Institute investigator and co-senior author Christine Seidman, M.D., of Brigham and Women’s Hospital and Harvard Medical School. “When the consortium examined the specific genes involved, many of them were highly expressed in both the developing heart and brain, suggesting that a single mutation can contribute to both congenital heart disease and neurodevelopmental abnormalities.”

“We can pretty clearly tell the parents of children with congenital heart disease what's going to happen after the heart surgery, but there's always a big question: Will my kid learn well in school?” Dr. Seidman added. “If we could identify children at high risk for neurodevelopmental delays, they could receive increased surveillance and earlier interventions than occur now.”

The Harvard investigators explained that the mutations primarily affected genes involved in three areas: morphogenesis, chromatin modification, and transcriptional regulation. The perturbation of any one of these processes can lead to severe defects in a variety of organs.

“These genes are not just involved in shaping the heart,” Dr. Seidman said. “They are master regulators of organ development.”

For example, one of the mutated genes is RBFOX2, which encodes a molecule that regulates RNA splicing. While RBFOX2 has not been previously implicated in congenital heart disease, de novo mutations were identified in multiple affected children from the study.

At this point, it is still unclear how all the mutations affect the downstream developmental process, but the impact of finding these mutations could provide insight into the causes of many human congenital malformations.

“There are still many unanswered questions, including why the same mutation can cause very different clinical manifestations,” Dr. Seidman stated. “It's a long, long, long way down the road, but we'd like to believe that if you knew the steps by which these mutations perturbed the regulation of gene expression, there might even be ways to actually treat it.”

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