Genetic link between heart and neurodevelopment issues revealed

A team of scientists has determined why some children who are born with congenital heart disease also often have neurodevelopmental abnormalities, including impairments to cognitive, motor, language and social functioning.

The research, published in the Friday issue of the U.S. journal Science, suggested that these children accrue mutations very early in development that damage genes crucial for heart and brain formation.

Although almost everyone acquires new mutations in at least one gene, children with congenital heart disease "have bad luck because these new mutations hit genes necessary for heart and brain development," said Christine Seidman of Harvard Medical School, who co-led the study with Richard Lifton of Yale University and their colleagues in the Pediatric Cardiovascular Genetics Consortium.

About one percent of newborns suffered from congenital heart disease, in which structural flaws in the organ, such as misshapen valves or abnormal connections between major vessels, disrupt blood circulation.

With surgery or less invasive procedures, doctors can now correct defects that would have killed many of these children 30 years ago. However, when these children reached school age, many exhibited learning disabilities, difficulties with speech, and other signs that the brain or the rest of the nervous system hasn't developed properly.

In the new study, researchers used a technique called exome sequencing to genetically evaluate 1,220 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, which occur within egg, sperm, and fertilized cells, but are not part of the genetic makeup of the mother or father.

"This finding was especially high in patients who had congenital heart disease and another structural birth defect and/or a neurodevelopmental abnormality," said Seidman. "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."

Seidman noted that the findings have implications for basic research and clinical medicine.

"Through further analyses of these mutated genes, we expect to uncover new pathways that are critical for the development of the heart, brain, and other organs -- information that will contribute basic insights into the causes of many human congenital malformations," she said.

If the relationship between the de novo mutations and neurodevelopmental abnormalities in children continues to hold, clinical genetic tests, she said, 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, Seidman added. Endit