December 9, 2015 — Scientists have confirmed the role of a set of gene mutations in the development of congenital heart disease and simultaneously discovered a link between them and some neurodevelopmental abnormalities in children. These abnormalities include cognitive, motor, social and language impairments.
“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,” said Jonathan R. 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 study. Kaltman noted the findings from the study would have to be replicated and refined before a clinical test could be available. NHLBI is part of the National Institutes of Health.
Congenital heart disease — in which there are structural defects in the heart — is the most common type of birth defect in the United States, and one of the leading causes of infant death. Nearly 40,000 children are born with congenital heart disease each year, and experts estimate that approximately 1 to 2 million adults and 800,000 children in the U.S. currently live with the disease.
“Surgery is often performed early in life to repair heart defects,” said Kaltman. “However, we have found that once children reach school age, many exhibit various attention deficits, including attention deficit hyperactivity disorder and other neurobehavioral problems.”
In their study, published Dec. 4 in the journal Science, investigators from the Bench to Bassinet Program’s Pediatric Cardiac Genomics Consortium 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. De novo mutations 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 senior investigator Christine Seidman, M.D., of Brigham and Women’s Hospital, Howard Hughes Medical Institute and Harvard Medical School, Boston. “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 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.
Seidman added that if the relationship between the de novo mutations and neurodevelopmental abnormalities in children continues to hold, clinical genetic tests 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.
For more information: www.nhlbi.nih.gov
January 23, 2024 
