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Congenital heart disease, neurodevelopmental delays linked to same genes
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Mutations early in gestation appear to be responsible for damage to genes for both heart and brain development, according to research published in Science.
“This research suggests that among infants with heart disease, we may be able to identify those at higher risk for neurodevelopmental problems, and to intervene earlier with therapy during a crucial stage of brain development,” Elizabeth Goldmuntz, MD, from the division of cardiology at The Children’s Hospital of Philadelphia and the department of pediatrics at the Perelman School of Medicine, University of Pennsylvania, said in a press release.
Mutations identified
For the NIH-funded study, Goldmuntz and colleagues sequenced exomes from 1,213 children with congenital heart disease not from a clinically recognized genetic syndrome and their parents, who did not have congenital heart disease.
The researchers compared de novo mutations identified in the children with congenital heart disease occurring in isolation or in conjunction with congenital abnormalities, neurodevelopmental disabilities or both with those in a control group of 900 children with autism spectrum disorder and their unaffected parents.
According to the researchers, damaging de novo mutations in 4,420 genes in the top quartile of expression during the development of the heart were elevated in those with congenital heart disease compared with those without it (enrichment = 2.4; P = 5.1 x 10-24).
The mutations occurred in 20% of patients who had congenital heart disease, congenital abnormalities and neurodevelopmental disabilities, but in only 2% of patients with congenital heart disease alone.
The researchers determined that the mutations altered genes implicated in morphogenesis, chromatin modification and transcriptional regulation, and that there were multiple mutations in RBFOX2, a gene that regulates messenger RNA splicing.
When the researchers examined other cohorts examined for neurodevelopmental disabilities, the genes that mutated in those populations were enriched in those who also had congenital heart disease, especially in those who also had neurodevelopmental disabilities, according to the paper.
In all, the researchers identified 21 genes harboring the damaging mutations in more than one patient.
Genetic factors relevant
“Over the years … non-genetic factors couldn’t fully explain the neurological disabilities in these patients,” Goldmuntz said. “This new study supports what many of us suspected — that some genes control both heart and brain development.”
Although de novo mutations occur in almost everyone, children with congenital heart disease “have bad luck because these new mutations hit genes necessary for heart and brain development,” Christine E. Seidman, MD, from the department of genetics at Harvard Medical School and Howard Hughes Medical Institute at Harvard and Yale universities, said in a press release.
Jonathan R. Kaltman, MD
Jonathan R. Kaltman, MD, from the heart development and structural diseases branch of the NHLBI’s division of cardiovascular sciences and program administrator of the NHLBI’s Bench to Bassinet Program, said in a press release that “the risk of developing neurodevelopmental disabilities is so high when these particular gene mutations are present that we might consider testing them in all patients with congenital heart disease.” – by Erik Swain
Disclosure: The study was funded by the NIH/NHLBI. Goldmuntz reports no relevant financial disclosures. Kaltman is an employee of the NIH/NHLBI. Seidman reports holding equity in Myocardia. See the full study for a list of the other researchers’ relevant financial disclosures.
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