Spontaneous Gene Mutations Tied to Child Heart Defects

About 10 percent of congenital heart defects may come from spontaneous rather than inherited gene mutations, according to a study that offers new insight into a condition that can range from simple to severe.

Scientists investigated the DNA of 362 newborns with serious heart defects in families where neither the parents nor the child’s siblings had cardiac illness. The research, reported online yesterday in the journal Nature, found hundreds of mutations that were only in the affected children.

Congenital heart defects occur in 8 out of every 1,000 newborns in the U.S., or more than 35,000 children yearly, according to the National Heart, Lung and Blood Institute. While the findings may not help prevent the condition, identifying the variants may one day aid doctors in individualizing treatments for the children, the researchers said.

“One of the most important questions when a family has a child with congenital heart disease is why?” said Edwin Kirk, a clinical geneticist at the Sydney Children’s Hospital, who wasn’t involved in the study. “Any research that helps us understand the answer hopefully one day will be something we can apply to answering the question for individual families.”

Surgical Success

Understanding the role of the variants may eventually help improve outcomes, said co-author Christine Seidman, director of the Cardiovascular Genetics Center at Brigham and Women’s Hospital in Boston, in a statement.

“After we repair the hearts of these children, some children do great and some do poorly,” said Seidman, who is a researcher at the Howard Hughes Medical Institute in Chevy Chase, Maryland. Scientists have suspected this might be due to differences in the underlying disease causes, she said.

The researchers compared DNA from children with heart defects and in healthy babies. Both had about the same number of so-called de novo mutations, the non-inherited variants. The sick children, though, were much more likely to carry damaging mutations at two sites within a cellular pathway known to regulate genes key in heart development.

“This is really a major contribution because it gives us some hard facts about the incidence of new mutations and the rates at which they may cause congenital heart disease,” said David Winlaw, a pediatric cardiac surgeon at Children’s Hospital Westmead in Sydney, in a telephone interview. “The great difficulty is knowing the relevance of a specific mutation.”

The next step is to narrow down the list of genes known to be associated with congenital heart disease to a list that’s known to be causative, he said.

New Finding

“This class of proteins that they have identified as being important for congenital heart disease are involved in that regulatory process,” said Sydney Children’s Hospital’s Kirk in a telephone interview. “That’s new. There was some hint of it from a couple of rare syndromes, but for non-syndromic congenital heart disease, I don’t think we had any hint that this was going to be important.”

The findings will help guide future research in this field, he said.

“When we go looking for changes in genes to do with congenital heart disease, it gives a whole bunch of new targets to work on,” Kirk said. “That has a fairly important research impact.”

The research was undertaken by the Pediatric Cardiac Genomics Consortium, and involved scientists at nine U.S. centers and one in the U.K.

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