Scientists have discovered genetic changes that may be responsible for a link between developmental problems in the heart and in the brain.

Although doctors have long known that congenital heart disease (which includes conditions such as a hole in the heart) can be associated with brain development, they did not know whether brain issues arose from complications from the heart condition, or whether they had a common genetic cause. This latest research, published today in the journal Science, suggests the latter is most likely.

The researchers found that babies born with heart problems have a number of genetic changes in common, even when there is no family history of heart disease. These babies, who are at risk of going on to develop problems with brain function as well as difficulties with their hearts, could be helped if they were tested and the genetic abnormalities they carry identified. This might lead to interventions that could improve school performance, employability and quality of life, the scientists say.

The work comes from a large consortium based in the US, collaborating with teams in the UK. James Ware, Clinical Senior Lecturer in Genomic Medicine at the MRC’s Clinical Sciences Centre (CSC) based at Imperial College, is co-lead author of the paper describing the results.

The researchers studied 1200 individuals with congenital heart disease; that is people who were born with heart problems such as a hole in the heart, or abnormal connections between the heart and main blood vessels. Some had heart problems only. Others had problems with brain function too. The scientists compared their genetic make-up with that of close family members and healthy controls, a process that involved de-coding and analysing the DNA blueprint, or exome, of some 6000 people.

They found several new genes causing congenital heart disease, and also found shared changes in individuals with congenital heart disease and people with developmental problems with brain function.

“We found that it’s all part of the one condition – the same genetic abnormalities are causing both sets of problems,” James Ware

Though it’s been known for a while that some people with congenital heart disease go on to have neuro-developmental problems, it has not been clear how the two are linked, and doctors have not been able to tell which patients will develop problems and might benefit from early help.

Ware explained: “One question has been whether these neuro-developmental problems are caused by the heart disease – perhaps due to problems with the blood supply to the brain, either because the connections to the heart are abnormal or because patients undergo complicated heart surgery, including heart bypass, as a baby – or whether the brain function problems and early heart problems are actually part of the same condition. We found that it’s all part of the one condition – the same genetic abnormalities are causing both sets of problems.”

The work was led by co-senior author Christine Seidman, the Thomas W. Smith Professor of Medicine at Brigham and Women’s Hospital and HMS professor of genetics.

Co-lead author with Ware was Jason Homsy, HMS research fellow at Massachusetts General Hospital. The authors say that the genetic signals they found could one day lead to testing that could help parents watch their children for signs of neurodevelopmental difficulties and allow them to find their children help and support even earlier than now possible. Further in the future, knowledge of the particular genes at fault may yield opportunities to treat both congenital heart disease and neurodevelopmental delays in advance.

“There might even be ways to actually treat it,” Christine Seidman

“These genes are not just involved in shaping the heart,” Seidman said. “They are master regulators of organ development.” The same mutation can cause many different clinical manifestations, Seidman said. These altered genes affect transcriptional pathways, the complicated sequences of molecular events directing development of organs or other tissues.

For now, Seidman said, knowing that a genetic mutation is present is different from knowing the outcome. “It’s a long, long, long way down the road,” Seidman said, “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.”

One of Ware’s key contributions to today’s study was analytical software, called “denovolyzer”, which analyses whether a specific gene is carrying more “de novo” mutations than might be expected. De novo mutations are those that arise sporadically rather than being inherited. He helped to develop the approach with a team of statisticians led by Professor Mark Daly at Massachusetts General Hospital and the Broad Institute in Boston. He describes it as a powerful new way to interpret genetic variation, and says he hopes this software, which is open source, will help other scientists working on similar problems in medical genetic research.

Dr Ware did his PhD and a post-doc at the CSC, before being appointed as a Clinical Lecturer at Imperial College. He has recently spent a year in the Genetics Department at Harvard Medical School in Boston – where he carried out this work in the laboratory of Professors Jon and Christine Seidman. He returned to the CSC from Boston in April to start a new group at Imperial College, working closely with Dr Stuart Cook, who leads the Cardiovascular Magnetic Resonance Imaging and Genetics group at the CSC. Dr Ware is funded by a Fellowship from the Wellcome Trust and is honorary consultant cardiologist at Royal Brompton hospital.

The US-centred collaborative effort behind today’s results included the Pediatric Cardiac Genomics Consortium, Pediatric Heart Network and the Cardiovascular Development Consortium.

 

Learn more about James Ware’s software here and here.
Read more about James Ware’s research in the news.

 

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