Hearts and minds: Study uncovers genetic links

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. The researchers, who's results are published today in the journal Science, 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.

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.

Dr James Ware, co-first author of the paper and Clinical Senior Lecturer in Genomic Medicine at the MRC's Clinical Sciences Centre (CSC) based at Imperial College 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."

One of Dr 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, then spent three years 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 October 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.