Largest genomic study of heart disease in children reveals inherited genetic roots and new disorders

The international study sequenced and analysed the protein-coding segments of the genome of 1,900 congenital heart disease patients and their parents

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Nature Genetics doi: 10.1038/ng.3627
CDK13 protein produced by novel gene with causative mutations for newly discovered congenital heart disorder
In one of the largest international genetic studies of congenital heart disease (CHD), researchers have discovered gene mutations linked to three new rare congenital heart disorders. Published in Nature Genetics today (1 August), the researchers also found the first clear evidence of genetic differences between two forms of the disease, and that one form can be traced back to healthy parents.

To help them understand the genetic causes of heart disease, researchers from the Wellcome Trust Sanger Institute and their international collaborators sequenced and analysed the protein-coding segments of the genome – known as the exome – of 1,900 CHD patients and their parents.

CHD is one of the most common developmental defects, occurring in 1 per cent of the population world-wide and affecting 1.35 million new-borns with CHD every year. It causes problems like holes in the heart, which in severe cases can require corrective surgery. Heart disease can cause life-long disability and is the largest cause of infant mortality in the western world after infectious disease.

Most CHD patients – around 90 per cent – have only isolated defects of the heart, and are called non-syndromic. The remaining 10 per cent of patients are described as syndromic CHD patients who have additional developmental problems such as abnormalities in other organs or an intellectual disability. It had previously been thought that both of these forms of the disease might be caused by spontaneous new mutations which are present in the child and absent in the parents.

The study confirmed that the rarer syndromic CHD patients often had spontaneous new mutations likely to interfere with normal heart development that were not seen in the parents. However, it also showed that non-syndromic CHD patients did not have such spontaneous mutations, and for the first time conclusively showed that they often inherited damaging gene variants from their seemingly healthy parents.

Parents who have a child with CHD often want to find out how likely it is that any future children will be affected. While even larger studies are needed to pinpoint the exact combination of genetic and environmental factors that contribute to heart disease, understanding these factors could one day help doctors advise parents more accurately about their chances of having a second child with the disease.

Studying these new mutation events across the genome, the researchers also found three new genes in which mutations can cause rare syndromic CHD disorders. This could help further studies identify biological mechanisms important for normal development of the embryo.

“We are aiming to understand the genetics of the development of the human heart. This is the first study to quantify the role that rare inherited variants play in non-syndromic CHD, and is extremely valuable as these patients make up 90 per cent of CHD patients worldwide. We are trying to find the subset of genes with the highest risk of causing non-syndromic CHD.”

“As these are rare disorders this has meant sharing data globally so we can properly investigate the genetic origins of this disease – the families that shared these data and chose to be involved in this study have helped push forward understanding of these disorders.”

Dr Mathew Hurles Lead author from the Wellcome Trust Sanger Institute

“Here, research has shown for the first time that congenital heart defects are often a question of genetic inheritance. In the future, as a direct result of this research, doctors may be able to offer much clearer advice to families where one member has congenital heart disease.”

Professor Jeremy Pearson Associate Medical Director at the British Heart Foundation which part-funded the research

“Previous smaller scale studies have hinted at the possibility that non-syndromic CHD could be caused by inherited gene variants, but this is the first time that we have been able to show it with statistical evidence. This was only possible due to the global collaboration of centres in the UK, Germany, Belgium, Canada, the United States of America and Saudi Arabia integrating data from many clinicians on a large number of families. We now know that some of the causative factors of the disease are inherited from their healthy parents, which will be extremely helpful for designing future studies of non-syndromic CHD, helping to understand what causes the disease.”

Marc-Phillip Hitz Joint first author on the paper from the Sanger Institute and the University Medical Center of Schleswig-Holstein

More information

About Congenital Heart Disease

Congenital heart disease means a heart condition or defect that develops in the womb, before a baby is born. There are many different types of congenital heart disease. For example, a baby’s heart valves may not be properly formed or there may be holes between the chambers of their heart.

Most cases are due to something going wrong in the early development of the foetus. If there’s a family history of congenital heart disease, the mother has diabetes during pregnancy, or the mother has taken certain medications while pregnant (anticoagulants or antiepileptics) a baby may be at slightly higher risk of congenital heart disease.

Participating Centres include:

  • Wellcome Trust Sanger Institute, Cambridge, United Kingdom
  • Department of Congenital Heart Disease and Pediatric Cardiology, UKSH Kiel, DZHK (German Center for Cardiovascular Research), partner site Kiel, Germany
  • School of Life Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham, United Kingdom

For a full list of participating centres please see the paper.


Funding was provided by the Wellcome Trust, the British Heart Foundation, and the MRC amongst others. For a full list of funders please see the paper.


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Selected websites

  • The University Medical Center of Schleswig-Holstein (UKSH)

    The UKSH with both locations in Kiel and Lübeck is one of the largest medical centers in Europe. The unique feature of the University Medical Center is the interplay of patient care, research and teaching to the effect that scientific knowledge in the health care is incorporated (interpreted) directly. Together with the Dean of the Medical Faculty of the University of Kiel and the section of Medicine, University of Lübeck, the UKSH faces the challenges of the medicine of the 21st century. The only maximum care of the northern state of Germany guarantees an annual individualized diagnosis and treatment for 500,000 people – every 6th resident – and provides servicers for a quarter of all hospitals in Schleswig-Holstein. The 85 clinics and institutes are equipped with the full range of modern medicine and are a guarantee for patients that require a highly differentiated and interdisciplinary care, as well as an emergency care around the clock. As the largest employer and an important training establishment in the country that UKSH employs 13,000 people and therefore plays an a very important role in the health industry.

  • The University of Nottingham

    The Univeristy of Nottingham has 43,000 students and is ‘the nearest Britain has to a truly global university, with a “distinct” approach to internationalisation, which rests on those full-scale campuses in China and Malaysia as well as a large presence in its home city.’ (Times Good University Guide 2016). It is also one of the most popular universities in the UK among graduate employers and the winner of ‘Outstanding Support for Early Career Researchers’ at the Times Higher Education Awards 2015. It is ranked in the world’s top 75 by the QS World University Rankings 2015/16. More than 97% of research at The University of Nottingham is recognised internationally and it is 8th in the UK by research power according to the Research Excellence Framework 2014.

  • The Wellcome Trust Sanger Institute

    The Wellcome Trust Sanger Institute is one of the world’s leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.

  • The Wellcome Trust

    The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.