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, 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.
Dr Mathew Hurles, lead author from the Wellcome Trust Sanger Institute, said: "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."
Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation which part-funded the research, said: "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."
Marc-Phillip Hitz, joint first author on the paper from the Sanger Institute and the University Medical Center of Schleswig-Holstein, said: "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."
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Alejandro Sifrim and Marc-Phillip Hitz et al. (2016) "Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing", Nature Genetics. DOI: 10.1038/ng.3627