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Exome Sequencing Helps Uncover New Congenital Heart Defect Disorders in Children

NEW YORK (GenomeWeb) – A team led by researchers at Wellcome Trust Sanger Institute have found three new congenital heart defects (CHDs) in children and a clear genetic difference between two forms of CHD.

CHD is one of the most common developmental defects in newborns and causes problems like holes in the heart. This disease occurs in one percent of the worldwide population and affects nearly 1.4 million newborns each year. In severe cases, patients have to undergo corrective surgery and can suffer lifelong disability.

The new findings, published today in Nature Genetics, are from a large international genetic study on congenital heart disease. The researchers found clear evidence of genetic differences between two forms of the disease: syndromic and non-syndromic CHD. They also discovered several gene mutations linked to three new rare syndromic CHD disorders.

"We are aiming to understand the genetics of the development of the human heart," Matthew Hurles, corresponding author from the Wellcome Trust Sanger Institute, said in a statement. "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 percent of CHD patients worldwide. We are trying to find the subset of genes with the highest risk of causing non-syndromic CHD."

The team began their study by collecting blood samples from 1,900 CHD patients and their parents. They then sequenced the exomes of these patients on an Illumina HiSeq platform, and analyzed and validated de novo protein-truncating variants.

The researchers were able to confirm that syndromic CHD, the rarer of the two conditions, often had spontaneous new mutations, which were likely to interfere with normal heart development. These mutations were not seen in parents of patients with this condition.

However, they also observed that non-syndromic CHD patients did not have such spontaneous mutations, instead finding that these patients often inherited damaging gene variants from their seemingly healthy parents.

"Here, research has shown for the first time that congenital heart defects are often a question of genetic inheritance," Jeremy Pearson, associate medical director at the British Heart Foundation, part-funder of the research, said in a statement.

"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," Marc-Phillip Hitz, co-first author on the paper from the Sanger Institute and the University Medical Center of Schleswig-Holstein, said in a statement. "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."

The researchers also identified genome-wide significant syndromic CHD disorders caused by de novo mutations in the CHD4, CDK13, and PRKD1 genes, all of which ares involved in protein coding.

In addition, the researchers identified 16 genes associated with CHD. Of those identified, twelve were known developmental-disorder associated genes; one — MYH6, a gene that codes the protein MHC-α — was associated with CHD but not with developmental disorders; and three— CHD4, CDK13, and DIAPH3 — were previously unknown candidate genes.

"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," Hurles said.

While the researchers acknowledge that more studies are necessary to determine to what degree genetics and environmental factors each contribute to the development of heart disease and disorders like CHD, they feel that these findings lay the groundwork for helping to understand some of these mechanics. They hope that this could help identify biological mechanisms important for healthy development of the embryo and enable clinicians to better advise their patients.