Researchers discover more than 1300 genes linked to congenital heart disease – BioWorld Online

Researchers from Monash University in Melbourne have developed a method for determining which genes are "in play" in causing cardiac abnormalities, and the technique not only confirmed well-known congenital heart disease genes, but also discovered 35 new genes not previously suspected in the disease.

Published in Genome Biology, the goal of the study was to find congenital heart disease genes, because nearly 1% of the babies born have congenital heart disease, and it is the leading cause of death in newborns, Travis Johnson, from Monash University's School of Biological Sciences, told BioWorld Science.

"Genetics have an awful lot to do with congenital heart disease, and we really have very few genes that we know of that contribute to this disease. Our goal was to try and find more potential candidate genes that could be involved in causing congenital heart disease," said Johnson, who co-led the work with Mirana Ramialison, from Monash University's Australian Regenerative Medicine Institute and the Murdoch Children's Research Institute.

The current conventional approach focuses on screening genes that are present in the heart only, he said, which often overlooks genes that are present in other tissues as well.

Despite the wealth of knowledge from these conventional gene discovery studies, the origin of congenital heart disease is unknown in 80% of cases, suggesting that several determinants of heart disease, including genetic, are yet to be identified, study authors said.

"Making the heart is almost like a symphony," Johnson said. "You need all the different instruments to play their role," he said, likening the genes to instruments.

"We looked at the sheet music -- what was switched on and when it was switched on -- and that gave us a long list of genes that could be causing heart disease.

"We found a lot of the genes that are already known to be involved in heart disease, which was really nice validation, but we found more than 1,000 other genes that are quite good candidates that have not been looked at before," said Johnson, who is a fly geneticist.

He teamed up with Ramialison, who developed bioinformatic software that mined existing databases to look for genes that were not only switched on in the heart during development but also at genes that are switched on in other places but that also work in the heart.

The resulting computational pipeline identified not only genes specific for the heart but genes that may also be associated with other organs such as the liver or kidney.

"These could comprise many of the missing congenital heart disease genes, but have been, to date, discounted because they are not unique to the heart," Ramialison said.

Fruit fly model

The researchers used the fruit fly, Drosophila melanogaster, as a testing model to determine some of the functional impacts of these novel genes. Drosophila is a well-established model organism to understand the genetic mechanisms of many human diseases, Johnson said, largely because about 75% of human disease-causing genes are found in the fly in a similar form.

"The fly has a heart muscle, and we looked at all the fly versions of the gene that we pulled out of the software pipeline. Because flies are easy to manipulate genetically, we used our genetic tools to systematically go through and knock them all out just in the heart.

"We asked which ones affect the development of the fly heart, and we found that more than 70% of them affect the development of the fly heart. We did that as a functional validation of genes. It's one thing for a computer program to spit out genes, but it's another thing to go into the lab and test them in an animal," he said.

The fly studies revealed "a long list of high-quality candidate genes for causing heart abnormalities in humans, giving real insight into just how susceptible this organ is to genetic mutations."

"All in all, we tested more than 35 of the genes in flies. As you can imagine, there's still a huge list of genes that are highly likely to be involved in forming the heart in utero."

"With this pipeline, we retrieve 76% of the known cardiac developmental genes and predict 35 novel genes that previously had no known connectivity to heart development. Functional validation of these novel cardiac genes by RNAi-mediated knockdown of the conserved orthologs in Drosophila cardiac tissue reveals that disrupting the activity of 71% of these genes leads to adult mortality. Among these genes, RpL14, RpS24 and Rpn8 are associated with heart phenotypes," study authors note.

"The pipeline enabled the discovery of novel genes with roles in heart development. This workflow, which relies on screening for noncoding cis-regulatory signatures, is amenable for identifying developmental and disease genes for an organ without constraining to genes that are expressed exclusively in the organ of interest," they said.

Next steps

The challenge now is to determine which genes are involved, when they are not working, and whether genetic screening can determine if a child is at risk of having a congenital heart defect.

"We now have a long list of genes and can sift through genetic data," Johnson said, noting that these genes are the ones most likely to be the important ones to look at, because the team narrowed it down to the "cream of the crop" for its validation strategy.

The research opens the way for more accurate prenatal genetic testing for congenital heart disease, and the method can now be applied to look at other organ development diseases, he said.

"But the heart is the top of the list because the heart is very sensitive to genetic noise -- it's the most important symphony to get right. We've been able to add a lot of genes to that list that will help people predict who is more likely to develop congenital heart disease.

"We're hoping that other researchers will take notice and start investigating the functions of these genes or potential roles in congenital heart disease."

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Researchers discover more than 1300 genes linked to congenital heart disease - BioWorld Online