Looking Outside the Heart Detects More Congenital Heart Disease-Causing Genes

Image of a heart with a DNA double helix in front of it to indicate genetic heart diseases such as familial hypercholesterolemia.
Credit: iStock/SvetaP DNA double helix: iStock/Kagenmi

Researchers from Monash University in Melbourne, Australia have developed a computational/functional genomic pipeline to determine which genes are most likely to cause cardiac abnormalities.

Their technique not only confirmed well-known congenital heart disease (CHD) genes, but also discovered 35 new genes previously not suspected in the disease. The researchers say these findings open the way for more accurate prenatal genetic testing for congenital heart disease.

This study was published in Genome Biology and co-led by Associate Professor Mirana Ramialison from Monash University’s Australian Regenerative Medicine Institute and the Murdoch Children’s Research Institute, as well as Travis Johnson, a researcher from Monash University’s School of Biological Sciences.

One in every 100 babies is born with CHD, and that is the major cause of death in newborns. However, the genetic cause of these developmental disorders is not fully understood, hindering the development of accurate pre-natal genetic testing.

Typically, disease-causing genes are identified by screening for those that display heart-specific expression during development.

This team aimed to improve on this methodology  “which focuses on screening genes that are present in heart only– an approach that often overlooks genes that are present in other tissues as well, despite still playing important roles in heart development,” said Hieu Nim from the Australian Regenerative Medicine Institute, the first author of the study.

“The trick was to mine genome databases to identify genes that were specifically ‘switched on’ in the heart,” added Nim. 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.

They first created a pipeline of genome-wide discovery based on the identification of a cardiac-specific cis-regulatory element signature that points to candidate genes involved in heart development and congenital heart disease. With this pipeline, they retrieved 76% of the known cardiac developmental genes and predicted 35 novel genes that previously had no known connectivity to heart development.

The researchers then used the fruit fly, Drosophila melanogaster, as a testing model to determine some of the functional impacts of these novel genes. About 75% of human disease-causing genes are found in this fly in a similar form, it is easy to work with, breeds quickly, and many tools are available to manipulate any genes in it.

According to Johnson, the Drosophila 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.”

Functional validation of these novel cardiac genes by RNAi-mediated knockdown of the conserved orthologs in Drosophila cardiac tissue revealed that in 71% of these genes, disrupting their activity leads to adult mortality. Among these genes, RpL14RpS24, and Rpn8 are associated with heart phenotypes.

Johnson cautioned that the identification of dozens of new CHD candidate genes is some way from providing more accurate prenatal genetic testing for CHD. “We now need to conduct functional studies on all of these genes in animal experiments to determine what they actually do, so its early days, but we now have an excellent starting point.”

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