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In a remarkable new genetic discovery, researchers at UHN, Ted Rogers Centre and SickKids have found strong evidence that rare DNA variations can lead to Tetralogy of Fallot (ToF) – a cardiac abnormality with four heart defects that occur together.
Genetics in Medicine, the study is the first to use whole genome sequencing for ToF.
The causes and mechanisms that lead to ToF are as of yet largely unclear. For years, scientists have been studying the possible role of genetic changes.
Whole genome sequencing is used to determine the identity and order of the three billion chemical building blocks or units – made from four different "bases" – that make up a DNA molecule. By analyzing the sequences, scientists are able to determine the type of genetic information that is in a DNA segment. Genes, which are made up of DNA, provide the code to produce proteins and help us understand how a protein functions in a system or pathway.
A collective effort supported by
The Dalglish Family 22q Clinic at the Peter Munk Cardiac Centre, the
Ted Rogers Centre and
SickKids, the team found that the “vascular endothelial growth factor” (VEGF) signaling pathway was strongly implicated in adult patients with ToF.
Specifically, the researchers discovered harmful changes in the genetic code for proteins important in blood vessel and heart development. These proteins were all part of the VEGF cellular pathway. By understanding the changes to cell signalling in this important pathway, diseases like ToF may be treated more effectively.
In ToF, the four cardiac defects begin in-utero and require specialized life-saving surgery typically performed within the first month of life. ToF represents around one in ten of all cases of congenital heart disease.
Surgery can repair the defects and most patients with ToF now live well into adulthood. However, patients require life-long follow-up and may need repeated surgeries or further treatment to address a failing right ventricle while facing a higher risk for complications including endocarditis, arrhythmia and heart failure.
"Whole genome sequencing will allow us not only to better understand causes for ToF, but the results could have implications on how we treat patients and support them throughout their life," says Dr. Anne Bassett, senior scientist at the Toronto General Hospital Research Institute, director of The Dalglish Family 22q Clinic at the Peter Munk Cardiac Centre and senior author of the study.