Researchers at the Ted Rogers Centre for Heart Research have developed an innovative approach to better understanding the complex signaling mechanisms underlying heart failure. A recent publication in the Proceedings of the National Academy of Sciences (PNAS) offers...
In a remarkable new genetic discovery, researchers at the Peter Munk Cardiac Centre, University Health Network (UHN), Ted Rogers Centre for Heart Research and The Hospital for Sick Children (SickKids) have found strong evidence that rare DNA variations can lead to Tetralogy of Fallot (ToF).
Published in Genetics in Medicine, a journal which is part of Nature Publishing Group, the study is the first to use whole genome sequencing for ToF – a cardiac abnormality with four heart defects that occur together. 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 3 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. In humans, genes vary in size from a few hundred DNA bases to more than 2 million bases.
Targeting the VEGF 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.
“VEGF is a well-known pathway in such areas as cancer or vascular biology, but here we have identified that it is likely to play an important role in the formation of our heart,” says Dr. Raymond Kim, scientific lead at the Ted Rogers Centre’s Cardiac Genome Clinic, and one of the authors of the study.
Researchers have found that these rare DNA changes in genes associated with the VEGF pathway – unobserved in the general population – accounted for over 10% of the 175 adult patients with ToF whose genomes were sequenced at The Centre for Applied Genomics at SickKids.
‘Major step forward’
Today, around 20% of patients with ToF are diagnosed with genetic conditions such as 22q11.2 deletion syndrome. Researchers are still looking for answers as to what may have caused this heart abnormality for the remaining 80% of patients.
“We have been searching for genetic causes for ToF for several years and this represents a major step towards understanding this condition,” says Miriam Reuter, Research Associate, Genetics and Genome Biology, The Hospital for Sick Children and member of the Ted Rogers Centre, and first author of the study.
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.
A firehose of data
Because of its broad lens, analyzing whole genome sequencing data is like searching for the proverbial needle in the haystack. In this study, that search was performed by Dr. Reuter, who combed through sequencing data on a very large number of genetic variants.
“Among several million variants per person, you must prioritize which ones to look at,” she says. “You need a hypothesis first about which are most likely to cause disease.”
One way to build a hypothesis is to concentrate on a cellular pathway. This research focused on VEGF because a recent study suggested one of its receptors to be involved in ToF. Dr. Reuter used this information to look deeper into other genes associated with VEGF signaling, and analyzed patient data for rare variants in these genes.
The vast majority of genetic variations are not associated with a disease. “So you must filter out all these variants to find the needles in the haystack,” says Dr. Kim.
Armed with the data, details about the biology of ToF, expertise in WGS studies and about ToF in the patients from UHN and SickKids, the researchers dug through 175 “haystacks” looking for a pattern amongst them. The pattern that threaded the “needles” in many of these cases turned out to be the VEGF pathway.
This represents a significant step toward individualized patient care in ToF. Understanding the mechanisms of a disease is essential to create truly individualized diagnostic and treatment strategies for patients.
“The results of this study represent many years of research participation by patients followed at the Adult Congenital Cardiac Clinic at Toronto General Hospital. Our next exciting steps will be to perform further whole genome sequencing studies of patients with ToF, investigate the role of the VEGF pathway in cardiac development using cellular models, and translate the benefits of this research to patients and their families,” says Dr. Bassett.
This study was funded by a donation from the W. Garfield Weston Foundation, Canadian Institutes of Health Research (CIHR) grant, University of Toronto McLaughlin Centre, and by the Ted Rogers Centre for Heart Research. The authors declared no conflicts of interest.
About the Ted Rogers Centre for Heart Research
The Ted Rogers Centre for Heart Research aims to develop new diagnoses, treatments and tools to prevent and individually manage heart failure – Canada’s fastest growing cardiac disease. Enabled by an unprecedented gift of $130 million from the Rogers family in 2014, the Centre was jointly conceived by its three partner organizations: The Hospital for Sick Children, University Health Network, and the University of Toronto. Together, they committed an additional $139 million toward the Centre – representing a $270 million investment in basic science, translational and clinical research, innovation, and education in regenerative medicine, genomics, and the clinical care of children and adults. It is addressing heart failure across the lifespan. www.tedrogersresearch.ca / @trogersresearch
About the Peter Munk Cardiac Centre
The Peter Munk Cardiac Centre (PMCC), established through the generous support of the Peter and Melanie Munk Charitable Foundation, is the premier cardiac centre in Canada. Since its opening, the PMCC has saved and improved the lives of cardiac and vascular patients from around the world. Each year, over 163,000 patients receive innovative and compassionate care from multidisciplinary teams in the PMCC, which trains more cardiologists, cardiovascular surgeons, and vascular surgeons than any other hospital in Canada. The PMCC is based at the Toronto General Hospital, Toronto Western Hospital and Toronto Rehabilitation Institute – all members of University Health Network. For more information, visit www.petermunkcardiaccentre.ca
About The Hospital for Sick Children (SickKids)
The Hospital for Sick Children (SickKids) is recognized as one of the world’s foremost paediatric health-care institutions and is Canada’s leading centre dedicated to advancing children’s health through the integration of patient care, research and education. Founded in 1875 and affiliated with the University of Toronto, SickKids is one of Canada’s most research-intensive hospitals and has generated discoveries that have helped children globally. Its mission is to provide the best in complex and specialized family-centred care; pioneer scientific and clinical advancements; share expertise; foster an academic environment that nurtures health-care professionals; and champion an accessible, comprehensive and sustainable child health system. SickKids is a founding member of Kids Health Alliance, a network of partners working to create a high quality, consistent and coordinated approach to pediatric health care that is centred around children, youth and their families. SickKids is proud of its vision for Healthier Children. A Better World. For more information, please visit www.sickkids.ca.