Gene discovery may lead to cure for broken hearts
by Sharon Gray
Touched by the plight of families in Newfoundland affected by ARVC (arrhythmogenic right ventricular cardiomyopathy), the molecular genetics research lab in the Faculty of Medicine led by Dr. Terry-Lynn Young made a group decision to concentrate their efforts on identifying the responsible gene. They were successful and on Feb. 28 the results of their research were published in the American Journal of Human Genetics.
PhD students Nancy Merner and Kathy Hodgkinson are the first authors of the article.
“A year and a half ago our whole lab met an affected individual from one of the recruited ARVC families,” said Ms. Merner. “I was touched deeply by hearing first hand the effects of the disease. After that experience I wanted to join the ARVC team and seriously hunt for the disease gene. This was a priority project with me and a few other lab members working overtime to find the gene.”
Ms. Merner said identifying the disease gene took a lot of effort. “It was such a success because of perseverance, dedication and amazing team work. I learned so much from the experience. I feel proud to have worked on this project during my graduate studies.”
While Ms. Merner was the team leader for the molecular component of the research, Ms. Hodgkinson worked with the team to amalgamate the clinical epidemiology data with the lab data. “I worked with them to sort out the disease status of participants for accurate linkage assessment because ARVC is difficult to diagnose,” she said.
Ms. Hodgkinson knows just how difficult the diagnosis is, and how heartbreaking the disease is. She has worked as a genetic counsellor for a decade with ARVC families, and there have been lots of tears along the way. Men in affected families often die without warning at a young age. In fact, clinical information collected from affected families indicates that only half of male carriers survived to 41 years of age.
Now that the ARVC gene has been identified, a blood test can reveal whether or not a person carries the gene.
At a March news conference about the gene discovery, two members of affected families told their stories. Rosalie Cater had a defibrillator implanted six years ago after a heart incident. She carries the gene and one of her sons is also affected; he has a defibrillator and it has already gone off once, saving his life. Vicky Connolly comes from another ARVC family, but as a result of the gene discovery she now knows that she does not carry the gene.
Dr. Young explained that before now, the location of the gene associated with the disease was known to be on a specific but rather large region of chromosome 3.
“We sequenced the 20 genes in this critical disease region, and found a mutation in a novel gene (entitled TMEM43) in all clinically affected family members,” she noted. “The gene codes for a protein in the membrane of the cardiac cell, but its function is currently unknown.” As a result of this discovery researchers will further investigate this gene for other forms of heart disease.
Over several years the team has used the knowledge of the gene’s location on chromosome 3 to identify carriers of the lethal mutation. Defibrillators have been implanted in adult carriers and on development of ventricular fibrillation (the event causing sudden death) a shock has been delivered to the patient’s heart, thus reversing the ventricular fibrillation.
“We have inserted nearly 100 defibrillators in mutation carriers, and clearly demonstrated that lives were saved,” reported cardiologist Dr. Sean Connors, a member of the interdisciplinary team that identified the gene. “In fact survival after defibrillator implantation was excellent compared to those who did not receive a defibrillator.”
Another team member, Dr. Patrick Parfrey, said he is so proud that the work on identifying the ARVC gene was all done in Newfoundland through the hard work of multidisciplinary teams. “This is a model for future genetic work.”
The strategic plan for clinical research at Memorial University and Eastern Health has identified genetic disease research as its priority, and has established an interdisciplinary research team in human genetics to ascertain families with genetic disease; to determine their genetic cause; to examine the ethical, economic, environmental, legal and social issues associated with the application of genetic tests in the community; and to determine the impact of genetic and clinical screening programs in the community.
“The sudden cardiac death project is a successful example of research deriving from this approach in which genetic counsellors, molecular geneticists, clinical epidemiologists, cardiologists, philosophers, and health policy experts have functioned as a team and coalesced around trying to solve a major clinical problem,” said Dr. Parfrey.
The sudden cardiac death research was funded by Genome Canada, the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, the Janeway Hospital Foundation, the Government of Newfoundland and Labrador and St. Jude Medical. Collaborators included Dr. Ludwig Thierfelder at the Max-Delbruck-Centrum fur Molekulare Medizin in Berlin, Dr. William McKenna at the Heart Hospital in London, England, and Dr. Anne Bassett at the University of Toronto.