Heart Disease Gene Discovery is still Saving LivesPublished: February 28th 2018
Update: Drs. Terry-Lynn Young, Kathleen Hodgkinson, Sean Connors and Daryl Pullman were awarded a Governor General’s Innovation Award in May 2018 for their groundbreaking work identifying the lethal gene mutation that causes Type 5 ARVC, dubbed the “Newfoundland Curse”.
Watch the family curse video on the ARVC story, click here.
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a deadly heart condition that runs in families and is a cause of unexpected death in seemingly healthy young people. ARVC is particularly prevalent in Newfoundland and Labrador where it exists in a high proportion of the population, with as many as one in 1,000 people affected.
In 2008, researchers at Memorial University discovered the gene responsible for ARVC. Until the causative gene and mutation were found, families with the disease in their medical histories lived in constant fear of sudden death, which was often the only symptom of the condition. Now, thanks to the research team’s discovery, a simple blood test can diagnose ARVC and prophylactic action can be taken with an implanted defibrillator, to jolt a dangerously frenzied heart beat back into a safe, normal rhythm.
The gene was found by studying 15 ARVC-affected families. They had 257 members, of which 144 were found to carry the same mutation in the TMEM43 gene.
Dr. Terry-Lynn Young, a molecular geneticist and Dr. Kathy Hodgkinson, a clinical epidemiologist who specializes in ARVC, are located at the Craig L. Dobbin Genetics Centre at Memorial University and are part of the inter-disciplinary research team that made the gene and mutation discoveries in 2008. Their work formed part of The Atlantic Medical Genetics and Genomics Initiative (AMGGI), a $9.2 million project funded in part by Genome Canada and managed by Genome Atlantic, to pinpoint and molecularly characterize previously unexplained genetic disease disorders in Atlantic Canada.
Genome Atlantic contacted Drs. Young and Hodgkinson to find out how their discovery changed the outlook for ARVC suffers in Newfoundland and Labrador and world-wide.
Genome Atlantic: How many people have you found with the disease?
Drs. Young and Hodgkinson: We have ascertained 27 families with this disease that we know all share a common ancestor, more than 11 generations back, as all these patients have the same genetic footprint. This work was all done in Dr. Young’s laboratory at Memorial University.
The largest of these families is 11 generations deep. Dr. Hodgkinson collected all available medical information, back to the earliest date of 1799.
In total, we now have information on over 1,000 people who were born with a 50% risk – a one-in-two chance – of getting the gene, and thus the heart disease ARVC, due to this mutation.
Although we obviously do not have DNA from family members departed long ago, some of them we know were ‘affected’ because they died suddenly at a young age; they passed the gene on to their children, or we have their DNA and found they have the mutation in the TMEM43 gene. The only folks we are sure don’t have the mutation are those that had a negative genetic test.
So far, approximately 500 people from Newfoundland and Labrador have had the genetic test for this lethal mutation.
We have recruited many other patients whose familial cardiac disease that is not due to mutations in the TMEM43 gene. So, for these families, at least they know that this mutation is not the cause. Through our collaboration with Eastern Health, hundreds of additional people have been tested through the Knowledge Transfer Laboratory that Dr. Young has helped to establish for these purposes.
Genome Atlantic: How many, as a result of the tests, were implanted with defibrillators?
Drs. Young and Hodgkinson: Our team cardiologist, Dr. Sean Connors, and his colleagues have implanted 163 people with an ICD [implantable cardioverter defibrillator] as a result of this disease and the genetic testing. Other ARVC patients have also been fitted with the device in centres in mainland Canada, the USA, Denmark, Germany, Spain, Norway, and in other countries around the globe.
Genome Atlantic: Is genetic testing for ARVC continuing?
Drs. Young and Hodgkinson: Yes. Both the research and the clinical testing continue. We routinely test new families who are referred to our research program because they have family histories with incidences of early sudden cardiac death. They are tested either to see if they have the gene mutation for ARVC or to discover whether there are other genetic causes for their heart condition.
As well, children in families known to have this mutation are looked after by paediatric cardiology services and genetic testing is offered to them during this process.
Genome Atlantic: What, in your opinions, was the major impact or impacts of the project – recognizing you’re coming at it from different perspectives (one from a clinical perspective, one from a research perspective)?
Drs. Young and Hodgkinson: The major impact clinically and socially has been the increase in survival for ARVC patients due to the treatment with ICDs. We already knew, because of the work we did on large family trees, that in affected people, 50 per cent of males would die before age 40, and 80 per cent would die by age 50. The equivalent figures in women were 5 per cent and 20 per cent.
We were able to show, using a robust method, that following ICD treatment, 30-plus years could be added to the lifespan for men who received the ICD following a genetic test. These were the figures available at the beginning of 2016. Survival was statistically improved for all people who got the ICD.
The other major impact has been a much better understanding of how the disease affects people from birth until death – the natural history of the condition – such that we can provide accurate information about the disease to family members and people at risk. We can now, of course, also provide them accurate information on the effect of the treatment.
This has allowed much more accurate information to be available to all persons with this rare mutation worldwide. Many people beyond Canada’s shores are benefiting from our research.
Our growing team continues to gain insights into the interplay between genetic predisposition and environmental exposures using the rich resource of patients and clinical data that we have gathered to search for other genomic signatures of disease, on a population-basis, for life-threatening diseases due to genetic mutations. We are also forging new collaborations towards developing gene corrective therapies in the future for TMEM43.
Attaining an understanding of the complexities of genetic disease, with the multiple interactions between genes, epigenetic effects and environmental influences is complex, time consuming and difficult. But academic university research teams like ours are dedicated to vigorous data collection and analysis and will continue to work towards improving health care outcomes in Newfoundland and Labrador, and across Canada.