For at least nine generations a curse of sudden death has stalked families in Newfoundland.
Men and women have literally dropped dead in the primes of their lives -- eating supper on the sofa, cleaning the stove, teaching a math class.
For 12 years researchers have hunted the culprit gene behind the scourge that can stop hearts without warning. But that search is over.
In a discovery that is already saving lives and soothing minds, researchers with Memorial University in St. John's have at last identified the precise genetic glitch responsible for centuries of heartbreak on 'The Rock.' "This has caused massive young deaths across the generations... the stories have been recorded in the family bibles," said Kathy Hodgkinson, co-author of the report published Thursday in the American Journal of Human Genetics.
Newfoundlanders aren't the only ones who suffer from Type 5 Arrhythmogenic Right Ventricular Cardiomyopathy, or ARVC. But the clustering of affected families, many of whom descend from the remote island's first few settlers, brought attention to the lethal disorder after their plight was described in the New England Journal of Medicine in the 1980s. Still, ARVC is not well understood and estimates of its prevalence in the general population range from one in 1,000 people to 1 in 5,000 people.
"It's hard to diagnose ... you have to have a family history of people dropping dead," said senior author and molecular geneticist Terry-LynnYoung "Some people believe it's vastly under-diagnosed."
The genetic heart condition is thought to be highly prevalent in Newfoundland and Labrador, but there are no numbers available.
In people who suffer ARVC, healthy heart cells are mysteriously replaced by fatty, fibrous tissue, particularly on the right ventricle. Eventually the build up results in an arrhythmia that can trigger the heart to beat more than 300 times per minute, quivering until it finally halts.
"The first symptom is often death," said Ms. Hodgkinson, the genetic counsellor who spent a dozen years tracking affected families, their tragic histories and collecting their DNA.
In 1998, along with German collaborators, MUN researchers tracked the culprit to a region on chromosome 3. This allowed researchers to estimate who faced a high or low risk of the disorder, but it carried a 5 per cent error rate. People at high risk were offered defibrillators. One hundred people chose to have them implanted under their skin to jolt their hearts in the event of sudden arrest.
But a gene test can now tell people with certainty if they are indeed at risk of sudden cardiac death.
"It's the first time this gene has been associated with a human disease," said Dr. Young, a native Newfoundlander who left the University of Washington to head the gene hunt at MUN. (Dr. Young noted that the discovery marks the first time a gene behind a disorder that afflicts Newfoundlanders in high numbers has been found in Newfoundland. The province has long been a magnet for international gene hunters due to its small-founding population and "usually the samples are shipped off" she said.) Researchers found the gene in a study of 15 affected families with a total 257 members. More than half of those affected by the disorder -- or 144 people -- all carried the same mutation in a gene known as TMEM43. The mutation, said Dr. Young, involves just a single chemical change in the code. The 'typo' was not seen in any control subjects, or in the unaffected family members.
"That one change is enough to cause the replacement of healthy heart cells with fat and fibre," said Dr. Young. Researchers also found people need inherit only one copy of the "missense mutation" for the condition to strike - which is why, Dr. Young said, "it strikes every generation."
Men who carry the mutated gene have a median life expectancy of 41 years, women of 71. Researchers suspect hormones may offer pre-menopausal women some protection from the heart condition.
While the find opens up new avenues for research, unlike most gene discoveries, this one also has immediate applications. For Rosalie Cater, 56-year-old mother of three from Grand Falls-Windsor, "it the best news anyone can ever hope for."
She had grown up with the fear. She'd heard about maternal grandfather who went turned up for his shift at the mill on Boxing Day, pulled on one of his work boots and slumped over. He was 49. It killed her mother at 72. All three of her brothers were affected -- Graham died at a Chinese restaurant at 26, it killed Terry on the back porch at 43, and although Doug died of cancer, he passed it to his son, who collapsed in front of his math students at age 28.
"I always had that inkling that I had it ... but I thought women get it later," said Ms. Cater, who had a defibrillator implanted in 2002. But it was for her three sons she worried most.
"Every morning of my life when my two feet hit the floor, I'd go see if they were still breathing and thank God for another day," she said. "You went to bed with it, you woke up with it."
Genetic testing has since confirmed that only her eldest son, Tim, 30, carries the gene mutation, and knowing has already saved his life twice. His defibrillator went off four times one night while he played hockey, she said, once when he was snowmobiling.
"Think of the lives a defibrillator could have saved," Ms. Cater said. Maybe, she added, by the time her grandchildren grow up, they won't even need to have defibrillators implanted in their chests, maybe there will be something even better for them.
Victoria Connolly, who lives in Conception Bay South just outside of St. John's, had always assumed that she too was a carrier. One brother died at 42, her sister died at 56, one nephew died at 39, another at 26.
"Oh I was convinced I had this," said Ms. Connolly, 54. "You learn to expect it with all the death around you."
"I'd wake up in the middle of the night in a sweat, my heart pounding out of my body, and I'd grab my husband -- 'Paul, is this it? Is this it!?'" she recalled.
Ms. Connolly was afraid to go to the gym or go anywhere alone. She'd look at her daughters, in the kitchen, opening the fridge, and worry for them as well -- "wondering which day it was going to be." She had to go for regular assessments at the hospital, as doctors were unable to estimate her risk level earlier.
Then, two weeks ago she heard the astonishing words from Ms. Hodgkinson: "My dear, you are 100 per cent in the clear!"
"It's hard to describe the relief," Ms. Connolly said.
Sometimes she feels pangs of "survivor's guilt," she said, with so many of her extended family members affected.
"But they're happy for me," she said. "I can go to bed now and sleep."