Scientists identify gene that causes sudden death from heart disorder

Researchers studied Newfoundland families to develop test for lethal DNA glitch

A lethal gene killed Victoria Connolly’s mother, her brother Keith and sister Thelma, and is now cutting a swath through the younger generation.

Her nephew Tim died at 40, and her grandnephew Trevor dropped dead at 26. “He was getting ready to go to bed, collapsed and died,” says Connolly. “No warning, no idea there was anything wrong.”

But Connolly’s huge extended Newfoundland family now knows exactly what is wrong—a team at Memorial University announced Thursday the discovery of the gene responsible. They say it is one of the worst genetic demons ever encountered.

Victims can appear perfectly normal, and then drop dead.

“Suddenly they faint and they don’t get up,” says Dr. Terry-Lynn Young, who leads the team that has identified the gene after a 12-year quest.

The researchers have also devised a test to identify individuals who have the gene, which causes a disorder known as arrhythmogenic right ventricular cardiomyopathy Type 5, or ARVC5.

ARVC5 is believed to affect as many as one in 1,000 people and cause many of the 350,000 sudden cardiac deaths in North America each year.

Is it not known how many people carry the lethal gene the team has uncovered, but Young and her colleagues believe it may affect many unsuspecting individuals.

“There will be many more people of Newfoundland ancestry, and they’ll probably be people who have never seen Newfoundland, who have this same gene problem,” says geneticist Kathy Hodgkinson, co-author of a report on the gene in the April issue of the American Journal of Human Genetics.

Hodgkinson works closely with 15 large extended Newfoundland families that have long felt “cursed,” as Connolly describes it, because they’ve seen so many die young. The largest family includes 1,200 individuals dating back nine generations.

The clusters of premature sudden death in the families attracted gene-hunters from Germany and U.S. in the 1990s, who took DNA from hundreds of people but could not find the gene responsible.

Hodgkinson persuaded Young to pick up the quest in 2004. Her team, financed largely by the Canadian Institutes of Health Research and Genome Canada, narrowed the search to a chunk of DNA on Chromosome 3. Then came the eye-glazing task of combing through the suspect DNA, comparing thousands of bits of gene sequence in individuals known to have the disorder with those who do not.

The culprit turns out to be a gene with a tiny but deadly mutation—a single typo in a string of 400 genetic letters. “It’s as if you had word the Mississippi and you changed one of those P’s to a T,” says Young.

It may be tiny, but she says the mutation is “insidious,” setting off a process that slowly replaces heart muscle with fibrous tissue and fatty deposits. Eventually the extra tissue throws the heart out of rhythm. Sometimes, fainting spells warn of trouble. But tragically, many victims just suddenly collapse, and then die.

“If you are male, the first symptom may be your last,” says Hodgkinson, noting how the gene is far more lethal in men. Without treatment half of males with the gene die before their 42nd birthday. Among women, five per cent die by age 40 and 15 per cent by 50.

Finding the gene is not a cure, the researchers stress, but it is seen as a big step forward as it has led to a highly accurate gene test, which is being welcomed by many of the affected families.

Victoria Connolly is one of the lucky ones. She has found out she did not inherit the gene and did not pass it on to her two daughters and three grandchildren.

“I must have cried for two days,” says Connolly, 54, of the relief she felt.

She hopes the discovery of the gene will lead to better understanding of the disorder and more effective treatment.

More than 100 high-risk individuals—some of them teenagers—from affected families have opted to have defibrillators (thin battery-operated devices) implanted near the collarbone. When the devices detect an irregular heartbeat or arrhythmia, an electrical shock restores a healthy heartbeat, bringing them back from death’s door.

The defibrillators are life-saving, but some individuals are so severely affected they have undergone heart transplants. One of Connolly’s nephews got a new heart, but died 11 years later at age 40.

Young, with irreverent Newfoundland humour, calls them “the walking dead.”