Research Finds New Genetic Link to Sudden Cardiac Death

An international team of investigators, including a cardiologist from the Miller School, has found a new association between a variant in a specific gene and Brugada syndrome, an inherited disorder associated with life-threatening arrhythmias. The identification of this genetic variant in affected families offers hope of identifying more individuals at risk for sudden cardiac death among family members of affected individuals. The research report, “Mutations in SCN10A Responsible for a Large Fraction of Brugada Syndrome Cases,” will be published in the July 8 issue of the Journal of the American College of Cardiology.

“Until now, the scientific community has been able to identify the culprit gene in only about 35 percent of affected patients,” said Robert J. Myerburg, M.D., professor of medicine and physiology, the American Heart Association Chair in Cardiovascular Research, and one of the researchers in the multicenter study. “The new gene associated with Brugada, called SCN10A, appears to be present in another 16 percent of cases, improving our ability to identify a susceptibility gene to approximately 50 percent of affected individuals and their families.”

Brugada syndrome is estimated to affect 5 people in 10,000, or nearly 160,000 in the U.S. The majority of affected individuals are younger men, many of whom are asymptomatic prior to having a life-threatening heart rhythm disturbance. The annual mortality rate for individuals with untreated symptomatic Brugada syndrome may be as high as 10 percent, at an average age of 30-40 years. Asymptomatic patients have a mortality rate of at least 10 percent over 20 years, considerably higher than the expected risk in their age group.

“This gene was targeted for investigation because we already knew that variants of another cardiac sodium channel gene, SCN5A, were linked to Brugada syndrome,” said Myerburg. SCN10A also encodes a sodium channel and is adjacent to the SCN5A gene, and experimental evidence suggested that the two might interact. The study was carried out in patients who were diagnosed with Brugada syndrome, but who did not have any of the known variants associated with the syndrome. Clinical analysis and direct sequencing of Brugada-syndrome-susceptibility genes were performed on 150 such patients, 17 family members and 200 healthy controls. A total of 17 SCN10A mutations were found in 25 of the patients, some of whom had multiple variants.

“Our study identifies SCN10A as a major susceptibility gene for Brugada syndrome, thus greatly enhancing our ability to genotype patients and risk-stratify family members,” said Myerburg. The potential family connections, however, raise other issues.

“When you diagnose a patient with Brugada syndrome, you want to screen any siblings and children, too,” said Myerburg. “If a family member does not carry the gene variant identified in the primary patient, it means their children will not be at risk. If a family member tests positive, however, they have to be watched closely.”

Even though a susceptibility gene can now be identified in 50 percent of the affected families, there still remain 50 percent in whom the culprit is unknown. “A negative study doesn’t mean you don’t have the disease; it may just mean we can’t identify the genetic marker,” said Myerburg. This, he added, is where decision-making gets tricky, and why further studies will be conducted to try to identify additional culprit genes.

“There is also controversy over what to do when a person tests positive for the gene but is asymptomatic,” said Myerburg. Fainting spells, thought to be due to disturbances in heart rhythms, are the most common warning symptom. Concern is reinforced by the presence of specific changes in EKG recordings.

“The best current treatment for documented cases is an implantable defibrillator,” said Myerburg. “Researchers are also exploring alternative treatment approaches, including pharmacological and interventional options, for patients who are profiled to be at high risk. We still have a lot more work to do.”

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