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Genes converge to boost risk of sudden death

By Leigh MacMillan
January 2010

Congenital long-QT syndrome, an inherited cardiac disease, is a known cause of sudden death, especially in young adults and children. But not all people who have gene mutations that cause congenital long-QT syndrome have symptoms (fainting, cardiac arrest, sudden death).

The big question mark is how to manage a patient who has a long-QT gene mutation, but doesn’t have any symptoms, said Alfred George Jr., M.D., director of the Division of Genetic Medicine at Vanderbilt University Medical Center.

“The concern, of course, is that the first symptom could be sudden death,” he said. “And everything needs to be done to try to prevent that.

“But does every mutation carrier need an implantable defibrillator? Pharmacological therapies? Or should they just be watched?”

The variability in symptoms suggests that other factors play a role – either to promote or prevent symptoms.

George and a multinational research team searched for “genetic modifiers” of long-QT syndrome – genes (other than the disease-causing gene) that play a role in the disease. The investigators studied an extended South African family affected by long-QT syndrome – of 500 characterized family members, 205 carry the same long-QT causing mutation.

They found that people who had the primary long-QT-causing mutation and one of two common variants of a gene called NOS1AP had a higher probability of cardiac arrest and sudden death than primary mutation carriers who didn’t have those NOS1AP variants. The findings, reported in the journal Circulation, will help in assessing the risk of sudden death – and assigning therapy – in patients with this syndrome.

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