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Test results unraveled: Understanding mysterious genetic variants for heart disease

Stanford researchers use gene editing and stem cell technologies to determine whether to worry — or not — about mysterious genetic test results.

When doctors shrug their shoulders and tell you that your genetic testing for potential heart disease shows that you have a certain gene variation that might — or might not — be dangerous, it can cause a good deal of alarm. 

Now, with the increasingly commonplace use of genetic testing for heart disease, this is becoming an even greater issue of concern, according to a Stanford-led study published in the Journal of the American College of Cardiology. The research outlines a potential method for figuring out whether these "variants of unknown significance," as they are called, are benign or pathogenic. As Joseph Wu, MD, PhD, a professor of cardiovascular medicine and radiology and senior author of the study, says in the press release I wrote:

This is a really big problem. If someone tells me I have a genetic variant that could be lethal, I’m going to be very scared. The result could be a lifetime of unnecessary worry for a patient when in fact, the mutation may be completely benign.

To address the issue, researchers worked with a 39-year-old patient who was told by his Stanford doctor that he had one of these mysterious mutations. His particular variation put him at increased risk for a heart-rhythm condition called long QT syndrome, which can cause erratic heartbeats, fainting and sudden cardiac death.

By using advanced genetic-editing tools and stem cell technology the team was able to determine that, indeed, the variant did indicate that he had long QT syndrome and that he should be treated with ongoing medication.

In another recent study published in Circulation and also led by Wu, researchers used the same genetic-editing tools and stem cell technology to determine that a variant of uncertain significance, which doctors worried could have been an indication of a dangerous heart condition known as hypertrophic cardiomyopathy, was actually benign. The condition, which causes a thickening of the heart, can lead to heart failure, irregular heartbeat and sudden cardiac death. "We were able tell the patient not to worry about it," Wu told me.

Evidence from both these studies indicate that the same methods could be used for all types of genetic variations of uncertain significance, Wu says. As I wrote in the press release:

The success of using these same methods to determine whether two different patients were at risk for two completely different diseases suggests that this platform is a promising risk-assessment tool for variants of uncertain significance in general, Wu said.

'The results of these studies are particularly exciting to me because we used precision health methods to address an unmet need for a patient,' he said. 'This means we now have the ability to go deeper and tell a patient what a variant of uncertain significance means.'

Photo by stux

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