Study IDs Group of Rare DNA Variants Linked with Sudden Cardiac Death

Study IDs Group of Rare DNA Variants Linked with Sudden Cardiac Death
Unrecognizable businessman having chest pain and heart attack, hand holding the painful spot.

In the largest study of its kind on individuals with sudden cardiac death, researchers from Massachusetts General Hospital and the Broad Institute of MIT and Harvard performed whole-exome sequencing of 600 patients with adult-onset sudden cardiac death matched with 600 controls. They identified 5,178 genetic variants classifying 14 as pathogenic or likely pathogenic. None of these variants were found in healthy controls yet were detected in 15 individuals who had succumbed to sudden cardiac death. The study was published in the Journal of the American College of Cardiology and announced at the Scientific Sessions of the American Heart Association on November 16.

The team also assessed 4,500 middle-aged adults with no indications of heart disease who had been followed for more than 14 years as part of a prospective study. They found 41 (0.9 percent) of them carried one of these pathogenic variants. Extrapolated out to the entire US population, the authors concluded that approximately 1%, or 3 million individuals, harbors a rare genetic variant for sudden cardiac death. Strikingly, the individuals found to have a pathogenic rare variant had a three-times higher risk of death from cardiovascular events like cardiomyopathy, coronary artery disease, and arrhythmias over the 14-year follow-upafter adjustment for sex, age and race (95% CI, 1.2-8.79).

This study is important not just because of the discovery of rare genetic variants linked with sudden cardiac death but because it suggests a path towards identifying individuals who are most at risk. Lead by first author Amit Khera, MD, associate director of the Precision Medicine Unit at MGH’s Center for Genomic Medicine and the Broad Institute’s Cardiovascular Disease Initiative, and Sekar Kathiresan, MD, whose laboratory at MGH is dedicated to understanding the genetic roots of heart disease to improve cardiac car, this research is another step forward showing the power of using genome-wide testing to help find asymptomatic people with increased risks for heart disease.

Their goal is to use information gained from studies like this to perform genetic sequencing on thousands of adult patients at MGH and affiliated hospitals to identify individuals among that cardiac risk 1% who would benefit from prevention before symptoms develop. MGH already maintains an active Cardiovascular Genetics Program providing testing and treatment plans for patients at risk for inherited cardiovascular conditions.

“Integration of genomics into practice will require new clinical infrastructure, said Khera at the AHA meeting on November 16. And earlier this month, he and his colleagues launched a new Preventive Genomics Clinic embedded within primary care in response “focused on using human genetics as a tool to identify high-risk individuals and empowering them to overcome any inherited risks.” They have already begun sequencing the first 10,000 patients in the hospital who will be offered personalized prevention strategies to help mitigate inherited risk.