Amit V. Khera
PHILADELPHIA — Gene sequencing was used to identify a subset of the population predisposed to sudden cardiac death by a DNA variant, according to data presented at the American Heart Association Scientific Sessions.
Amit V. Khera, MD, MSc, associate director of the Precision Medicine Unit in the Center for Genomic Medicine at Massachusetts General Hospital and the Cardiovascular Disease Initiative at the Broad Institute of MIT and Harvard and a Cardiology Today Next Gen Innovator, and colleagues assembled a nested case-control cohort for sudden cardiac death and a prospective cohort study.
The researchers performed gene sequencing in 600 samples from adults with sudden cardiac death and 600 matched controls, searching for pathogenic or likely pathogenic variants of 49 genes that have been shown to be related to known causes of sudden cardiac death, including cardiomyopathy, CAD, arrhythmia syndromes or aortopathy/aortic dissection.
Among the 1,200 patients with sudden cardiac death and controls, the researchers analyzed 5,178 genetic variants, 14 of which were classified as pathogenic or likely pathogenic.
“[To classify the 14 variants], I took this list [of 645 variants] and turned it over to a laboratory geneticist, and I said, ‘I’m not going to tell you anything about the patients' phenotype, but in a blinded fashion, you tell me which of the variants you would be comfortable calling pathogenic on a clinical grade report,” Khera said during a presentation here.
The 14 variants were seen in 15 patients, all of whom had sudden cardiac death. This corresponded with a pathogenic variant prevalence of 2.5% (95% CI, 1.4-4.1) in patients with sudden cardiac death vs. 0% in controls (95% CI, 0-0.6; P < .0001).
“This really provides confirmation that these mutations are substantially enriched in people who suffer from adult-onset sudden cardiac death,” Khera said.
An independent population of 4,525 patients from a prospective cohort study who were asymptomatic also underwent gene sequencing to determine whether the pathogenic or likely pathogenic variants were associated with CV death.
Within the independent patient population, 0.91% had a pathogenic or likely pathogenic variant. These patients also had a 3.24-fold higher risk for CV death during a median follow-up of 14.3 years after adjustment for sex, age and race (95% CI, 1.2-8.8).
“What does this mean and how can we translate this observation into improved care for our patients? At Mass General, we said we really need a new clinical infrastructure,” Khera said during the presentation. “Just this month, we launched a Preventive Genomics Clinic. It’s embedded within our primary care practice and includes a team of physicians, genetic counselors and laboratory geneticists. We plan to sequence thousands of patients from our hospital’s biobank to find the 1% of people who have one of these mutations, and they’ll be offered tailored prevention programs on the basis of these mutations. Our goal is to help empower them to overcome any increase in their inherited risk for a tragic health outcome.” – by Darlene Dobkowski
Khera AV, et al. Featured Science EP. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.
Khera AV, et al. J Am Coll Cardiol. 2019;doi:10.1016/j.jacc.2019.08.1060.
Disclosures: The study was sponsored by a research agreement from IBM Research, and sudden death confirmation was supported by grants from Novo Nordisk Foundation. Khera reports he served as a consultant for Color Genomics and Navitor Pharmaceuticals and has a patent related to a genetic risk predictor. Please see the study for all other authors’ relevant financial disclosures.
Editor's note: This article was updated on Nov. 16, 2019, to include the correct image of Amit V. Khera, MD, MSc.