Gene variants that can cause sudden death mapped
Using a high-throughput technique, an international collaboration led by Vanderbilt Health researchers has created a "map" of 1,757 genetic variations that can trigger a life-threatening heart rhythm disorder called long QT syndrome.
An international team of researchers, led by Vanderbilt Health, has mapped over 1,700 genetic variants that can lead to life-threatening heart rhythm disorders known as long QT syndrome (LQTS). This finding, published in the journal Circulation, could improve diagnosis and treatment of LQTS, which causes sudden death in about 3,500 people in the United States annually, often in prime age individuals.
Led by Vanderbilt Health geneticist Andrew Glazer, Ph.D., and co-senior author Dan Roden, M.D., the researchers used a high-throughput technique called multiplexed assay of variant effect (MAVE) to evaluate nearly 13,000 possible variations in the KCNQ1 gene, which encodes a protein regulating potassium ion flow during each heartbeat. This approach enabled the study to assess the clinical impact of at least 70% of variants identified through genetic testing, which previously had unclear clinical significance.
The researchers found that 1,757 of the variants studied demonstrated strong pathogenic evidence, while 6,600 showed moderate benign evidence. They then analyzed the electronic health records of over 700,000 people, finding that patients with loss-of-function variants in their genetic sequence also had a prolongation of the long QT interval, a hallmark of LQTS.
Glazer and Roden emphasized that understanding which genetic variants are particularly dangerous is crucial for precision medicine approaches to prevent arrhythmia. While beta blockers can treat LQTS, finding the condition early is key. The researchers hope their dataset will reduce uncertainty when new variants are identified, providing functional data to guide treatment decisions.
This collaborative effort, part of the CardioVar Consortium, represents a significant step towards applying genetic information in patient care and potentially uncovering the impact of multiple genes on heart function in the future.
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