Using an innovative, 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.
Their findings, published in the journal Circulation, may enable more precise diagnosis and treatment of a disorder that causes sudden death in about 3,500 people in the United States each year. Many are struck down in the prime of life.
"Our hope is that now that we have this map, we can find a broader set of people who have this disease and get them treated," said Vanderbilt Health geneticist Andrew Glazer , PhD, the paper's corresponding author. "With proper management, … you can really reduce the risk of sudden death."
Glazer, Assistant Professor of Medicine in the Division of Genetic Medicine and Clinical Pharmacology, is the paper's co-senior author with Dan Roden , MD, the Sam L. Clark, MD, PhD Professor of Medicine and Senior Vice President for Personalized Medicine at Vanderbilt Health.
"It's becoming clear that using genetic information to care for patients will be an increasing part of the way we practice medicine," said Roden, who is internationally known for his research on arrhythmias and variability in drug responses.
"One of the barriers to that vision is sorting out which variants are especially dangerous and which can be ignored," he said. "That's the challenge we addressed in this study for one key gene where variants can cause serious or even fatal heart rhythm abnormalities."
Long QT syndrome (LQTS) is a heart rhythm disorder that affects the electrical system of the heart. Named for its primary characteristic, an abnormally long QT interval on the electrocardiogram, LQTS can trigger fast, chaotic heartbeats that can cause fainting or even death.
LQTS is a congenital, or inherited, condition, and the most common cause is loss-of-function variants in a potassium channel gene, KCNQ1, which encodes a protein that regulates the flow of potassium ions during each heartbeat.
Determining how KCNQ1 variants affect normal ion channel function is critical to developing precision medicine approaches to prevent arrhythmia. Yet the clinical impact of at least 70% of variants identified through genetic testing is not fully understood, and there are too many of them to assess using standard laboratory techniques.
"We're sequencing more and more people every year and finding new mutations faster than we can study them," Glazer said. As a result, most newly discovered mutations are labeled "variants of uncertain significance."
The traditional way to test whether a particular variant is likely to cause disease is to determine the function of the mutated ion channel protein in a laboratory-grown cell. But that approach, isolating one variant at a time, can take months or years, Glazer said.
In this study, the researchers used an emerging high-throughput genetic technique called multiplexed assay of variant effect (MAVE) to generate and measure the functional impact of nearly all possible variations, over 13,000, in the amino acid sequence of the ion channel protein encoded by KCNQ1.
The paper's first author, Lorena Harvey, PhD, a staff scientist in the Roden and Glazer labs, led the high-throughput experimental work and analyzed how the findings relate to disease risk.
"It's one thing to identify a genetic variant in a patient, but it's another to understand what that variant actually does and whether it could increase their risk of disease," Harvey said. "Our work helps bridge that gap by providing experimental evidence for thousands of variants that we previously knew very little about."
Of the variants studied, "1,757 (variants) demonstrated strong pathogenic evidence, while 6,600 showed moderate benign evidence," the researchers reported.
The researchers then scoured the matching electronic health records of more than 700,000 people whose sequenced DNA is stored in three large biobanks, including Vanderbilt Health's BioVU. They found that patients with loss-of-function variants in their genetic sequence also had been diagnosed with a prolongation of the long QT interval.
"Our hope is that with our dataset … there will be less uncertainty going forward when patients are found with a new variant, because we already have some functional data available," Glazer said. "This disease is pretty treatable."
Cardiovascular medications called beta blockers are highly effective, and patients are also advised to avoid certain drugs that can trigger an abnormal heart rhythm. But, he added, "You really want to find it ahead of time.
"Now that we've gotten these methods working, we can apply them to a much broader set of genes that impact important diseases," Glazer said. "That's what we're working on next … to (investigate) not just one or two genes over a decade, but several per year."
The study was conducted by the CardioVar Consortium , a multi-institutional effort led by Roden and his colleagues to map genetic variations affecting heart function. The effort was supported by an $8.2 million grant (R01HL164675) awarded in 2022 by the National Heart, Lung, and Blood Institute of the National Institutes of Health.
"Vanderbilt Health may be one of the only places in the world that could have led this study," Glazer said. "We have a great focus on arrhythmia biology," he said, through the Vanderbilt Center for Arrhythmia Research and Therapeutics, directed by Bjorn Knollmann, MD, PhD, the William Stokes Professor of Experimental Therapeutics and a co-author of the paper.
Coupled with BioVU , the world's largest repository of genetic material linked to de-identified electronic health records that is based at a single academic center, "it made this the perfect place to do this experiment," he added.
Other Vanderbilt coauthors were Ellen Osborn, MS; Megan Lancaster, MD, PhD; Jeremy Smith, MS; Temidayo Abe, MD; Ayesha Muhammad, MD, PhD; Rose Kannankeril; Tao Yang, MD, PhD; Maria Calandranis; Daniel Blackwell, PhD; Richard Dolder III; Jessa Aldridge, PhD; Matthew Fleming, MD, PhD; Marcia Blair, MS; Eduardo Soria; Giovanni Davogustto, MD, MSCI; and Brett Kroncke, PhD.
Collaborators from Stanford University, Harvard Medical School, University of Pittsburgh, The Ohio State University, and others from Australia also contributed to the study.
Other support for the study was provided by the NIH (grants R00HG010904, R35GM150465, R01HL160863, K12CA090625 and K08HG014001), American Heart Association, and Medical Research Future Fund: Genomics Health Futures Mission.
