Lab map flags 1,757 gene variants that can cause sudden death

Many of the people who die from long QT syndrome are struck down in the prime of life. The disorder, known as LQTS, disturbs the electrical system that drives the heartbeat, and it causes sudden death in about 3,500 people in the United States each year. An international collaboration led by Vanderbilt Health has now mapped 1,757 genetic variations that can trigger it, a list that gives doctors a reference for variants that until now had no clear meaning.

The bottleneck lies in reading the genetic results. Sequencing finds new mutations faster than laboratories can study them, and at least 70% of the variants identified through testing have a clinical impact that is not fully understood. Such variants are labeled variants of uncertain significance. The traditional check grows the mutated ion channel protein in a laboratory cell and examines it one variant at a time, a task that the lead researcher said can take months or years. The most common cause of LQTS is a loss-of-function change in KCNQ1, a gene that encodes a potassium channel, the protein that regulates the flow of potassium ions with each heartbeat.

The team, led by geneticist Lorena Harvey and her colleagues in the Roden and Glazer labs, used an emerging method called multiplexed assay of variant effect, or MAVE, which generates and measures the effect of nearly all possible changes in the protein, over 13,000 of them. Of these, 1,757 showed strong pathogenic evidence and 6,600 showed moderate benign evidence. The researchers then searched the health records of more than 700,000 people whose sequenced DNA is held in three biobanks, and found that patients with loss-of-function variants had been diagnosed with a prolonged QT interval.

For patients, the immediate change is less uncertainty when a new variant appears. Andrew Glazer, the paper's corresponding author, said the team hopes that with this dataset, "there will be less uncertainty going forward when patients are found with a new variant." Beta blockers are highly effective for this disease, and patients are advised to avoid certain drugs that can trigger an abnormal rhythm, but the aim is to find carriers early. The study does not give a date for when the map will enter routine clinical use.

The method is now meant to scale up. Glazer said the team is working to study "not just one or two genes over a decade, but several per year." The work was carried out by the CardioVar Consortium, a multi-institutional effort to map genetic variations affecting heart function, and draws on the Vanderbilt Center for Arrhythmia Research and Therapeutics, directed by Bjorn Knollmann.