A glitch in the rhythm: how a genetic map can help identify dangerous arrhythmias

Hereditary cardiac arrhythmia can occur without noticeable symptoms, and then lead to fainting or cardiac arrest. An international team of scientists has created a map of the KCNQ1 gene changes that may be associated with this risk. The researchers evaluated more than 13,000 variants and obtained strong evidence of pathogenicity — the ability to cause disease - for 1,757. Why the result of a genetic test does not always give an unambiguous answer and how a new card can help prevent dangerous arrhythmias — in the Izvestia material.

What happens when the electrical rhythm of the heart is disrupted

The work is devoted to the long QT syndrome, a violation of the electrical activity of the heart. Its name is associated with the section of the electrocardiogram that reflects the excitation and subsequent electrical recovery of the ventricles.

If this process takes longer than it should, the risk of dangerous rhythm disturbances increases. The heart may begin to contract too quickly and inefficiently, which can lead to loss of consciousness, circulatory arrest, and death.

However, dangerous arrhythmia does not occur in every person with this syndrome. In some cases, the disease proceeds without symptoms. There are hereditary and acquired forms of QT prolongation. The new study focuses on the genetic mechanism of changes in KCNQ1, one of the key genes associated with hereditary syndrome.

Why does the heart need potassium channels

KCNQ1 contains instructions for the production of a protein involved in the formation of potassium channels. These are structures in the cell membrane through which electrically charged particles, potassium ions, pass.

In the heart muscle, such channels help restore the electrical state of the cells after each contraction. Due to the coordinated work of ion channels, the heart maintains a normal rhythm.

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Some changes in KCNQ1 reduce the ability of channels to pass potassium. Electrical recovery slows down, which can increase the risk of arrhythmia. However, different variants of the same gene act differently. Some significantly disrupt protein function, while others have almost no effect on it. Therefore, it is not enough to detect a change in DNA: it is necessary to understand exactly what it does.

Why does genetic analysis sometimes leave more questions?

Modern methods allow you to quickly read DNA sequences and find rare changes. But the rate of accumulation of genetic data outstrips the possibilities of studying them.

If there is insufficient data on a specific find, it can be classified as a variant of uncertain value — VUS. This means that the association of the change with the disease has not yet been confirmed or refuted.

As MedlinePlus, a resource of the US National Library of Medicine, explains, such a result by itself does not allow to confirm or exclude the diagnosis. Medical history, family cases, and other data are taken into account for interpretation.

It is this uncertainty that scientists have tried to reduce. Instead of waiting for the accumulation of clinical observations for each rare variant, they created an experimental dataset on the effects of thousands of changes on protein function.

How more than 13 thousand variants were tested

The study was performed by the CardioVar consortium led by Vanderbilt Health specialists. The senior authors are Andrew Glazer and Dan Roden, and the first author is Lorena Harvey. The traditional approach involves exploring individual options: scientists create cells with a modified protein and test its operation. According to Glazer, a consistent assessment of such finds can take months or years.

In the new work, the method of mass assessment of the effects of genetic variants, MAVE, was used. It allows you to study many changes in parallel and compare their effect on protein function.

In total, the team obtained data for 13,403 KCNQ1 variants. The researchers evaluated the changes affecting the amino acid sequence of the protein it encodes. This is an experimental map of a specific gene, not a universal catalog of all causes of sudden death. Her task is to help understand the consequences of a specific genetic finding.

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What do 1757 potentially dangerous options mean?

According to a scientific publication, strong evidence of pathogenicity was obtained for 1,757 studied variants. For another 6660, there is moderate evidence of good quality.

These categories describe the strength of the evidence provided by the research. They do not mean that every carrier of the first set of variants is necessarily at risk of sudden death, and a person with the second set is guaranteed the absence of any heart disease.

Laboratory results help to assess the effect of the change on the protein. The clinical risk of a particular patient requires a separate assessment. It is also important to identify options that do not violate the studied function. Such data can help to avoid the mistaken attribution of a genetic finding to the causes of the disease.

According to Harvey, detecting a variant in a patient and understanding its consequences are different tasks. The new work provides experimental information about thousands of changes for which there was little information before.

What did the comparison with medical records show?

To verify the relationship of laboratory results with the condition of people, scientists turned to three large biobanks, including BioVU at Vanderbilt Health. They compared the genetic information with the electronic medical records of more than 700 thousand people. Variants that reduced protein function were associated with QT prolongation. Thus, the experimental data were supported by the analysis of clinical information.

This is an important stage of verification: the disruption of the channel in the laboratory system should be correlated with what is happening in humans. However, this comparison does not mean that the exact probability of complications is already known for each of the thousands of variants.

As MedlinePlus notes, even a positive result of genetic testing usually does not allow predicting the exact course or severity of the disease. Genetic data is considered together with other medical information.

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How the card can help patients

The authors expect that the accumulated results will reduce the uncertainty in the detection of new KCNQ1 variants. If the change has already been studied in the experiment, the specialist receives an additional basis for its interpretation.

This can be useful in clarifying the diagnosis and examining the family. According to the National Heart, Lung, and Blood Institute of the United States (NHLBI), in case of hereditary syndrome, a doctor may recommend cardiological examinations and genetic testing to relatives.

Detecting the disease makes practical sense: there are ways to reduce the risk of dangerous arrhythmias. Beta blockers are used in the treatment, and in some cases implantable devices and surgical methods are used. The tactics depend on the patient's condition.

It is also important to consider medications that can prolong QT. The choice of therapy and restrictions are discussed with the doctor. The new card does not replace the ECG and clinical assessment. It adds information that is often missing after genetic analysis, and can help identify patients in need of follow-up and prevention in a timely manner.

Why research is important for genetic medicine

The work demonstrates an approach to one of the main difficulties of modern genetics: it becomes easier to read DNA than to explain the significance of the detected changes. According to Dan Roden, in order to use genetic information in everyday medicine, it is necessary to learn how to distinguish between dangerous and neutral variants. The KCNQ1 study solves this problem for one important gene.

The team intends to apply the proven methods to other genes associated with diseases. Glazer expects to move from studying one or two genes per decade to several per year.

For patients, the value of such projects lies in a more meaningful response after testing: not only which change has been found, but also which experimental data helps to assess its consequences.