World's First Gene Mutation Test Predicts Risk of Sudden Cardiac Death

Scientists at the Victor Chang Cardiac Research Institute and Vanderbilt University Medical Center have developed a novel, individualized risk prediction tool for patients with specific heart arrhythmias, particularly those associated with Long QT Syndrome (LQTS). This gene mutation-specific test, described as the first of its kind, offers a tailored approach to predicting the risk of sudden cardiac arrest.

Background: Long QT Syndrome and Risk of Sudden Cardiac Death

Long QT Syndrome (LQTS) is a hereditary heart rhythm disorder that increases the risk of sudden cardiac death, affecting otherwise healthy individuals. This condition impacts 1 in 2,000 Australians, emphasizing the need for precise risk assessment to prevent adverse events. Traditional genetic testing could confirm a diagnosis but was limited in predicting the severity and risk of cardiac events.

Research Overview: Analyzing Genetic Variants in LQTS

The research team, led by Professor Jamie Vandenberg, analyzed 533 genetic variants or mutations associated with LQTS from 1,458 patients. These mutations, affecting ion channel function, were analyzed using a high-speed electrical test known as a high-throughput automated patch clamp assay.

"This will provide patients and their families with answers and better enable clinicians to tailor treatment appropriately," said Professor Vandenberg, Deputy Director at Victor Chang Cardiac Research Institute.

Key Research Steps

1. Identified Genetic Variants: Analyzed genetic mutations associated with LQTS.
2. Functional Testing: Conducted high-throughput automated patch clamp assays to assess mutation impact on ion channels.
3. Risk Stratification: Compared findings against traditional testing and patient records to evaluate cardiac risk.

Findings: Identifying High-Risk Mutations

The team found that mutations impacting ion channel function could significantly increase the risk of major cardiac events such as arrhythmias and sudden death. Specifically:

• Mutations that reduced ion channel function by 90% resulted in a 13.3-fold increase in risk.
• A 75% reduction in ion channel function was associated with an 8.6-fold greater risk of cardiac events.

"We have shown that not every diagnosis of Long QT is equal, and the risk can vary dramatically depending on the exact genetic mutation," said Dr. Chai-Ann Ng, co-author of the study.

Clinical Impact and Future Applications

This new gene mutation test is expected to enhance personalized treatment for LQTS patients by providing specific risk assessments. The test could be adapted for use in other heart arrhythmias and neurological conditions.

Clinical Benefits

• Tailored Risk Stratification: Allows for individualized assessment of cardiac risk based on genetic mutation severity.
• Improved Patient Care: Enables more precise clinical interventions and treatment for those at high risk.

"Our findings will make a huge difference in how these high-risk patients are cared for in the future," said Dr. Ng.

Future Directions and Research

The team aims to expand this approach to patients with other cardiac arrhythmias and even neurological conditions. The individualization of genetic testing could mark a significant advance in preventive cardiology and precision medicine.

Reference

• O'Neill, M. J., et al. (2024). Assays of Variant Effect and Automated Patch Clamping Improve KCNH2-LQTS Variant Classification and Cardiac Event Risk Stratification. Circulation. DOI: 10.1161/CIRCULATIONAHA.124.069828

Journal Information: Circulation
Provided By: Victor Chang Cardiac Research Institute, MedicalXPress