Researchers join forces to ‘map’ specific variations in more than 25 key heart disease genes

One in 100 people have genetic variations that can lead to life-threatening heart conditions, including high cholesterol (lipid disorders), heart muscle disease (cardiomyopathies), and abnormal heart rhythms (arrhythmias).

However, the functional impact of most of these cardiovascular genetic variants -; if they interfere with normal function or are harmless -; is unknown. That’s about to change.

Researchers from Vanderbilt University Medical Center, Stanford Medicine, the University of Toronto and Brigham and Women’s Hospital in Boston have joined forces to “map” specific variations in more than 25 key heart disease genes that negatively affect heart disease. heart function.

Funded by a four-year, $8.2 million grant from the National Health Lung and Blood Institute of the National Institutes of Health (NIH), their newly formed CardioVar Consortium will generate a comprehensive atlas of “variable effect maps” to distinguish between variant pathogens from harmless ones.

The goal is to shed light on the molecular mechanisms of cardiovascular disease, the leading causes of death and disability worldwide, and to improve real-time diagnosis and early treatment.

As genetic testing in patients with heart disease is increasingly adopted, a common finding is a “variant of uncertain significance.” Our high-throughput studies will provide data on the function of thousands of variants – which will help to both guide the treatment of individual patients and provide insights into the underlying biology.”

Dan Roden, MD, Grant Principal Investigator, Senior Vice President for Personalized Medicine at VUMC

Roden, Sam L. Clark, MD, PhD, Endowed Chair at Vanderbilt University School of Medicine, is known internationally for his studies of arrhythmias and the role genetic variations may play in adverse drug reactions .

Roden’s co-principal investigators are Euan Ashley, MBChB, DPhil, professor of medicine, genetics, and biomedical data science at Stanford School of Medicine and founding director of the Stanford Center for Inherited Cardiovascular Disease, and Frederick Roth, PhD, Professor of Molecular Genetics and Computer Science at the Donnelly Center at the University of Toronto and in the Departments of Molecular Genetics and Computer Science.

“At the current rate of clinical sequencing, it would take more than a hundred years to find most genetic variants relevant to heart disease even once in the population,” said Ashley, Associate Dean and Professor Roger and Joelle Burnell of Genomics and Precision Health at Stanford School of Medicine. “The card variants we are building will allow us to dramatically accelerate this timeline, providing vital information to the families we see in the clinic today.”

Almost every DNA change that can occur already exists today in the human population,” added Roth, principal investigator at Sinai Health’s Lunenfeld-Tanenbaum Research Institute and co-founder of the Atlas of Variant Effects Alliance. “So why keep testing one variant at a time? We are grateful to the NIH for supporting our efforts to organize ourselves and begin systematically testing all variants.”

Known worldwide for their work in experimental and computational genomics, Roth and his colleagues have already published variant effect maps for nine human proteins, including one for calmodulin, a calcium-sensitive protein, allowing rapid diagnosis of arrhythmias. potentially fatal in young children and genetic testing. members of their family.

Another key co-investigator is Calum MacRae, MD, PhD, vice chair of scientific innovation in the department of medicine at Brigham and Women’s Hospital, co-director of the genomic medicine clinic and professor of medicine at Harvard Medical School.

“Understanding the functional consequences of individual variants is the central requirement for interpreting genetic test results,” MacRae said. “This project will transform clinicians’ ability to diagnose and manage every patient with inherited heart disease.”

As a first step, researchers will develop, optimize and validate a range of high-throughput cellular assays capable of directly measuring variant function and distinguishing pathogenic from benign variants.

They will then use state-of-the-art techniques to mutate or insert altered gene sequences into pools of cells and use the assays they have developed to generate and validate variable effect maps of cells.

Finally, through a combination of hypothesis-based analyzes and machine learning models, they will reveal relationships between variant effects, protein structure and function, and human phenotypes -; the specific effects of pathogenic variants on cardiac function.

The goal is to develop a variant-focused decision support system that will be widely shared to help clinicians assess functional evidence of disease in patients undergoing genetic testing for heart disease.

The research is funded by NHLBI grant number HL164675.


Vanderbilt University Medical Center

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