Mapping more than 25 key heart disease gene variants that negatively affect heart function

1 in 100 people have genetic variants that can lead to potentially life-threatening heart disease, including high cholesterol (lipid disorders), myocardial disease (cardiomyopathy), and arrhythmias

However, the effects of most of these cardiovascular gene variants on function — whether they disrupt normal function or are harmless — are unclear

Researchers from Vanderbilt University Medical Center, Stanford Medical School, the University of Toronto and Brigham and Women's Hospital in Boston joined forces to "map" specific variants

With a four-year, $8.

The goal is to elucidate the molecular mechanisms of cardiovascular disease, which is the leading cause of death and disability globally, and to improve real-time diagnosis and early treatment

"As genetic testing in patients with heart disease is increasingly adopted, a common outcome is a 'variant of uncertain meaning,'" said

Roden is a professor at Sam L.

Roden's co-principal investigators are Euan Ashley, MBChB, DPhil, Professor of Data Science in Medicine, Genetics and Biomedicine at Stanford School of Medicine, Founder Director of the Stanford Center for Hereditary Cardiovascular Diseases, and Dr Frederick Roth, Professor of Molecular Genetics and Computer Science at the Donnelly Centre and Department of Molecular Genetics and Computer Science at

Professor Ashley, Associate Dean of Genomics and Precision Health at Stanford Medical School and Professor Roger and Joelle Burnell, said: "At the current rate of clinical sequencing, it will take more than 100 years to detect even one major genetic variant associated with heart disease in a population

"Almost every DNA change that could occur is already present in humans today," adds Roth, a senior fellow at the Ronanfield-Tananbaum Institute for Sinai Health and co-founder

Roth and his colleagues are known for their work in experimental and computational genomics, and they have published variant effect maps of nine human proteins, including the calcium-sensitive protein calcineurin, enabling rapid diagnosis of arrhythmias in life-threatening young children and genetic testing

Another key co-investigator is Calum MacRae, MD, Associate Director of Scientific Innovation at the Department of Medicine at Brigham and Women's Hospital, Co-Director of the Genomic Medicine Clinic, and Professor of Medicine at

"Understanding the functional consequences of individual variation is a core requirement for interpreting genetic test results," MacRae said

As a first step, the researchers will develop, optimize, and validate a range of high-throughput cell analysis methods that can directly measure variant function and distinguish between pathogenic and benign variants

They will then use cutting-edge techniques to mutate or insert altered gene sequences into cell pools and use the analytical methods they developed to generate and validate variation effect maps

Finally, through a combination of hypothesis-driven analysis and machine learning models, they will reveal the relationship between variation effects, protein structure and function, and human phenotypes—the specific effects

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

The study was funded
by NHLBI grant number HL164675.