CRISPR-based heart test pinpoints genetic risk for severe cardiomyopathy

EKG rhythm
Penn scientists inserted a gene variant into stem cells that turned into cardiac cells; then they watched for signs of irregular heartbeat. (Pixabay/PublicDomainPictures)

Severe hypertrophic cardiomyopathy, a dangerous disorder that causes an abnormal thickening of the heart walls, can run in families—and it’s often associated with a variant in the gene TNNT2. A team of scientists at the University of Pennsylvania has developed a test with CRISPR and other gene-editing tools that they believe can be used to screen for potentially harmful variations of TNNT2.

They developed the test with the help of one family affected by severe hypertrophic cardiomyopathy, they explained in a statement. Last year, a 65-year-old woman was treated at the Penn Center for Inherited Cardiac Disease. Her gene sequence revealed the presence of abnormal TNNT2, but it wasn’t clear if the variant was causing her disease. Nor did her physicians know if her two children and six grandchildren were at high risk.

So they used gene editing to create induced pluripotent stem cells (iPSCs) containing the woman’s TNNT2 variant. They then prompted the iPSCs to turn into mature heart muscle cells and exposed them to an adrenaline-like chemical to induce faster beating. Had the beats been irregular, that would have been a sign that the gene variant was pathogenic, because severe hypertrophic cardiomyopathy causes irregular heartbeats. But the cells responded normally—a sign that the patient’s TTNT2 variant was benign.


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In developing the test, the Penn scientists created a library of 14 unique TTNT2 variants. They used a combination of CRISPR and other editing tools to create a platform that allows for the rapid insertion of gene variants into iPSCs. Most of the variants they included in the test are pathogenic, they reported in the journal Circulation.

RELATED: Using CRISPR to predict heart disease risk

CRISPR has mostly drawn interest for its potential use in editing out disease risk—and not all of the attention has been positive. (Witness the recent outrage over claims by a Chinese researcher that he used CRISPR to confer HIV resistance on live embryos.)

But CRISPR could prove useful in genetic screening, too. Over the summer, scientists at the Stanford University Cardiovascular Institute announced they created a CRISPR-based test that employs stem cells to identify benign and pathogenic variants of the gene MYL3, which is associated with hypertrophic cardiomyopathy.

CRISPR pioneer Jennifer Doudna, Ph.D., has also investigated gene editing as a screening tool. Earlier this year, startup Mammoth Biosciences licensed a technology from Doudna’s lab that it’s using to create a diagnostic tool that will be able to screen for many different diseases.

The Penn team used its TTNT2 assay to determine that the family members of the woman who inspired the test did not need to undergo genetic screening but that they should be monitored for abnormal thickening of the heart wall. They believe the technique they developed could be used to detect 4,000 TTNT2 variants in a single test.

"This could help any person in the world found to have a variant in TNNT2 make better choices about their care," said team leader Kiran Musunuru, M.D., Ph.D., an associate professor of cardiovascular medicine and genetics at Penn in the statement.

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