Featuring: Elizabeth McNally, MD, PhD and Anthony Gacita
A team of Northwestern Medicine investigators have identified specific genetic regions that regulate the expression of genes associated with inherited cardiomyopathy which may be able to predict overall disease severity, according to findings published in Circulation.
The study, led by Elizabeth McNally, MD, PhD, the Elizabeth J. Ward Professor of Genetic Medicine and director of the Center for Genetic Medicine, has the potential to help guide the development of novel therapeutic approaches and help clinicians develop more personalized treatment plans for patients.
Inherited and non-inherited forms of cardiomyopathy — when the heart is unable to effectively deliver blood to the body — have similar outcomes, including arrhythmia and heart failure. The challenge, however, is determining whether someone has inherited cardiomyopathy because its symptoms present similarly to those of non-inherited cardiomyopathy.
Inherited cardiomyopathy, specifically, is associated with mutations in cardiomyopathy-related genes that, for some patients, can cause severe and early onset heart failure. These mutations are controlled by genetic modifiers, or mutations in various regions of the genome that influence how the primary genetic mutation produces a specific phenotype. When the heart fails, it undergoes a specific pattern of gene expression changes and these changes include expressing developmental forms of genes.
“With an increase in whole-genome sequencing and genetic data that is now available to clinicians, the goal is to use genetic information to predict which patients will have more severe and less severe disease,” said Anthony Gacita, a seventh-year student in the Medical Scientist Training Program (MSTP) and lead author of the study.
In the current study, investigators compared epigenomic profiles of human heart tissue samples and stem cell-derived cardiomyocytes to identify genetic regulators for cardiomyopathy-causing genes.
One of the genes, MYH7, encodes the main molecular motor of the sarcomere, a fiber-like unit in heart cells that drives heart contraction. Mutations in MYH7 which directly change the protein are known to alter heart function and cause hypertrophic cardiomyopathy, a condition in which the heart becomes abnormally thick or “hypertrophied”. Other MYH7 mutations can cause the heart to enlarge and weaken.
The investigators identified a prominent genetic enhancer which regulates the expression of MYH7 and the neighboring gene, MYH6. Utilizing engineered heart tissues and CRIPSR gene editing, the team found that deleting this enhancer increased MYH6 expression and decreased MYH7 which increased the rate of heart tissue contraction. They also identified a DNA sequence change within a nearby enhancer region, called rs875908, and patients with this variant had faster cardiomyopathy progression.
“This is probably the first time in cardiomyopathy that a variant outside of the coding sequence has been associated with severity of phenotype,” Gacita said.
The findings may help guide the development of new therapeutic approaches for the disease, and the investigators’ integrated genomics approach could be used to study more than 150 known cardiomyopathy-related genes, according to Gacita. Whole-genome sequencing may also help inform clinicians of these genetic mutations earlier, allowing them to predict disease severity and provide more personalized treatment plans for patients.
In the future, McNally said the team hopes to use CRSIPR to increase or decrease cardiomyopathy gene expression by manipulating the noncoding parts of genes in an effort to decrease disease severity.
“We think this is a more tractable approach given the tools we have available now. New gene editing methods are being developed at a very rapid pace, and these newer modalities might have even more possibilities for genetic surgery to treat heart disease,” said McNally, who is also a Professor of Medicine in the Division of Cardiology and of Biochemistry and Molecular Genetics.
This work was supported by the National Institutes of Health grants HL128075, HL142187, HL141698 and the American Heart Association grant 18CDA34110460.
This article was originally published in the Feinberg School of Medicine News Center on March 1, 2021.
Elizabeth McNally, MD, PhD, the Elizabeth J. Ward Professor of Genetic Medicine and director of the Center for Genetic Medicine, was senior author of the study published in Circulation.
Anthony Gacita, a seventh-year student in the Medical Scientist Training Program, was lead author of the study.
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