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Determining the Genetic Cause of Cardiac Diseases

Imagine a world where genes not only tell the story of a person’s future health, but also allow physicians to intervene early and prevent future health problems. The fast-growing field of cardiogenetics allows for improved screening and early treatment of certain inherited cardiovascular disorders. At MedStar Heart & Vascular Institute (MHVI), great strides are being made on two fronts— offering current genetic testing for individuals with familial cardiac syndromes and state-of-the-art research into the genetic contributions of diseases such as coronary disease.

A subset of arrhythmias and cardiomyopathies are known to have a monogenic cause, that is, the disorder is caused by a single mutation in one of a number of known genes (see chart). For these conditions, efforts are underway to identify individuals and families at risk through genetic counseling and testing.

Susan O’Donoghue, MD, electrophysiologist,
and Aime Agather, genetic counselor in Cardiology

Susan O’Donoghue, MD, an electrophysiologist and the director of Cardiogenetic Services at MHVI, says, “A number of inherited disorders can cause arrhythmias, congestive heart failure and sudden death. In the past, diagnosis was based on clinical findings, EKG and imaging. But that has limitations.” Syncope, palpitations during exercise, a young age at diagnosis of heart failure, or sudden cardiac death in a family member are red flags signifying a possible underlying genetic component to the symptoms or disease. “If we identify a specific mutation [or genetic change] in one family member, we then test other family members,” Dr. O’Donoghue says. Aime Agather, MS, CGC, a certified genetic counselor in Cardiology at MHVI, works closely with Dr. O’Donoghue. “When we do identify a cause [a mutation],” Agather says, “it can be a lifesaver to rule-in or rule-out a disorder in close family members.”

Cardiovascular genetic counseling is both art and science, with no single genetic test. In Long QT syndrome, for example, there are 15 causative genes known to date. Dr. O’Donoghue says, “You have to be specific in what you are looking for.”

Even when the right test is ordered, interpretation of test results is not always straightforward. Agather cautions that just because a change is identified, it does not always mean it is the answer for that individual and family. Variants of uncertain significance (VUSes) must be researched and explained. Hours are spent understanding the results in the context of patients and their family history, and then those patients and families are counseled about what the results may mean.

Dr. O’Donoghue acknowledges that cardiogenetics is an evolving science as new mutations are identified and VUSes are reclassified as disease-causing or benign. “Because of this complexity,” she says, “the consensus guidelines advise that genetic testing only be carried out at dedicated centers with genetic counseling before and after testing. Patients with known or suspected inherited cardiac disorders or a family history of sudden cardiac death benefit from referral to a specialized center such as MHVI.”

Coronary Artery Disease Research

Family history of disease may be worrisome for some patients. For coronary artery disease, family history is a risk factor, but the genetic basis for the disease is less understood than the monogenic disorders seen in the cardiogenetics clinic. Research is underway to identify the genetic risks that may predispose some individuals to the disease.

Jose Vargas, MD, PhD, a cardiologist and researcher with MHVI, based at MedStar Georgetown University Hospital, is working toward further elucidating the genomic components of atherosclerosis. “The human genome project has opened up opportunities not available before,” he says. “For a relatively low cost with little effort, we can interrogate the human genome for genetic information. We are poised to really understand the difference in genetic codes of individuals and how it relates to disease status.”

Genome-wide association studies, in which all the genetic variations in individuals are tested against a given disease, have already isolated one variant in chromosome 9 that is associated with coronary artery disease. But although this association has been replicated many times, existing studies do not represent a diverse population. Instead, they are based mostly on a Caucasian population.

Dr. Vargas is determined to enhance diversity in genomic research. In one study with the National Institutes of Health, he is recruiting African American individuals for state-of-the-art genomic sequencing and cardiovascular imaging. “Testing needs to be more inclusive, more accurate, so we can understand disease physiology even better, and different disease manifestations in different people,” he says.

Dr. Vargas cites the results of one of his recently published studies in which he explored genetic associations with coronary artery disease in 6,000 individuals in the Multi-ethnic Study of Atherosclerosis (MESA). “Looking for the chromosome 9 variant,” he says, “to our surprise, we confirmed the association with coronary artery disease in Caucasians and Hispanics, but there was no association in Chinese Americans and African Americans, despite a very in-depth study of the entire chromosome 9 region.”

Genetics is just one piece of the puzzle, he notes. “Now we’re also looking at genomics so we can better understand the role that DNA methylation, RNA and protein play in disease risk/pathophysiology. There are examples of mutations present exclusively in RNA that are not present in the corresponding DNA sequence. This is opening a whole new avenue of research.”

In 10 to 20 years, Dr. Vargas expects that genetic testing will be a central part of the physical exam. “We will be able to understand who is at risk for specific diseases and target them with the appropriate medication. We will be able to offer truly personalized medicine.”