Genetic Testing: Unlocking the Secrets of Your DNA with Dr. Pankaj Arora

This article was written in collaboration with Dr Pankaj Arora, Associate Professor at the University of Alabama at Birmingham, School of Medicine, Cardiovascular Disease, Comprehensive Diabetes Center, Nephrology Research and Training Center, Minority Health and Research Center

Genetic screening for cardiovascular disease (CVD) can provide valuable insights into an individual’s risk factors, potential genetic causes, and personalized treatment options. The decision to undergo genetic screening for CVD should be made in consultation with a cardiologist and a genetic counselor, based on factors such as family history, clinical presentation, and the specific type of cardiovascular condition. Here are some general guidelines on who might benefit from genetic screening for cardiovascular disease:

1. Familial History: Individuals with a strong family history of specific cardiovascular conditions, such as familial hypercholesterolemia (FH), hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and certain arrhythmias, may be candidates for genetic testing. Patients with a strong family history of cardiomyopathy or sudden cardiac death at a young age may also benefit. If there is a known genetic mutation associated with CVD in the family, other family members may also be screened.
2. Early-Onset Cardiovascular Disease: People who develop cardiovascular disease at a younger age (e.g., before age 50) without traditional risk factors (such as smoking, hypertension, or obesity) may be candidates for genetic testing. Patients who develop cardiomyopathy at a young age or present with severe symptoms may be candidates for genetic testing. Early onset of the disease may indicate a genetic cause.
3. High-Risk Patients: Individuals with particularly high-risk profiles, such as those with severe hyperlipidemia such as Familial Hypercholesterolemia (FH), may benefit from genetic testing to identify specific genetic factors contributing to their condition. FH is a monogenic, autosomal dominant disorder. Specific genetic variants in LDLR, apolipoprotein B (APOB), PCSK9, and apolipoprotein E cause profound disruption in the LDLR pathway which results in severe hypercholesterolemia with markedly increased cardiovascular risks.
4. Response to Medications: Genetic information can sometimes provide insights into how a person may respond to certain medications used to treat cardiovascular conditions. This can help guide treatment decisions and medication choices. The ABCD-GENE score has been developed to predict the response of the P2Y12 inhibitor, clopidogrel, in patients with coronary artery disease treated with a coronary stent but its accuracy in making precise treatment decisions in an individual patient remains to be proven.
5. Inherited Conditions: Genetic testing can be valuable in identifying inherited cardiovascular conditions, such as Long QT syndrome, Brugada syndrome, cardiac conduction disease with patients requiring a pacemaker at a young age, familial atrial fibrillation, and inherited aortopathy that can result in aortic aneurysm and dissection. This could be the result of a degenerative aortopathy type or syndromic such as Marfan syndrome, Turner syndrome Ehlers-Danlos syndrome. Inherited cardiomyopathy, (disease of the cardiac muscle), can be associated with a dilated (left and/or right ventricle) DCM or hypertrophic (HCM) form of cardiomyopathy. Some cases can present primarily with arrhythmias (ACM) and sudden death, in other cases the left ventricular anatomy can be normal but not functioning well or hypokinetic.
6. Evaluation of Family Members: If a genetic mutation is identified in an individual with cardiovascular disease, other family members may be advised to undergo genetic testing to determine if they carry the same mutation and assess their risk. This is called cascade testing.

WHAT IS THE OVERALL APPROACH TO GENETIC SCREENING?

It’s important to emphasize that genetic screening is just one component of a comprehensive cardiovascular risk assessment. In our center, patients are seen by a cardiologist and referred to a cardiologist specializing in inherited diseases of the heart and blood vessels. A detailed medical and family history is taken with documentation of a comprehensive 3-generation pedigree with a visual road map for capturing inheritance patterns and communicating testing recommendations to families.

Also included in screening are a detailed physical exam, blood test, ECG, and echocardiogram at rest and sometimes with exercise (in HCM). Depending on the results of the screening, the patient may be offered Genetic testing after discussing the risks, benefits, and limitations. This is a DNA test that is carried out if you are suspected of having an alteration in a gene that can cause an inherited cardiovascular condition.

Genetic testing may involve a blood test or saliva sample to analyze specific genes associated with a condition. Some tests can take months while others can take weeks to come back. The Genetic team will make sure that the appropriate test is ordered and will play a critical role in the interpretation of the results.

GENETIC TESTING RESULTS: WHAT DO THEY MEAN?

Genetic counselors are instrumental in not only choosing the appropriate genetic test but in the pre-and post-test counseling helping with the interpretation and recommendation of ongoing follow-up to make sure the patients receive information about the possible reclassification of certain gene variants.

For cardiomyopathies, large multigene panels are used and compared to referenced human genome sequencing and variants are classified according to the American College of Medical Genetics and Genomics into pathogenic, benign, and variants of uncertain significance (VUS).

1. Having a gene that is pathogenic means that you have a change in your genes that is known to cause a heart condition. Due to the variable penetrance of certain genes, having a positive genotype does not imply having the disease. In addition, because of the different expression of certain genes, relatives can have different severity of the disease at different ages. Therefore, relatives with a positive variant should have clinical surveillance to initiate treatment early when the disease becomes manifest. If clinical screening detects a reduction of LV function, starting ace inhibitors/ARB or ARNI (Entresto) can prevent further deterioration of the heart function. In mild HCM, non-obstructive cardiomyopathy should be treated with ace inhibitors to delay the progression of hypertrophy. The LMNA mutation has a 100% penetrance and can be associated with malignant arrhythmia and heart failure. Primary prevention use of ICD should be considered in carriers. Desmosomal genes are associated with arrhythmogenic CM and ventricular arrhythmias and should be treated with prophylactic ICD particularly when the LV function is reduced.
2. Having a test that is negative means that you do not have a change in your gene that is associated with a heart condition. Since not all cardiomyopathies follow the same genetic pattern, some genetic counselors suggest that relatives testing negative for a single familial pathogenic variant should be still followed intermittently since other undetected variants could pose a risk.
3. Sometimes it’s not clear what the results mean for your health but doctors may have a better understanding in the future. Variants of uncertain significance (VUS) are those with insufficient data available to determine more definitely. Because of their uncertainty, VUS is not helpful for cascade testing. Some VUS may have been misclassified pathogenic variants. Broader population data that include diverse ethnic groups and better tools for the classification of variants will lead to better diagnostic accuracy.

As genetic research and technology continue to advance, the availability and accuracy of genetic testing are likely to improve. Therefore, individuals should stay informed about the latest guidelines and recommendations from medical experts and organizations in the field of cardiovascular genetics.

This article was written in collaboration with Dr. Pankaj Arora, Director, UAB Cardiogenomics Clinic Program; Director, Cardiology Clinical and Translational Research Program, Associate Professor of Medicine, at University of Alabama at Birmingham.,

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