Frequently Asked Questions

Genetic and genomic testing can both play roles in diagnosing cardiovascular disease. Broadly speaking, genetics refers to the study of genes while genomics refers to the study of the entirety of a person’s genes, known as the genome. Genetic testing is the analysis of specific changes in individual genes and whether those genetic changes are passed from one generation to the next, or the changes are present for the first time in the particular individual. Genetic tests help determine if a patient has a specific altered gene that can lead to a hereditary heart condition. Genomic testing looks broadly for harmful changes in the entire genetic material that can affect cardiovascular risk. Genomic testing can also be referred to as genomic sequencing.

The CardioGenomic Testing Alliance is committed to raising awareness and utilization in both genetic and genomic testing in cardiology. CGTA is encouraged by the progress of genomic testing for cardiovascular disease.

CGTA will consider genomic testing in cardiology to be an inclusive term that refers to both genetic testing and genomic testing in this space as the field continues to expand and actionable insights related to cardiovascular disease continue to grow.

Healthcare providers should offer genetic testing in cases where patients are at a high risk of developing cardiovascular disease as a result of a confirmed or suspected diagnosis of a heritable cardiovascular condition or pathogenic variant in them or their family. This identification should depend on a comprehensive evaluation of at least three generations of the patient’s family history. After this history is sufficiently examined, providers should refer the patient to genetic specialists and/or counselors if a patient’s medical record suggests they may have inherited a form of cardiovascular disease. ¹

Genomic testing in cardiology allows patients and family members to learn if they have a cardiovascular condition passed down from previous generations or due to a de novo mutation.² Genomic testing in cardiology provides a deep insight into genetic risk of cardiovascular disease and can assist with appropriate therapy selection and medical management, if needed. In addition to providing actionable insights into the health of a patient and their first-degree family members, genomic testing also empowers patients to make informed decisions for themselves and for their families.

In particular, the exploration of the possibility to extend genomic testing to individuals at risk within a family even when they are asymptomatic. This modality is called “cascade testing”. More details can be found in the cascade testing section of this FAQ.

Genomic testing provides cardiologists with a more precise view of a patient’s genetic cardiovascular condition, improving the effectiveness with which often underdiagnosed single-gene mutations are identified and treated.³ Additionally, genomic testing can help healthcare providers to identify specific relatives at risk of developing certain cardiovascular conditions.⁴ By targeting the specifically identified genetic variation in patients with heritable cardiovascular conditions, healthcare providers can more effectively test for the presence of the genetic variation in the patient’s family members.

A genetic heart condition is a disorder caused by changes in certain genes that can be passed down from parent to child.

Genomic testing is useful in diagnosing and managing cardiovascular diseases such as:

• cardiomyopathies, heart muscle diseases that can lead to heart failure;
• thoracic aortic aneurysms and dissections, that can cause the body’s major artery to balloon and rupture;
• arrhythmic disorders that predispose people to potentially fatal abnormal heart rhythms; and
• familial hypercholesterolemia, or high LDL elevated cholesterol levels, that greatly increase the risk of heart attack.⁵

There are several practice guidelines and consensus statements that provide clear guidance for recognizing and targeting patients with likely inherited cardiovascular disease. The AHA Scientific Statement on Genetic Testing for Inherited Cardiovascular Diseases summarizes several of these guidelines and statements, providing a robust overview and clear expectations for genetic testing.⁶

Check out CGTA’s resource to learn more about this Scientific Statement and stay tuned for additional guideline/statement resources.

Cascade testing is a predictive approach for identifying relatives at risk for cardiac conditions. Cascade testing is an essential component of genetic testing and determines whether a disease-causing genetic variant identified in the proband (the original family member in which the variant has been identified) is present or not in relatives, even when they are asymptomatic.⁷ Early detection through cascade testing can reduce morbidity and mortality of family members carrying the same variant.⁸ The United States Centers for Disease Control Office of Public Health Genomics classifies cascade genetic testing for familial hypercholesteremia as a Tier 1 genomic application, which means there is strong and clear evidence supporting its implementation into clinical practice.⁹ The alliance is encouraged by this classification as it signals the importance of cascade testing for heritable cardiovascular conditions.

Cascade testing can identify relatives that are at-risk for an cardiac condition who require additional medical evaluation and possible early interventions. Relatives who test positive through cascade testing should discuss the most appropriate approach for medical management with their healthcare provider, which could include ongoing monitoring, medical therapy, or device implantation.

Relatives who test negative are not at increased risk for the familial cardiac condition. This also means their children or any future children most likely are not at an increased risk. However, family history and environmental factors must still be evaluated by their healthcare provider to determine additional risk. Baseline general population risk for cardiovascular disease will continue to remain relevant for all individuals.

Genetic counselors are professionals within the healthcare continuum, supporting patients’ medical, genetic, and psychological needs. Specifically, a clinical genetic counselor is an allied healthcare professional with specialized training in medical genomics, education, and counseling. Genetic counselors support patients and families seeking more information about how genetic conditions might affect them and help interpret genomic test results.¹⁰

Genetic counselors that specialize in cardiovascular disease provide guidance to individuals and families experiencing the diagnosis or prospective diagnosis of a cardiovascular condition.¹¹ Cardiovascular genetic counseling activities include:

• Family history risk assessment
• Identifying the most informative relatives for genomic testing
• Selecting the most appropriate genomic test
• Educating the patient and family members about genomic testing
• Ensuring accurate variant interpretation
• Communicating results to the patient and any necessary family members

Genetic counselors support patients and their families during both pre and post genomic testing. Prior to testing, counselors discuss how the testing might impact patients and their families while gathering any relevant medical and family health history and presenting available testing options. If a patient chooses to move forward with testing, genetic counselors will help each patient understand their test results and treatment options while answering any questions the patient may have. Please visit the National Society of Genetic Counselors website to learn more.

https://www.nsgc.org/

Providers are encouraged to refer patients for genetic counseling. Below are helpful resources available to find a genetic counselor near you or virtually:

• The National Society of Genetic Counselors’ directory offers access to over 3,300 genetic counselors.¹²
  The American Board of Genetic Counselors’ Certified Genetic Counselor Directory lists board certified genetic counselors.¹³

Similar to other medical tests, providers can order genetic and genomic tests for cardiovascular disease through testing companies, including several CGTA member companies. Please visit their websites to learn more about ordering these tests for your patients.

A blood sample stored in ethylenediaminetetraacetic acid (EDTA) is the gold standard for genomic testing in cardiology. However, depending on the testing laboratory, other samples may be acceptable, including:

• cultured cells [from skin or different organs, as well as chorionic villus sampling (CVS) and amniotic fluid in prenatal cases]
• buccal swabs
• dried blood spots
• frozen tissue or blood
• bone marrow
• DNA extracted from another laboratory
• some autopsy and postmortem samples (not acceptable if the sample is in Formalin-Fixed, Paraffin-Embedded (FFPE) tissue blocks and slides)

Further discussion and coordination of sample shipment with the testing lab is recommended.

Yes, samples obtained postmortem can be used for genomic testing. Several types of samples can be accepted in this situation, but sample type and sample collection information (date, time of collection after death, storage conditions, etc.) may play a very important role in successfully obtaining DNA from such samples. Further discussion with the testing lab is recommended.

Once genomic testing has been completed, a health care provider can expect to receive a report from the performing laboratory that summarizes all reportable identified genetic variants. Based on the type of test results, the information may influence a patient’s medical management and if other family members should be tested.

Broadly, results of genomic testing in an affected patient (proband) may be positive, negative, or inconclusive.¹⁴ These results are specific to patients receiving genomic testing and do not apply to cascade testing of relatives.

• Positive results: the test identified a genetic variant that is classified as pathogenic or likely pathogenic. These results may have direct implications for the medical care of your patient and their family.
• Inconclusive results: the test identified a genetic variant that is of uncertain clinical significance; these should not be used to direct patient care.
• Negative results: the test has not identified genetic variants with clinical or unknown significance.

In addition to results regarding a patient’s cardiovascular risks, genomic testing may also include secondary, or incidental, findings associated with health risks for non-cardiovascular conditions.

A negative result cannot rule out a genetic risk for an affected patient. It is possible that a patient has a genetic risk that could not be identified on the testing based on the technology used or due to the current knowledge and understanding of the variant(s) identified. It is also possible that a patient’s risk is the sum of many genetic variants together (polygenic disease), but the test is unable to identify them. Environmental and lifestyle factors can also potentially play a role in a person’s risk.

Panel testing targeting genes associated with cardiovascular disease also may yield results that convey a risk unrelated to cardiovascular disease, such as a syndrome that presents with both cardiovascular and neuromuscular involvement. With genomic testing, which looks more broadly for gene alterations (or harmful changes) anywhere in the genetic code, both syndromic conditions and incidental findings may be identified. Genomic testing may identify incidental findings that are unrelated to cardiovascular disease (such as cancer or metabolic conditions), although these findings are uncommon.^15,16 Patient preferences regarding these types of results should be reviewed in pretest counseling/consenting.¹⁷ During the pretest consultation, patients may opt in or out of receiving results that are unrelated to their personal and/or family history of cardiovascular disease.

While guidelines from the College of American Pathologists (CAP) establish which information must be included in genomic test reports, labs vary in the depth of information they choose to include and in how the information is displayed. The specific genetic variants reported typically follow Human Genome Variation Society (HGVS) nomenclature for consistency across labs, but information regarding how a variant was classified, the medical significance, and next steps for the patient can vary by laboratory. Labs also may offer different options regarding the reporting of secondary/incidental findings.

Like other medical tests and procedures, genetic and genomic testing for cardiovascular disease may be covered by insurance. Coverage is dependent on several factors, so it is recommended that each health care provider check with the corresponding insurance provider and testing laboratory for each patient.

The Genetic Information Nondiscrimination Act (GINA) protects patients from discrimination based on information obtained from genetic testing.¹⁸ GINA prohibits health insurers and employers from making decisions based on genetic information. Specifically, insurers cannot request or purchase genetic information to use in eligibility or coverage decisions. For more information on how GINA protects patients from genetic discrimination in health insurance and employment, visit ginahelp.org.

Cardiovascular genetic and genomic testing in children has an important diagnostic role in determining the risk of developing heritable cardiovascular disease. A Scientific Statement from the American Heart Association was released in 2021, outlining the key points and recommendations for pediatric cardiovascular genetic and genomic testing. Please refer to “Genetic Testing for Heritable Cardiovascular Diseases in Pediatric Patients: A Scientific Statement From the American Heart Association” for details.¹⁹