AHA Calls for Individualized Approach to Pediatric Cardiovascular Genetic Testing

Genetic testing of children can play a key role in determining a child’s risk of developing heritable cardiovascular disease. But testing should be limited to children with a high likelihood of disease. It should also be undertaken as part of a specialized multidisciplinary effort that involves pre- and post-testing. Those, at least, are the key points made in a new scientific statement from the American Heart Association (AHA).

The Diagnostic Challenge

Analysis of genetic alterations at the gene/chromosome or DNA sequence level is capable of detecting many common diseases affecting the cardiovascular system, such as cardiac channelopathies, cardiomyopathies, aortapathies, hypercholesterolemias and structural diseases of the heart and major blood vessels. Accordingly, genetic testing is often used to inform diagnosis, clinical management and prognosis of cardiovascular disease. Tests can be performed diagnostically in individuals suspected of having a cardiovascular genetic disease or to gauge risk for a relative of someone with a pathogenic or likely pathogenic variant and cardiovascular disease.

There are a number of existing guidelines and best practices for cardiovascular genetic testing. But very few of them focus on the pediatric setting. That poses a problem to the extent that infants, children and adolescents are a vulnerable population that poses unique challenges. These include both ethical issues stemming from this population’s lack of capacity to provide legal consent or assent and clinical issues associated conditions that might not pose a risk until adulthood.

The AHA Recommendations

With these considerations in mind, an AHA working group set out to analyze the existing literature and practices and develop a set of recommendations for pediatric cardiovascular genetic testing. Their findings are set out in the scientific statement published in the August 2021 issue of Circulation: Genomic and Precision Medicine. Specifically, the statement makes five key points.

1. Need for a Multidisciplinary Approach

According to the statement, genetic testing should always involve comprehensive pre-testing and post-testing counseling. Ideally, such testing should occur in or in partnership with a specialized multidisciplinary setting that includes cardiology experts, medical genetic experts, genetic counselors and other healthcare providers. “Because of the central role that a patient-specific comprehensive clinical evaluation plays in determining whether gene testing should be done, and what scope of testing is ideal, engaging teams of specialists who can support this evaluation is important,” noted first author Andrew Landstrom, a Duke University School of Medicine pediatric cardiologist and cardiovascular geneticist.

2. Limit Diagnostic Testing to Children at High Risk

The statement also cautions against improper utilization. In general, pediatric genetic testing for cardiovascular conditions should be guided by likelihood that the disease may present in childhood, the potential for mortality during childhood, the availability of therapies, and the family’s values. “Genetic testing should be done in the context of a comprehensive clinical evaluation which is tailored to the child, their medical history, and their family’s medical history,” notes Landstrom. Specifically, genetic testing for purposes of diagnosis should be

considered in children with a high likelihood of disease, to the extent that test results, in many cases, can help refine clinicians’ diagnostic suspicions and guide treatment options.

3. Limit Risk-Predictive Testing to Children of Family Members with P/LP Variant

Risk-predictive genetic testing should be performed in children after identification of a pathogenic/likely pathogenic (P/LP) variant in a family member with disease. This is particularly true in cardiomyopathies that carry a high positive yield on diagnostic genetic testing, i.e., hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Similarly, risk-predictive genetic testing should be considered early in childhood, particularly when disease is likely to manifest before the child is able to provide assent, and therapies or other preventive measures can be implemented for at-risk children.

4. Timing of Testing Should Account for Disease Characteristics

According to the AHA working group, the timing of genetic testing in children should take into account disease-specific considerations of disease penetrance, the likelihood of pediatric disease presentation, the availability of effective therapies or lifestyle modifications, and the possibility of psychological distress in the family attributable to uncertainty.

The authors suggest that parents wait to conduct risk-predictive genetic testing for an adult-onset disease until the child reaches adulthood or is old enough to participate in the decision-making process and provide assent. However, some conditions can develop during childhood and even for adult-onset conditions, there may be lifestyle changes or therapies that can be started at a younger age. In the case of children with a family member with genetically confirmed familial hypercholesterolemia (FH), they suggested that risk-predictive genetic testing be conducted as well as lipid screening.

5. The Importance of Follow-Up 

Finally, the statement stresses that continued follow-up of genetic test results is important to re-evaluate or confirm variant pathogenicity over time, as well as to address the changing needs of the patient and family as genomic and precision medicine evolves.

Takeaway

Genetic testing has proven its clinical value in detecting and informing treatment of heritable cardiovascular diseases. However, all patient populations are not the same. Specifically, the existing guidelines and practices that pertain to adult patients are not necessarily suitable for use in infants, children and adolescents. The value of the AHA scientific statement is in being among the first to recognize that and seek to adapt the general standards for use of genetic cardiovascular testing in a pediatric setting.