Ahmad F, McNally EM, Ackerman MJ, Baty LC, Day SM, Kullo IJ, Madueme PC, Maron MS, Martinez MW, Salberg L, Taylor MR, Wilcox JE; American Heart Association Council on Genomic and Precision Medicine; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Basic Cardiovascular Sciences; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Stroke Council.
Circ Genom Precis Med. 2019 May 23:HCG0000000000000054. doi: 10.1161/HCG.0000000000000054. [Epub ahead of print]
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Take Home Points:
- Cardiovascular genetics is evolving as a new frontier with advances in genome sequencing, genetic testing with application to a wide variety of cardiac conditions.
- The next big leap is to integrate clinical cardiovascular findings with genetic information to allow for improved diagnosis, prognostication of genetically vulnerable families with identification of proband.
- This scientific statement outlines current best practices for establishing clinical cardiovascular genetics programs (CVGPs) and on delivering cardiovascular genetic evaluation and care in both the pediatric and the adult settings, with a focus on a heart team approach along with a medical geneticist.
- It would be interesting to see the evolution of the medicolegal aspect of CV genetics given the vast information from genetic testing. Genetic Information Nondiscrimination Act (GINA) provides protection against denial of employment or health insurance based on genetic test results.
- Prediagnosis with genetic studies, antemortem imaging or invasive studies and postmortem information when needed constitutes a full spectrum analysis of a heritable cardiac condition.
- Depending on the heritable CVD under consideration, genetic testing can impact diagnostic, prognostic, and therapeutic decision making. In some disorders, such as LQTS, FH, and aortopathies, the impact is robust in all three respects, whereas in other disorders such as familial atrial fibrillation, the impact is limited perhaps to identification of potential at-risk family members by cascade testing.
- Despite the effort by the American College of Medical Genetics and Genomics to standardize guidelines for interpretation, genetic testing laboratories may not agree on variant interpretation. Misclassification of variants has serious clinical implications.
- The American College of Medical Genetics and Genomics identified 59 genes as medically actionable, indicating that variants in these genes should prompt follow-up medical care. Thirty-one of the 59 genes are linked to CVDs, including cardiomyopathies, heritable arrhythmias, aortopathies, and FH.
- The use of multigene panels is standard for most clinical cardiovascular genetic testing because of the extent of locus and allelic heterogeneity in cardiac conditions.
- The development of formal CVGP clinics is a relatively new phenomenon. Detailed studies of their impact, resource needs, funding models, patient outcomes, and overall roles and value within the healthcare system generally have not been conducted.
- Core personnel include cardiologists, medical geneticists, genetic counselors, nurse managers, and clinical coordinators.
Comment from Dr. Khyati Pandya (Mississippi), section editor of Congenital Electrophysiology Journal Watch: Major advances in the field of molecular genetics have expanded our ability to identify genetic substrates underlying the pathogenesis of various disorders that follow Mendelian inheritance patterns. Included among these disorders are the potentially lethal and heritable channelopathies and cardiomyopathies for which the underlying genetic basis has been identified and is now better understood (Ackerman et al).
Inherited cardiac conditions (ICCs) comprise a broad range of syndromes that affect the heart and major blood vessels, including cardiomyopathies, arrhythmias, aortopathies, familial hypercholesterolemia (FH), and congenital structural heart defects. Collectively, these disorders are relatively common and are associated with adverse clinical outcomes such as sudden cardiac death (SCD), heart failure, and premature coronary heart disease (CHD).
Advances in sequencing technology have expanded testing panels for inherited cardiac conditions and driven down costs, further improving the cost-effectiveness of genetic testing. However, this expanded testing requires great rigor in the identification of pathogenic variants, with domain-specific knowledge required for variant interpretation (Walsh et al).
The table below is a comprehensive list of the major genes associated with various inheritable cardiac disorders. (Walsh et al; Clinical Chemistry 63:1 116–128 (2017) )
There are significant challenges to the establishment of clinical cardiovascular genetics programs (CVGPs) in smaller programs, as these require presence of on-site clinical geneticist, genetic counselors and a significant time commitment from multiple specialties for effective coordination. The presence of remote support from genetic counselors via telemedicine may serve to mitigate this problem. A lot more remains to be desired regarding insurance coverage for genetic testing, although, it has considerably improved compared to previous.
Illustrative workflow for evaluation and management in a cardiovascular genetics program clinic of new patients who do not have a known pathogenic variant.
Illustrative workflow for evaluation and management in a cardiovascular genetics program clinic of members of families with a known pathogenic variant.
The principal benefit of clinical genetic testing in the current era, is the cascade screening of family members of patients with a pathogenic variant, enabling targeted follow up of presymptomatic genotype-positive individuals and discharge of genotype-negative individuals to health. For the proband, diagnostic sequencing can also be useful in discriminating inherited disease from alternative diagnoses, directing treatment, and for molecular autopsy in cases of sudden unexplained death. Advances in sequencing technology have expanded testing panels for inherited cardiac conditions and driven down costs, further improving the cost-effectiveness of genetic testing. However, this expanded testing requires great rigor in the identification of pathogenic variants, with domain-specific knowledge required for variant interpretation. Diagnostic sequencing can potentially become an integral part of the clinical management of patients with inherited cardiac conditions. However, to move beyond just confirmatory and predictive testing, a much greater understanding is needed of the genetic basis of these conditions, the role of the environment, and the underlying disease mechanisms. With this additional information it is likely that genetic testing will increasingly be used for stratified and preventative strategies in the era of genomic medicine. The establishment of CVGPs is probably the most effective and comprehensive method for diagnosis and treatment of a wide array of heritable cardiac conditions, that, heretofore, remained somewhat elusive. These programs are up and running in some major/ tertiary institutions. However, making this a routine practice for diagnosis of heritable cardiac conditions, would be the standard of care. Till such time, that the creation of CVGPs is made uniform practice, a primary need, is establishing screening programs. These maybe in the form of community screening which in turn maybe achieved by distributing screening questionnaires to identify individuals at risk for sudden cardiac death, premature atherosclerosis or heart failure. Once identified, these patients can then be referred to CVGPs for further investigations. Genetic counselors form the cornerstone of CVGPs and serve as a liaison between the clinician and the patient. As of today, cardiogenetics largely remains underutilized due to various factors. A fully established CVGP is an exciting frontier for identification and management of heritable cardiac conditions. Collaborating with the coroner for cascade screening of families of young individuals who have suffered sudden cardiac death cannot be overemphasized.