![]() ![]() Yellow boxes denote key steps in the classification of rare genetic variation based on American College of Medical Genetics and Genomics (ACMG) criteria. ![]() Light orange boxes denote basic considerations pertaining to the initiation of genetic testing. By assisting the multidisciplinary team with (1) the generation of multigenerational pedigrees and identification of the most appropriate individual(s) to test initially, (2) the selection of appropriate genetic tests, (3) the accurate interpretation and continued reassessment of genetic test results, and (4) assuring that psychosocial ramifications of genetic testing are adequately addressed, genetic counseling provides additional assurance that genetic testing will be utilized appropriately and that high-quality, cost-effective care is delivered.įigure 1 A rational approach to cardiovascular genetic testing, rare variant interpretation, and the reassessment of variants of unknown/uncertain significance. Regardless of the responsible health care professional, the patient and family should receive genetic counseling. When feasible, the ordering, interpretation, and communication of CVD genetic test results should be done under the guidance of a genetically oriented cardiologist and/or medical geneticist with expertise in heritable CVDs in conjunction with a cardiovascular-genetic counselor. Given these nuances, the initiation and interpretation of cardiovascular genetic tests requires a multidisciplinary approach involving the coordinated efforts of general practitioners/general cardiologists, genetic counselors, medical geneticists, and cardiovascular subspecialists with expertise in the CVD of interest. Therefore, a “one size fits all” mentality to genetic testing is ill-advised, and genetic testing should be undertaken only if considerable suspicion for an underlying genetic CVD remains after a thorough clinical evaluation, including, but not limited to, a detailed family history, comprehensive cardiovascular work-up, and assessment for multisystem syndromes. In other words, in patients with weak/nonequivocal clinical phenotypes, the diagnostic yield of genetic testing declines, the signal to noise ratio rises, and the risk of encountering false-positive results increases exponentially. Abbreviations and Acronyms: ACM ( arrhythmogenic cardiomyopathy), ACMG ( American College of Medical Genetics and Genomics), AF ( atrial fibrillation), BrS ( Brugada syndrome), CHD ( coronary heart disease), CPVT ( catecholaminergic polymorphic ventricular tachycardia), CVD ( cardiovascular disease), DCM ( dilated cardiomyopathy), EHRA ( European Heart Rhythm Association), FH ( familial hypercholesterolemia), GRS ( genetic risk score), GWAS ( genome-wide association study), HCM ( hypertrophic cardiomyopathy), HRS ( Heart Rhythm Society), LDL-C ( low-density lipoprotein cholesterol), LQTS ( long QT syndrome), LVNC ( left ventricular noncompaction), MFS ( Marfan syndrome), RCM ( restrictive cardiomyopathy), RCT ( randomized controlled trial), SCD ( sudden cardiac death), SNP ( single-nucleotide polymorphism), SUDY ( sudden unexplained death in the young), VUS ( variant of unknown/uncertain significance), WEMA ( whole-exome sequencing–based molecular autopsy), WES ( whole-exome sequencing)Īs such, the clinical utility of a given genetic test is highly dependent on the pretest probability of disease (ie, strength of clinical phenotype/diagnosis) and disease-specific genetic test performance metrics (eg, diagnostic yield, signal to noise ratio). ![]() In this review, we detail a practical approach to genetic testing initiation and interpretation as well as review the current state of cardiovascular genetic and pharmacogenomic testing in the context of relevant society and regulatory agency recommendations/guidelines. However, owing to a large burden of “complex” common diseases, emphasis on evidence-based practice, and a degree of unfamiliarity/discomfort with the language of genomic medicine, the development and implementation of genomics-guided approaches designed to further individualize the clinical management of a variety of cardiovascular disorders remains a challenge. As such, the use of genomics to enhance the care of patients with cardiovascular diseases has garnered increased attention from clinicians, researchers, and regulatory agencies eager to realize the promise of precision genomic medicine. In the 15 years following the release of the first complete human genome sequences, our understanding of rare and common genetic variation as determinants of cardiovascular disease susceptibility, prognosis, and therapeutic response has grown exponentially. ![]()
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