Genetic Testing in Cardiology: Incorporating into Clinical Care

The first draft of the human genome was published in 2001,¹ representing just over a decade of work and an investment of $1 Billion. This momentous feat, accomplished ahead of schedule and under budget, carried with it excitement that we were entering the genomic era of medicine. In this era, there is optimism that insights from, and potentially manipulation of, our genetic code could be used to personalize disease treatment and prevention. Excitement was further fueled by tremendous technological advances with DNA sequencing so that it now costs <$1,000 and takes <1 day to sequence the human genome. However, clinical translation of genetic and genomic information has not been as fast or impactful as hoped due to the extraordinary complexity of the human genome, as well as poorly understood epigenetic and non-genetic factors that influence how genetic background impacts health and disease.

In addition to incomplete understanding of genomic science, apprehension in the provider workforce has limited clinical implementation. Most physicians do not have robust knowledge of human genetics. There is limited exposure in medical school, information is rapidly evolving, and there is little to no formal training during residency. In a survey of 130 primary care physicians, over 60% reported no or minimal knowledge about when and how to incorporate genomic information into clinical practice.² Another study found that ~80% of internists felt inadequately prepared to order and interpret genetic testing or to counsel patients.³ Both studies found that most practitioners recognized the need to improve their knowledge base and were interested in training. Addressing this need will become increasingly germane. The use of genetic testing is expanding and more frequently ordered and managed by non-geneticists. Furthermore, even if providers do not intend to initiate genetic testing themselves, they will likely have to confront it nonetheless due to the rising use of direct to consumer genetic testing and research studies that will return individual genetic and genomic information deemed clinically relevant. Patients are then likely to seek advice from or be referred to a provider.

Providers are justified in feeling some degree of apprehension around genetic testing. Genetic testing is a valuable tool for managing inherited cardiovascular disease. It can identify the molecular etiology of disease, thereby improving diagnostic accuracy and refining family management. However, genetic testing brings unique challenges that distinguish it from traditional laboratory-based testing. To achieve the best outcomes, clinicians and patients need to have accurate expectations about genetic testing and understand the nuances of test interpretation and potential implications, including implications for the family. Indeed, genetic testing should be considered in the context of the family rather than the individual.

In order to successfully incorporate genetic testing into clinical practice, providers must be able to recognize when inherited cardiovascular disease may be present, determine the best genetic testing strategy, understand the complexities of interpreting results, and effectively communicate the results and implications to the patient. For example, the most critical aspect of the report is how the laboratory classifies the clinical relevance of identified genetic variants. The classification provided by the genetic testing laboratory represents their best estimate of how likely it is that the variant can cause disease, ranging from being highly confident (a classification of pathogenic or benign) or uncertain (classification as a variant of unknown significance). Only high confidence classifications are clinically actionable and suitable for use in predictive genetic testing for the family. As such, the results from genetic testing are probabilistic and interpretation will evolve as knowledge evolves. In the future, greater knowledge and developing reliable, high throughput in vitro functional assays will assist variant classification efforts. Until then, providers must recognize that classification is part science and part art. Therefore, they need to be able to scrutinize the results provided by genetic testing laboratories for accuracy and plausibility. This involves being aware of publicly available resources to aid variant interpretation. For example, ClinVar⁴ is an online database, hosted by the National Center for Biotechnology Information, that aggregates available variant-level information, indicates if conflicting interpretations are reported from different testing agencies, and periodically updates listing. Additionally, determining the best genetic testing strategy requires judgement. Bigger panels or even whole genome sequencing are not necessarily better and may not increase the yield of clinically actionable results.^5-7 Being parsimonious is typically preferable and it is important to know when it is appropriate to embark on a diagnostic odyssey. Providers without expertise in genetic testing will benefit from establishing referral or consultative networks with experienced clinicians in specialized multidisciplinary cardiovascular genetics clinics. Because such expertise may not be readily available, we must also develop new methods improve access with creative use of technology, including expanding venues for virtual health. Additionally, it is important to continue efforts to help increase genetic literacy and familiarity.^{8, 9} Human genetics should be incorporated into medical school, residency and fellowship training, emphasizing clinical application. More post-graduate and continuing medical education (CME) courses should be developed, recognizing that online CME programs were indicated to be the preferred mode of education for genomic medicine (42%), followed by professional meetings (21%), and in-person CME such as grand rounds (18%).²

This AHA Scientific Statement on Genetic Testing for Inherited Cardiovascular Disease is an important and welcome addition to the literature. Musunuru and colleagues provide an important resource to describe best practice for incorporating genetics into clinical care. The statement is a useful and highly practical roadmap for genetic testing in monogenic cardiovascular disorders including cardiomyopathies, inherited arrhythmias, aortopathies, and familial hypercholesterolemia. The authors succinctly summarize practice guidelines and expert consensus statements. They also provide guidance for recognizing and targeting patients with likely inherited cardiovascular disease through robust phenotyping and systematic ascertainment of family history. Appropriately focusing on the phenotypes and diagnoses best suited to genotyping, the authors lead the reader through the vagaries of genetic testing to facilitate clear communication of expectations, implications, limitations and benefits with patients. They highlight the most reliable genes, conditions, and applications of genetic testing, clearly describe both the science and the artform of variant classification. This and other ongoing efforts are essential to integrate genetic insights into the practice of medicine, thereby improving the care of our patients and families.