Clinical Cardiovascular Genetics Programs: A Call to Action and a Roadmap

I often ask my clinical colleagues, “How often do you diagnose a patient with a monogenic disease?” Recent attention has been focused on the hope of precision medicine and understanding how genetics contributes to common disease risk and drug response. However, the existence and genetics of more extreme, rare genetic diseases, so-called monogenic or Mendelian diseases, have been clearly established for decades. In fact, estimates suggest that more than one in every 25 people has a rare disease, of which ~80% are genetic in origin!¹ But the answer to the question I pose to my clinical colleagues is frequently “Never.”

In cardiovascular disease, we have many such monogenic diseases including hypertrophic and familial cardiomyopathies, long QT syndrome and Marfan syndrome. Unfortunately, these diseases are likely underdiagnosed. Further, patients and families who suffer from, or know they are at risk for, these cardiovascular genetic disorders often have difficulty finding clinics to provide the specialty care that they need. Historically, the landscape of clinics caring for these patients has been general medical genetics clinics or pediatric genetics clinics, with only a few dedicated cardiovascular genetics clinics across the country.

With an increasing recognition of the importance of genetics in understanding an individual patient’s risk of health and disease and of the under-diagnosis of monogenic disorders, there is a need for a more dedicated and structured effort around building clinics that provide comprehensive care of patients and families with these disorders. These clinics are also vital for keeping up with the pace of discovery and implementation science in genetics, while providing responsible and accurate interpretation of that science for a given patient. The American Heart Association (AHA) Scientific Statement “Establishment of Specialized Clinical Cardiovascular Genetics Programs: Recognizing the Need and Meeting Standards” is a call to action, excellently outlining the necessity of such clinics and laying out a roadmap for the structure and workflow of CVGP clinics. This is a very timely and useful document as the AHA, health systems and other organizations attempt to keep up with the expanding scientific evidence for use of genetics in patient care, as well as the growing desire from patients increasingly knowledgeable about the potential utility of genetics.

Rare monogenic diseases in aggregate are actually not that rare and are a “missed opportunity”

It is important to delineate between monogenic genetic diseases that individually are relatively rare in in. They are usually caused by a single or handful of genes with mutations in those genes being highly deleterious and thus maintained at a very low frequency in the population. Examples of such monogenic diseases in cardiology include hypertrophic and familial cardiomyopathy, long QT syndrome, Marfan syndrome, vascular Ehlers Danlos syndrome and familial hypercholesterolemia. This is in contrast to common complex diseases that have genetic risk factors (such as coronary artery disease, hypertension and atrial fibrillation) where up to hundreds of genetic variants contribute to disease with these variants having a relatively high frequency in the population and associated low individual relative risk of disease.

Rare diseases are those that affect less than one person out of 2000. Given that there are 5000 - 8000 rare diseases, most of them genetic, this would translate to more than one out of 25 potentially afflicted with a rare disease.² Thus, in aggregate, rare diseases are actually not that rare. Unfortunately, monogenic diseases are underdiagnosed.³ This is despite the fact that monogenic diseases are one of the most “evidence-based” areas in current precision medicine: diagnosis is critical for management, prognosis and therapeutic decision-making. Further, genetic counseling and testing can greatly assist with risk stratification in the family, potentially leading to earlier diagnosis in as-of-yet unaffected individuals. Thus, monogenic cardiovascular diseases are a “missed opportunity” in public health.

Why do we need specialized clinical cardiovascular genetics programs (CVGP)?

Ahmad and colleagues nicely outline the benefits of clinics that provide integrated cardiovascular medicine and genetics care. These CVGP clinics provide comprehensive cardiovascular clinical and genetic assessment including personal and family history, physical examination, clinical interpretation of imaging and other clinical testing, and genetic testing if indicated. Integrating components of this assessment, clinicians within CVGP clinics provide a comprehensive discussion of diagnosis, prognosis and treatment options for cardiovascular genetic disorders in affected patients, and importantly, address the potential need for risk assessment and cascade screening in family members. In as-of-yet unaffected family members, this can mean the difference between having to undergo longitudinal clinical screening (for example, with echocardiograms every few years) based on the potential for having been transmitted the disease-causing variant versus not having to be worried about risk of developing the disease if they are found to not carry the mutation causing disease in their relative. Studies have shown the effectiveness of such cascade screening in family members.⁴

CVGP clinicians include clinicians trained in genetics such as genetic counselors, medical geneticists and/or pediatric or adult cardiologists with a focused interest in genetic disorders. While all clinicians should receive general genetics education, these clinicians have more intensive training in the clinical care of cardiovascular genetic disorders. Clinicians in CVGP clinics are uniquely trained to provide pre-test counseling about the utility of genetic testing for a given individual, taking into account the patient’s family history, personal medical history, physical exam and imaging to determine whether a monogenic cardiovascular disorder may be the underlying cause of a presentation, and discussing implications of a possible positive or a negative test result to the patient and family members. This pre-test counseling also addresses other important issues that influence decision making around genetic testing such as out-of-pocket costs for testing to the patient (which vary depending on insurance and genetic testing company used), and discussions of potential downstream effects on the ability to obtain disability and life insurance. While the Genetic Information Non-Discrimination Act (GINA) law protects individuals from discrimination for health insurance and employment based on genetic test results, there are no laws prohibiting companies that provide long-term care, disability and life insurance from using genetic test results in making decisions about offering policies and at what cost.

Importantly, other individuals part of the CVGP team include specialist physicians, cardiovascular proceduralists and surgeons and cardiovascular nurses with expertise in cardiovascular genetics and may also include nurse managers and clinical coordinators.

Post-test counseling: genetic test results are often not as simple as positive or negative

While we like to clinical tests to be clearly delineated as positive or negative, unfortunately that is often not the case with genetic testing. The genetic community is still struggling with pathogenicity assessment (i.e. determining which variants across the genome actually cause disease) and classification of individual variants changes, as we glean more information from other families and across different ethnicities. Clinicians within CVGP clinics are trained in pathogenicity assessment of genetic test results and interpreting them in a clinical context for a given patient with a given clinical presentation. For example, patients may meet clinical criteria for a monogenic cardiovascular disease but a disease-causing (i.e. pathogenic) mutation is not identified. Clinical genetic testing companies often disagree about whether a given genetic variant is pathogenic and misclassification of variants can have serious clinical consequences. Variants of unclear significant (VUS) are often reclassified as either pathogenic or benign. Patients with “negative” genetic testing need to understand that there may still be a hereditary disorder in their family. All of these situations require careful post-test counseling by CVGP team members with interpretation placed in a clinical context and with possible reinterpretation of the genetic variant by the CVPG team from what is provided by the clinical genetic testing company.

These issues are becoming even more complex as research, clinical and direct-to-consumer genetic testing moves from panels of genes known to be associated with disease to whole exome and whole genome sequencing. Interpretation of pathogenicity of a broader set of genes, non-coding variation, and genetic incidental findings that are a result of this broader query of the genome will continue to be challenging and will require the expertise of CVGP clinics to provide accurate interpretation for patients. In fact, 31 of the 59 genes classified by the American College of Medical Genetics as “medically actionable” are linked to cardiovascular disease, such that identification of variants in these genes should prompt follow-up medical care.⁵

Challenges in establishing CVGP clinics

While the AHA statement clearly delineates the need and utility of CVGP clinics, there are challenges to more widespread establishment of these clinics. First, there is a major workforce issue in cardiovascular genetics. Genetic counselors are an integral component of clinical genetics care but there are insufficient numbers of genetic counselors to meet the burden of monogenic diseases. Interestingly, there are growing efforts to address this need through telemedicine. On the physician side, cardiovascular genetics is not recognized as a subspecialty of cardiovascular medicine, in part contributing to a dearth of cardiologists trained in genetics. Thanks to organizations such as the AHA and the National Society of Genetic Counselors there are an increasing number of resources for genetics training. However, standards for the “cardiovascular geneticist” or “genetic cardiologist”, and the optimal balance between the more restrictive view that all genetic cardiologists should do a medical genetics fellowship vs. the more liberal view that online courses and some hands-on training are sufficient are not yet defined. Another major challenge in establishing CVGP clinics is at the level of health systems that are increasingly feeling financial pressures, in such systems, genetics subspecialty clinics that require multiple specialists and long clinic visits may be perceived as revenue negative. Accounting for new patients brought into a health system and tracking downstream revenue from imaging and other procedures may help obviate concerns about any perceived financial burden of CVGP clinics and needs to more systematically studied.

The future of monogenic cardiovascular disorders and CVGP clinics

As detailed in this AHA statement, “systematically designed, implemented, and validated models for CVGP clinics are largely lacking.” The future holds great promise though, as there is a growing recognition of the need for such clinics and for studying the most effective models for delivering genetics care. Educational efforts in cardiovascular genetics are growing and it is likely that standards will be delineated for the “genetic cardiologist”. As well, these educational efforts will help primary care doctors and non-genetic cardiologists recognize when patients need to be referred for specialty CVGP care. Telemedicine will likely be increasingly used to ensure accessibility to all populations. Sharing of data in public databases, collaborations with genetic testing companies, studying non-white populations, and better preclinical models and use of patient-derived induced pluripotent stem cells for functional assessment will greatly improve clinicians ability to determine pathogenicity of variants. Many thanks to Dr. Ahmad, Dr. McNally and colleagues for this call to action and for laying a roadmap for the structure and workflow of CVGP clinics. There is great hope for addressing the missed opportunity of monogenic cardiovascular diseases and thereby decreasing the morbidity and mortality associated with these not-so-rare diseases.