Cardiovascular Genetics

INTRODUCTION

Most primary care physicians have been or will be asked about genetic testing by their patients, but many do not feel adequately prepared to discuss this topic.^1,2 Some patients may have no personal or family history of a potentially genetic disease but are interested in learning about their genetic risk. In years past, high cost of clinical genetic testing was often a barrier, but with the progress in genetic testing technologies, cost has decreased and genetic testing is increasingly being performed in those with suspected genetic cardiovascular diseases as well as in some healthy people. There is still much to learn about the genetic risk factors that influence cardiovascular disease development, as well as how we might seek to mitigate that risk. In this review, we provide information about genetic testing for cardiovascular diseases and a framework for primary care physicians and their teams to better understand situations in which genetic testing may contribute important information to patient care.

GENETIC TESTING

For Which Types of Cardiovascular Conditions Should Genetic Testing Be Offered?

Many professional societies have published guidelines on genetic evaluation in cardiovascular diseases, and genetic testing is recommended for many cardiovascular phenotypes. The American Heart Association and other professional societies have recognized that cardiogenetic evaluation requires specific expertise and is best performed in the setting of a multidisciplinary specialist clinic.³ Team members in these clinics include cardiologists, advanced practitioners, and genetic counselors with expertise in cardiovascular genetics among others (Fig. 1). Obtaining a detailed three-generation family history is of utmost importance in the genetic evaluation of cardiovascular disease. This information can greatly impact the care of patients and their families more than genetic testing can in some cases.

Fig. 1.

Members of a multidisciplinary cardiogenetics team.

Cardiovascular genetic testing can be helpful for risk stratification or providing management guidance in some with cardiovascular disease and is also helpful for reproductive planning and aiding in cascade screening of at-risk family members. In most cases, a diagnosis is made based on clinical cardiovascular testing. However, the presence of a causative genetic variant can be part of the diagnostic criteria for certain conditions, including catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular cardiomyopathy, Loeys-Dietz syndrome, and Marfan syndrome. For some conditions, genetic test results can aid in risk prediction for clinical events and may impact the choice of medical therapy or timing of certain interventions. There are some conditions, however, like atrial fibrillation, for which genetic testing is not typically recommended. Because the paradigm of genetic testing is probabilistic and not deterministic, negative genetic test results on a proband with disease can almost never rule out a genetic predisposition. The degree to which genetic test results can be helpful as well as the detection rate, or the likelihood of identifying a genetic cause, can also vary greatly by phenotype. We summarize this information for selected cardiovascular phenotypes in Table 1.

Table 1.

Genetic testing for select cardiovascular phenotypes

Phenotype	Guidelines Supporting Genetic Testing	Yield of Genetic Testing	Potential Impact on Medical Management
Cardiomyopathies	HFSA20	HCM: 30%–60%	Rarea
HCM	HRS/EHRA21	DCM: 30%–40%
DCM		ACM: ~60%
ACM
Arrhythmia conditions LQTS	HRS/EHRA22	LQTS: 50%–75%	Yes
BrS		BrS (SCN5A): 20%–25%
CPVT		CPVT: ~50%
Sudden cardiac death/ventricular arrhythmias	HRS/EHRA22 APHRS/HRS23	15–30%b	Yes
FTAAD	ACCF/AHA24	10–20%c	Yes
Familial hypercholesterolemia	NICE25 NLA26	60%–80%	Yes

Abbreviations: ACM, arrhythmogenic cardiomyopathy (including ARVC/D); AHA, American Heart Association; ; BrS, Brugada syndrome; CPVT, catecholaminergic polymorphic ventricular tachycardia; DCM, dilated cardiomyopathy; FTAAD, familial aortic aneurysms and dissections; HCM, hypertrophic cardiomyopathy; LQTS, long QT syndrome.

^aExceptions include LMNA, ACM genes and phenocopies of HCM, including TTR cardiac amyloidosis, and Fabry disease.

^bIn cases of sudden unexplained death (autopsy-negative sudden death).

^cYield is higher in those with Marfan syndrome and other syndromic forms of aortopathy.

Selecting the Appropriate Individual for Genetic Testing

All major guidelines for cardiovascular genetic testing recommend that the proband, or individual selected for the initiation of genetic testing in a family, be an individual affected with the disease. Ideally, this should also be the person in the family who is most severely affected and/or has the earliest age of onset, because this increases the likelihood of finding an informative result (Fig. 2).

Fig. 2.

Choosing the appropriate individual for genetic testing. ^aIf there are multiple affected individuals in the family, testing should ideally start with the individual who is most severely affected and/or had the youngest age of onset.

Genetic testing of unaffected individuals should only be performed for risk stratification when a causative variant has been identified in the family, and testing should be limited to that variant. Genetic testing of unaffected individuals as probands is not currently recommended for cardiovascular conditions, even when an affected family member is not available for testing. Because the yield of genetic testing for cardiovascular conditions is incomplete, negative genetic testing results from an unaffected person when a causative variant has not been identified in the family are uninformative: it is impossible to know, without testing the affected family member, whether the result is a true-negative or if there is a genetic predisposition present that is not identifiable on current testing. These uninformative negative results may, nonetheless, lead to false reassurance or inappropriate management by nonspecialist clinicians. A positive result, on the other hand, rarely changes management compared with screening recommendations guided by family history alone, and it can be difficult to confidently attribute disease in a family to a variant that has not been confirmed in affected individuals. In addition, the challenges of uncertain genetic test results, discussed in more detail in later sections, are even greater when testing unaffected individuals and may produce unnecessary anxiety and uncertainty. Genetic testing of unaffected individuals as probands is performed more often in cancer genetics because there are well-defined guidelines for such and genetic test results more often impact medical management. It is possible that this may one day be the case for cardiac conditions as well.

CASCADE SCREENING

Cascade screening is a process whereby family members are evaluated for a disease that runs in their family (Fig. 3). Cascade screening can involve either clinical screening or genetic testing, depending on the genetic test results of the proband. When genetic testing is used for this purpose, it is important that there is confidence that the genetic variant identified is actually causing the familial disease phenotype. Most genetic cardiovascular diseases are inherited in an autosomal dominant pattern such that all first-degree family members have a 50% chance of inheriting the genetic predisposition to develop disease regardless of sex. In most cases, a causative variant was inherited from a parent, and determining which parent allows for further cascade screening of appropriate aunts, uncles, and cousins of the proband. Testing children younger than 18 years of age for pathogenic variants in genes associated with cardiovascular disease can be considered, but special attention should be paid to whether the results will truly impact their management with consideration of the potential positive and negative effects of genetic testing. If families decide that the risks of genetic testing for their children outweigh the benefits, they can defer or forgo genetic testing and continue with periodic clinical screening to see if the disease phenotype emerges.

Fig. 3.

Cascade screening. LP, likely pathogenic variant; P, pathogenic variant; VUS, variant of uncertain significance; WES, whole-exome sequencing; WGS, whole-genome sequencing.

Owing to regulations imposed by the Health Insurance Portability and Accountability Act of 1996 (HIPAA), providers cannot reach out to family members at risk for disease directly, so the responsibility of informing family members of their risk lies primarily with patients in the vast majority of cases. In many clinics, genetic counselors write letters to help patients communicate this information with their families, but there are often family members who do not pursue cascade screening. As such, there are ongoing efforts to develop other ways of helping patients communicate this information.⁴

Some genetic causes of cardiovascular disease are fully penetrant, meaning that nearly everyone with the causative variant will develop some manifestation of disease, whereas most exhibit reduced penetrance and variable expressivity. For many cardiovascular risk genes and variants within those genes, precise penetrance estimates are still lacking; this can further complicate discussions surrounding cascade screening. Expert consensus groups including ClinGen are trying to better characterize risk of developing disease by gene and/or variant, but it will likely be many years before better risk estimates for most cardiovascular genetic conditions are available.⁵

Reproductive Options

Prenatal testing, including chorionic villus sampling (CVS) and amniocentesis, and preimplantation genetic testing for monogenic disease (PGT-M) were options first used for couples who were both carriers for the same recessive genetic conditions to ensure any children they had were not born with the disease or at risk for disease. In recent years, these technologies have been used in various cardiovascular diseases for which the genetic cause has been successfully identified. CVS and amniocentesis involve taking placental tissue or amniotic fluid samples, respectively, to test a fetus for a genetic condition. PGT-M, formerly termed preimplantation genetic diagnosis (PGD), requires the use of in vitro fertilization (IVF) to create embryos that are then tested for the causative genetic variant to determine if the embryo will be used for conception. Doing IVF with PGT-M may not be a feasible option for many due to high cost, but some insurance companies cover at least part of the cost, and there are clinical trials providing this service at low or no cost.

SELECTING THE APPROPRIATE GENETIC TEST

Panel Testing

Most genetic cardiovascular disorders have multiple possible genetic causes, and therefore assessment of multiple genes is typically the best approach for genetic diagnosis. At present, the most common type of diagnostic genetic testing for cardiovascular conditions is panel testing, in which a set of genes relevant to the patient’s phenotype are sequenced. When the phenotype is well defined, a narrow panel is most appropriate; broader panels may be helpful when the phenotype is less well defined, but they also increase the likelihood of uncertain or unrelated findings. The genes included on panels vary between laboratories and change over time, as new gene-disease associations are discovered.

Single-Gene and Single-Variant Testing

Single-gene testing may be appropriate when clinical suspicion is very high for a disorder caused by only one gene (eg, TTR in hereditary transthyretin amyloidosis). Single-variant testing, in which the presence or absence of a specific variant within a gene is assessed, is the appropriate test for family members when a causative variant has been identified in the family.

Whole-Exome and Whole-Genome Sequencing

Whole-exome sequencing (WES) and whole-genome sequencing (WGS), in which a patient’s protein-coding genes or entire DNA sequence, respectively, are analyzed, are currently of limited utility in adult cardiovascular care settings: they increase diagnostic yield only very modestly compared with panels and create a significantly greater burden of uncertainty.^6,7 However, they are more commonly used, and have more utility, in pediatric settings and/or when syndromic or multisystem disease is present. In addition, WES and WGS are commonly used in research studies and are useful for gene discovery.

Direct-to-Consumer Genetic Testing

Direct-to-consumer (DTC) genetic testing has grown rapidly in recent years. The first wave of DTC genetic tests were offered without the need for a physician’s approval, and often include health-related genetic data along with ancestry or other information. A newer model of DTC testing includes physician involvement; tests may be ordered by the patient’s own physician or by a physician employed by the DTC company. This type of testing is often referred to as “proactive” testing and is typically marketed to healthy individuals who want to learn more about their genetic predisposition to disease. Tests consist of genetic panels with genes selected for actionability, especially those associated with cardiovascular and cancer risk.⁸ Some major academic health care systems have recently made such tests available to their students and staff at no cost to them. Some DTC companies also provide patients access to their raw genetic data, which can be analyzed with the help of third-party services. Despite the perceived benefits of this open information exchange, these third-party analyses have been shown to lead to false-positive results.⁹ There are currently no guidelines for how clinicians should approach DTC testing. The clinical utility of DTC tests has not been comprehensively studied, and this represents an emerging need in genetics.¹⁰

Polygenic Risk Scores

Common cardiovascular diseases, including coronary artery disease, stroke, and atrial fibrillation, are known to have both environmental and familial components but typically do not have mendelian (single-gene) causes. Instead, the hereditary aspect is thought to arise from many common genetic variants, each with a small individual contribution to risk. Genome-wide association studies (GWAS) have been able to identify some of the common genetic variation underlying these conditions. In turn, polygenic risk scores (PRS) are tools that use information gleaned from GWAS to attempt to better risk stratify individuals for these disorders by genotyping them for common genetic variation. Despite growing interest in PRS and evidence suggesting that it can contribute to risk prediction for various common disorders, their clinical utility is limited at this time and there is not yet established guidance for if and how PRS should be used in practice.¹¹

POSSIBLE RESULTS FROM GENETIC TESTING

Variant interpretation is one of the more challenging aspects of clinical genetics. There is a great deal of genetic variation between individuals, most of which is benign. Distinguishing pathogenic from benign variation identified on genetic testing relies on multiple lines of evidence including case reports, population prevalence data, and computational and laboratory evidence. Classifying variants is generally the purview of the genetic testing laboratory, but laboratories do not always agree on variant interpretation. In 2015, to help address this issue of discordant variant classifications between laboratories and provide standardized guidance for variant assessment, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology issued updated guidelines for classification of sequence variants providing detailed criteria by which laboratories should classify variants into 5 categories: pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign (LB), and benign (B). LP and LB variants are defined as having a greater than 90% likelihood of being pathogenic or benign, respectively, whereas a VUS falls in the middle range of 10% to 90%.

P and LP variants can contribute to diagnosis, management, and familial risk stratification, although clinical correlation is important, because P or LP variants may sometimes be incidental findings that are not truly related to the indication for testing. VUS findings mean that evidence is insufficient or conflicting about the pathogenicity of the variant, and the variant cannot confidently be classified as pathogenic or benign. VUS results are very common in cardiovascular genetics and should not be used to guide management or risk stratify family members. B and LB variants are not associated with disease and are typically not reported by clinical laboratories.

Even with the detailed guidance offered by ACMG, variant classification is a complex art, and laboratories still often differ in their interpretation. Efforts to further harmonize and improve variant classification are ongoing. The ClinGen consortium, founded by the National Human Genome Research Institute in 2013, maintains the public ClinVar database wherein laboratories and other groups publicly share their variant classifications and organizes gene- and condition-specific working groups to review evidence for genes and variants.¹² Another important resource for variant classification is population prevalence data on genetic variants; the Genome Aggregation Database (gnomAD) is a public database of variant frequency in thousands of exomes and genomes of individuals unselected for disease, from multiple ethnicities.¹³ Although gnomAD has improved variant interpretation in minority populations, there is still greater potential for misdiagnoses based on genetic test results in minority populations.¹⁴

Clinicians with expertise in cardiovascular genetics often take an active role in variant interpretation by aggregating additional information on variants reported on genetic testing.¹⁵ To further elucidate VUS, clinicians may undertake additional investigations, including tracking VUS in affected family members to determine whether variants segregate with disease.

Variant Reinterpretation

The classification of variants can change over time as new data emerge. Variants may be upgraded or downgraded in their level of pathogenicity, which can have significant impact on management, especially in family members. There has been much debate on who has responsibility to stay abreast of potential changes in variant interpretation. Some have suggested that the responsibility lies with the genetic testing laboratories and others with clinicians. There are no clear guidelines on who maintains this responsibility, when to recontact patients, or how often to perform variant re-interpretation, but most recognize these tasks need to be performed periodically.^16,17 At present, clinical genetic testing laboratories are not routinely reinterpreting genetic variants but will do so when requested by a clinician or genetic counselor.¹⁸ If a variant is identified in numerous individuals at one laboratory and a change in interpretation occurs over time, the laboratories do have procedures in place to disseminate updated reports or contact the ordering provider for every patient with that variant identified at their laboratory. However, if a patient has moved or a clinician is no longer practicing at that location, communicating that variant update can be challenging. In our clinic, our genetic counselors handle much of these responsibilities, which can occupy a significant amount of non-face-to-face clinical time. In clinics with no or limited genetic counselor support, these responsibilities can fall on clinicians themselves or their staff, but in many clinics these tasks may never be performed.

COMMON CONCERNS REGARDING GENETIC TESTING

Discrimination and Privacy

Concerns over discrimination based on genetic information have been raised for decades and continue to be of concern, especially with the increasing availability of genetic testing. There are many state and federal protections in place in the United States, but gaps exist and discrimination may still occur. One such piece of federal protections legislation is the Genetic Information Nondiscrimination Act (GINA), which became law in 2008. GINA protects against employment and health insurance discrimination based on genetic information. Protected genetic information includes family history, participation in genetic research, genetic test results, and the use of genetic counseling and other services.¹⁹ GINA does not protect against life insurance, long-term care insurance, or disability insurance discrimination, and few state laws exist to protect people from discrimination for these types of policies. Consequently, some individuals chose to obtain these types of insurances before undergoing cascade screening. GINA does not apply to all groups; exclusions include people in the military or those who work at a company with less than 15 employees.¹⁹

In the United States, HIPAA requires that clinicians and clinical genetic testing laboratories keep patients’ test results, including genetic test results, confidential in most cases. Although the risk for patient’s privacy related to genetic testing performed at a clinical genetic testing laboratory is very low due to HIPAA and its protections, patients may express reluctance to undergo genetic testing due to privacy concerns such as access of genetic information by law enforcement or by previously unknown biological relatives, typically associated with DTC testing.

Cost

The cost of genetic testing is often highest for probands and currently ranges from $250 to a few thousand dollars, depending on the genetic test ordered (highest for WGS and WES, lowest for panels) and insurance coverage. If a pathogenic variant is identified in a proband, testing family members for just that variant can sometimes be done for free or at much lower cost depending on insurance coverage and genetic testing laboratory policy. Cost and access still remain as barriers, but these have improved significantly.

CASE STUDY

A 58-year-old man of European ancestry with a history of idiopathic dilated cardiomyopathy (DCM) presented for consideration of genetic testing. Although he did not report a clear family history of similar concerns (Fig. 4), genetic testing for cardiomyopathy risk genes was pursued. Genetic testing identified 2 VUSs, which could not be used to risk stratify his family members, and periodic clinical screening for DCM was recommended for his first-degree relatives. After a few years, we reanalyzed his results and one of the variants was downgraded to likely benign, whereas the other was upgraded to pathogenic. Unfortunately, the patient died due to complications of heart transplantation. His 3 children then presented to clinic for evaluation, and targeted genetic testing for the pathogenic variant identified in their father was offered. All 3 were negative for the pathogenic variant and dismissed from ongoing cardiac surveillance.

Fig. 4.

Pedigree. +, Positive for causative pathogenic variant; −, negative for causative pathogenic variant.

Case Study Discussion

VUSs are common in cardiovascular genetics and need to be reevaluated periodically, and genetic testing in appropriate probands yields the most helpful results. If we had not tested the appropriate genetic testing proband (the father) first and offered panel testing to each of his children instead, their results would have been negative or additional VUSs could have been identified. In that scenario, we would not have known that they were truly not at risk and they would have been recommended to continue with periodic clinical screening for DCM.

SUMMARY

Genetic testing for selected cardiovascular conditions can be helpful for patients and their families, but it is far from perfect. Understanding the complexities of the genetics of cardiovascular disease and the implications of such can make counseling about genetic risk of cardiovascular disease challenging even for the most-well-trained professionals. Genetic testing is integral to the goal of achieving truly personalized care for our patients, and to do it appropriately requires significant training and multidisciplinary expertise.

KEY POINTS.

• Genetic testing is recommended by guidelines for many cardiovascular conditions and is useful for diagnosis, management, and cascade screening.

• Genetic testing for cardiovascular conditions in healthy people with no family history is not widely recommended at this time.

• Appropriate pretest and posttest genetic counseling are crucial because of the complexity of genetic information and its implications for patients and their families.

CLINICS CARE POINTS.

• Genetic testing for selected cardiovascular phenotypes can provide useful clinical information for affected individuals and allow for cascade screening in unaffected relatives.

• Cardiovascular genetic testing in healthy individuals outside of cascade screening is generally not recommended at this time but is available.

• VUSs are common in cardiovascular genetics and should not be used for clinical management or cascade screening.

• Genetic test results need to be periodically reevaluated for potential updates in variant interpretation.