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Abstract

Rapid advances in genetic technologies have led to expanding use of diagnostic, research, and direct-to-consumer exome and genome sequencing. Incidentally identified variants from this sequencing represent a significant and growing challenge to interpret and translate into clinical care and include variants in genes associated with heritable cardiovascular disease such as cardiac ion channelopathies, cardiomyopathies, thoracic aortic disease, dyslipidemias, and congenital/structural heart disease. These variants need to be properly reported, the risk of associated disease accurately assessed, and clinical management implemented to prevent or lessen the disease so that cardiovascular genomic medicine can become both predictive and preventive. The goal of this American Heart Association consensus statement is to provide guidance to clinicians who are called on to evaluate patients with incidentally identified genetic variants in monogenic cardiovascular disease genes and to assist them in the interpretation and clinical application of variants. This scientific statement outlines a framework through which clinicians can assess the pathogenicity of an incidental variant, which includes a clinical evaluation of the patient and the patient’s family and re-evaluation of the genetic variant in question. Furthermore, this guidance underscores the importance of a multidisciplinary team to address these challenging clinical evaluations and highlights how clinicians can effectively interface with specialty centers.
Diagnostic genetic testing has been a critical component of the evaluation of heritable monogenic cardiovascular disease (CVD) for >3 decades. These conditions include cardiac ion channelopathies, cardiomyopathies, heritable thoracic aortic disease, and familial dyslipidemias. With decreasing cost, increasing accessibility, and expanding clinical indications, exome sequencing (ES) and genome sequencing (GS) are becoming frontline diagnostic tools in a host of scenarios, including heterogeneous and atypical presentations of disease, unclear diagnoses resulting in a prolonged diagnostic odyssey, and the critically ill infant and child, among others.
Although diagnostic genetic testing is performed when there is a clinical evaluation suggestive of a heritable CVD, ES and GS are frequently conducted for a primary indication unrelated to CVD but can uncover the presence of variants in CVD-associated genes. These so-called incidentally identified variants are often viewed as actionable markers of risk for disorders that confer a high degree of morbidity or mortality that may be prevented or reduced by clinical intervention. The American College of Medical Genetics and Genomics (ACMG) has provided guidance as to how these variants should be interpreted in the clinical arena. Specifically, variants that fall into actionable genes and are considered to be likely pathogenic or pathogenic (LP/P) are eligible to be reported back to the ordering clinician.1,2 ACMG defines these variants as secondary findings/variants. However, despite this paradigm-setting consensus, guidance as to how the referring clinician should incorporate this information into the evaluation and care of their patient for heritable CVD is lacking. For example, recent evidence suggests that the burden of incidentally identified genetic variants in CVD-associated genes is markedly higher than the prevalence of disease in the population. This highlights the diagnostic challenge in interpreting these variants to accurately predict the risk for disease development (ie, disease penetrance). Moreover, potentially actionable incidental variants are increasingly being identified outside of clinical ES and GS testing and in genes apart from the ACMG list such as in population genetic research studies or direct-to-consumer genetic testing. Thus, the goal of this scientific statement is to provide a comprehensive framework by which a clinician can interpret any incidentally identified CVD gene variant, incorporate this interpretation into a disease- and patient-specific cardiovascular evaluation, and arrive at a plan for patient, family, and variant follow-up.

Existing Literature

Recent expansion of the use of ES and GS for patients without clinical concern for heritable CVD has identified a growing number of incidentally identified variants in CVD-associated genes. This raises challenging questions related to the likelihood of disease risk for a given incidental variant and, if in a disease risk gene, how this risk should be incorporated into the evaluation and management of the individual. This scientific statement draws on existing orthogonal clinical practice guidelines, scientific statements, expert consensus statements, and key studies in the field to synthesize recommendations for these issues. Statements from the American Heart Association, American College of Cardiology, Association for Molecular Pathology, Clinical Pharmacogenetics Implementation Consortium, Heart Rhythm Society, ACMG, Heart Failure Society of America, European Society of Cardiology, European Association of Cardiovascular Imaging, European Heart Rhythm Association, Asian Pacific Heart Rhythm Society, Latin American Heart Rhythm Society, and Association of Inherited Cardiac Conditions were included. Literature that was in the English language and either human subject based or clinically focused was included. Because of the rapid evolution of genetic medicine, included studies were limited primarily to those published in or after 2010.

Guidelines for Reporting of Incidental Variants

Incidental variants refer to rare variants identified that are not related to the phenotype or disease presentation for which the testing was ordered. Herein, we use the term incidental to include secondary variants, as defined by the ACMG, as well as variants found through various nonclinical means that may be reported to clinicians or patients. Although CVD gene–specific panels represent the typical diagnostic test of choice in the evaluation of heritable CVD, incidental variants are often identified when ES and GS testing is used for other clinical presentations. When this testing is performed on an individual without a priori concern for CVD, discerning the diagnostic relevance of these variants remains challenging. The ACMG published guidance on clinically actionable genes, which currently has 78 named genes.2 Of these, 42 (54%) are CVD related (Table 1). Specific genes relating to CVD are included as a result of a recognized increase in morbidity and mortality from sudden cardiac death, aortic dissection, and heart failure syndromes and the availability of established evidence-based treatments.3–7 It is important to note that this list is dynamic and will continue to evolve and that there is a significant lag phase between the ACMG panel of genes and what experts in the field consider actionable. These variants are referred to as secondary variants. The Centers for Disease Control and Prevention advised a 3-tier system for actionable genomic applications: tier 1 genes are supported by a base of synthesized evidence that supports that identification should alter management to prevent the disease; tier 2 genes are supported by synthesized evidence if insufficient to support routine implementation for informed decision-making (eg, pharmacogenomics); and tier 3 genes for which there is no evidence that a variant is actionable clinically, including cases in which there are evidence-based recommendations against use, or is not ready for routine implementation in practice (eg, polygenic risk scores).8 At present, familial hyperlipidemia–associated genes represent the only CVD-related condition in the Centers for Disease Control and Prevention tier 1 list, with the remainder being cancer-related genetic applications. This is likely to evolve toward the inclusion of additional CVD-related genes, including hypertrophic cardiomyopathy–associated genes.
Table 1. Summary of CVD-Associated Genes With Yield of Incidentally Identified Variants by Disease Type*
ACMG actionable genesCurrent genesMIMInheritance modeConsiderationsClinGen definitive or strong-evidence genes not included in ACMG
Dyslipidemia     
 FHLDLR
APOB
PCSK9
143890
144010
603776
SD
AD
AD
 
Cardiomyopathy     
 ACMPKP2
DSP
DSC2
TMEM43
DSG2
609040
607450
610476
604400
610193
AD JUP (strong)
DES (moderate)
PLN (moderate)
 DCMTNNT2
LMNA
FLNC
TTN
BAG3
DES
RBM20
TNNC1
601494
115200
617047
604145
613881
604765
613172
611879
ADHigh penetrance, extreme of phenotype
Truncating variants
SCN5A (definitive)
MYH7 (definitive)
 HCMMYH7
MYBPC3
TNNI3
TPM1
MYL3
ACTC1
PRKAG2
MYL2
192600
115197
613690
115196
608751
612098
600858
608758
AD ALPK3 (definitive)
TNNT2 (definitive) included under DCM ACMG-73
Restrictive/infiltrativeTTR105210ADHereditary transthyretin amyloidosisDefinitive for HCM
 FabryGLA301500XL Only reported gene
 PompeGAA232300AR Only reported gene
 HHHFE235200AR Not yet curated
Arrhythmia     
 LQTS1
 LQTS2
 LQTS3
KCNQ1
KCNH2
SCN5A
192500
613688
603830
AD CALM1 (definitive)
CALM2 (definitive)
CALM3 (definitive)
TRDN (strong)
 BrSSCN5A601144AD  
 CPVTRYR2
CASQ2
TRDN
604772
611938
615441
AD
AR
AR
CASQ2 and TRDN reportable in trans or apparently homozygous.TECRL (definitive)
Thoracic aortic diseaseFBN1
TGFBR1
TGFBR2
SMAD3
ACTA2
MYH11
154700
609192
610168
613795
611788
132900
AD TGFB2
MYLK
LOX
PRKG1
 EDS (vascular)COL3A1130050AD Included with HTAD, not curated for EDS
ACM indicates arrhythmogenic ventricular cardiomyopathies; ACMG, American College of Medical Genetics and Genomics; AD, autosomal dominant; AR, autosomal recessive; BrS, Brugada syndrome; CPVT, catecholaminergic polymorphic ventricular tachycardia; DCM, dilated cardiomyopathy; EDS, Ehlers-Danlos syndrome; FH, familial hypercholesterolemia; HCM, hypertrophic cardiomyopathy; HH, hereditary hemochromatosis; HTAD, hereditary thoracic aortic disease (also known as familial thoracic aortic aneurysm and dissection); LQTS, long-QT syndrome; MIM, Mendelian Inheritance in Man; SD, semidominant; and XL, X-linked.
*
Based on current ACMG actionable genes (version 3.1).2 Although there are no genes associated with the development of isolated congenital heart disease phenotypes in the current ACMG actionable gene list, this is likely to evolve over time.
Emerging evidence suggests that BrS may be reclassified as a cardiomyopathy.
Sources of incidental variants include the use of ES or GS not only for clinical testing in clinical care, such as with undiagnosed syndromes and critically ill children, but also with direct-to-consumer genetic tests and individuals participating in research studies such as population biobanks. Furthermore, some health systems have implemented genomic medicine programs incorporating population-based genetic risk testing. These testing methods can include CVD genes interrogated by chance, without a valid clinical indication, or in the absence of disease, among others. The intent of action is thus preventive, that is, precision health, rather than management of established disease, that is, precision medicine, although unrecognized genetic CVD can sometimes be diagnosed. The ACMG recommends that only LP/P variants in ACMG-78 genes be communicated to the patient if the individual has not specifically opted out of this process. Patients typically are not informed of variants designated as a variant of uncertain significance (VUS) or benign. Previously, ES and GS were often not performed in a Clinical Laboratory Improvement Amendments–approved laboratory; thus, identified variants required confirmatory testing before the results could be communicated, which has made the communication of incidental variants challenging to implement. With the advent of Clinical Laboratory Improvement Amendments–approved ES and GS, confirmatory testing may not be necessary unless there are doubts about quality. Despite this guidance for reporting, there are no recommendations on the specifics of downstream clinical evaluation, leaving researchers, testing laboratories, and clinicians who referred these patients having to make difficult decisions without clear evidence-based or expert guidelines. Last, individual- and variant-specific evaluation is best conducted at a specialized multidisciplinary CVD center, which could impose a barrier to care.

Multifaceted Approach to Variant Reporting

Pretest/Posttest Genetic Counseling for Individuals Undergoing ES and GS

Pretest genetic counseling and informed consent are imperative to the process of broad-scale GS because variants outside of the specific genes of interest for the patient’s clinical presentation could be communicated to patients and have implications for their family members. This should be done before genetic testing is performed. Recommendations on the points to be discussed with patients during this pretest informed consent process are the following and should be provided to the patients in writing: a discussion of the likelihood and type of incidental results that may be generated, the types of results that will or will not be communicated, the benefits and risks of GS and its limitations, potential implications for family members (including the potential impact of a CVD-associated variant on insurability and the financial costs associated with evaluation of a such a variant), the distinction between clinical- and research-based testing, patient-level data sharing, and recontact policies as new knowledge is gained on the clinical significance of results.9 Patients’ reactions to receiving results may vary, yet having an open conversation about the possible outcomes of genetic testing is important. The possibility of identifying an incidental genetic finding that might confer disease risk and trigger an evaluation should be discussed, and patients should be asked whether they would want to receive these results.10,11 As more individuals undergo broad-scale genomic testing in both clinical and research settings, access to and scaling of pretest and posttest genetic counseling are needed, and certified genetic counselors are central to this. This counseling may be accomplished through alternative service delivery models, including telehealth, and may include digital health tools.12

Interpreting Variant and Gene Pathogenicity

Advancements in GS and CVD genetic testing have also posed complex challenges in variant interpretation and classification and the application of this information to clinical care.13,14 To address these challenges, a joint consensus recommendation from the ACMG/Association for Molecular Pathology including standards and guidelines for the interpretation of genetic variants was published in 2015.1 This established a scoring system for interpreting variants as LP/P (>90% chance of being disease associated) or likely benign/benign (>90% chance of being benign), with variants in between deemed VUSs. ClinVar,15 a publicly accessible curated database, was established to serve as a resource for variant-disease associations. However, even with these guidelines and resources, inconsistencies in variant interpretation and pathogenicity classification across genetic testing laboratories, clinicians, and ClinVar exist.16,17 Furthermore, reclassification of variants over time has occurred, with clinically relevant variant classification changes that affect medical management recommendations.18,19 Considerable variability also exists in the quality of evidence supporting the role of many genes as causative of their associated disease. Therefore, multiple international groups, organized through ClinGen,20 have performed evidence-based reassessments of gene validity for inherited CVD phenotypes. Although many genes have been reported to cause such conditions as long QT syndrome, Brugada syndrome, heritable cardiomyopathies, and others and are routinely included on clinical genetic testing panels, this curation of genes for clinical validity evidence has found that a much more limited group of genes have definitive or strong evidence for causing these conditions.21–26 Moreover, all the CVD-susceptibility genes residing in the current ACMG-78 gene panel are irrefutable disease-associated genes; however, every variant identified in a robust CVD gene is not necessarily a disease-associated variant. This highlights the need for continued multidisciplinary follow-up of genetic variants as these relationships evolve. Therefore, genetic cardiologists, cardiovascular genetic counselors, and geneticists will need to take a more active and consistent role in variant review to ensure that the most accurate information from genetic testing is being applied to patient care over time.

Establishing a Clinical and Genetic Evaluation Framework for Communication of Incidental Variants and Evaluation

The communication of incidental findings to individuals undergoing broad sequencing affords an opportunity to identify genomic risk, to diagnose genetic conditions that may otherwise be left undiagnosed, to initiate surveillance and management, and potentially to prevent diseases or bad outcomes associated with diseases. To actualize this preventive potential, clinicians managing patients with incidental findings will need to use established clinical frameworks for comprehensive genetic and cardiovascular baseline evaluation and follow-up evaluation. The approach should include medical history; family history; physical examination; relevant diagnostic testing; including imaging; and variant evaluation and correlation with the potential phenotype(s) in question with the goal of balancing the risks of overdiagnosis and health care overuse with the benefits of preventing serious adverse clinical outcomes.27

A Framework for Variant Interpretation

Incidentally identified variants in CVD genes should be interpreted within a framework that integrates the likelihood that an identified variant is truly disease associated with the likelihood that the individual positive for the variant has the disease associated with the variant in question (Figure 1). This establishes a probability of disease association that drives the scope and duration of follow-up and, if evidence of disease is identified, downstream management. Often, this framework is a re-evaluation of an already identified incidental variant and is best accomplished in a center with expertise in cardiovascular genetics. A framework for variant interpretation that reflects this probabilistic nature uses a Bayesian approach, which is commonly used in genetic risk assessment. In a Bayesian framework, an incidentally identified variant is assessed for likelihood of disease pathogenicity in a given individual on the basis of (1) a pretest probability of disease, defined by the likelihood that the person hosting the variant has the disease associated with the variant, and (2) modification of this pretest probability by the strength of association of the genetic variant with disease, defined by how likely it is that a specific variant may cause the disease in question, to arrive at (3) a posttest probability that the variant is truly disease associated, which determines downstream management and follow-up. Given the heterogeneity of practice in a rapidly evolving field, the major goal of this scientific statement is to establish an expert-based consensus framework. Specific details around each step of this framework are delineated in the following sections.
Figure 1. A framework for the evaluation of incidentally identified variants found in CVD-associated genes. In partnership with a specialized inherited cardiovascular disease (CVD) center, individuals found to have an incidentally identified variant should undergo a comprehensive clinical evaluation for the CVD in question. This pretest probability of having the CVD in question should be modified by the strength of the gene variant with CVD to arrive at a posttest probability that the variant in question places the patient at risk of developing disease. This determines the need for additional clinical evaluation, management, and follow-up. ACM indicates arrhythmic cardiomyopathy/arrhythmogenic right ventricular cardiomyopathy; BrS, Brugada syndrome; CPVT, catecholaminergic polymorphic ventricular tachycardia; CT, computed tomography; DCM, nonischemic dilated cardiomyopathy; HTAD, heritable thoracic aortic disease (also known as familial thoracic aortic aneurysm and dissection); HCM, hypertrophic cardiomyopathy; LDS, Loeys-Dietz syndrome; LQTS, long QT syndrome; LP/P, likely pathogenic/pathogenic; MRI, magnetic resonance imaging; RCM, restrictive cardiomyopathy; SQTS, short QT syndrome; vEDS, vascular Ehler-Danlos syndrome; and VUS, variant of uncertain significance. *CVD implicated by the incidentally identified genetic variant in question. **Can be considered on the basis of individualized patient evaluation.

Pretest Probability of Disease Association: An Individualized Clinical Evaluation

Identification of an incidentally identified LP/P variant predicted to put the patient at risk of disease development (ie, excluding carriers of autosomal recessive diseases) should trigger a comprehensive clinical evaluation of the individual hosting the variant to establish the pretest probability of disease. Specifically, a comprehensive medical history, family history (at least 3 generations), physical examination, and clinical testing should be conducted by a clinician who is knowledgeable about the potentially implicated disease. Clinical testing should be individualized on the basis of the findings of this evaluation, the specific disease, and the previous clinical testing that may have been performed. Although individual practice may vary, individuals with incidental findings of genetic variants associated with cardiac ion channelopathies should typically have an ECG, minimum 24-hour Holter monitor, and exercise stress test (if able to be performed safely by the individual). Patients with an incidental variant in a cardiomyopathy-associated gene should be evaluated with an ECG and echocardiogram. Advanced imaging (ie, cardiac magnetic resonance imaging for tissue characterization) can be considered given the individual patient evaluation. Individuals with a thoracic aortic disease–associated gene should be evaluated with an echocardiogram, and advanced imaging can be considered (ie, computed tomography or magnetic resonance imaging to evaluate for thoracic aortic disease). For individuals carrying a familial hypercholesterolemia–associated variant, a serum lipid panel should be performed, as well as, if appropriate, further testing such as computed tomography coronary angiography. Last, for individuals with congenital/structural heart disease–associated incidental variants, an ECG and echocardiogram should be performed.3,4,6,14,28–31 Advanced imaging such as cardiac magnetic resonance imaging can be considered in some cases with congenital heart disease–associated variants. On the basis of findings from this initial clinical evaluation, additional testing such as advanced imaging may be needed. This evaluation should be conducted by an individual or a multidisciplinary team qualified to evaluate for the disease in question because the goal is to determine the likelihood that the individual demonstrates evidence of the disease prompted by the incidental variant.
Although the ACMG recommends reporting of LP/P incidental variants, incidental VUSs may still be reported to patients through a number of mechanisms such as a patient-initiated request for expanded genetic testing findings or direct-to-consumer genetic testing. Although not all VUSs will be disease associated, some will be. The decision of whether to evaluate a VUS within this framework should be taken on a case-by-case basis and in close partnership with cardiovascular genetics experts in the context of a multidisciplinary team discussion.

Modification of Pretest Probability: Re-Evaluation of Gene and Genetic Variant Association With Disease

The pretest probability of disease established after a comprehensive clinical evaluation should be modified by the strength of the genetic variants associated with CVD. According to ACMG guidelines, only incidentally identified variants that are LP/P should be reported; however, genetic testing laboratories assign variant pathogenicity differently, and the pathogenicity assertions can change over time. Thus, it is critical for the clinician to re-evaluate the veracity of the pathogenicity assignment for each variant identified rather than relying solely on the laboratory interpretation (Figure 2). This evaluation and determination of subsequent follow-up is best done at, or in close consultation with, a multidisciplinary center specializing in cardiovascular genetics.32 Several resources exist, and several more are in development, to provide a contemporaneous assessment of variant pathogenicity with disease, including ClinVar, ClinGen, and others.33 ACMG guidelines on the evaluation of incidentally identified variants based on fulfillment of specific criteria remain central to this process.1,2,34 Recent work has suggested that incorporation of clinical phenotype into variant interpretation may aid in the identification of disease-causative variants among some CVDs.35–37 Because the strength of phenotype influences the probability of pathogenicity, integration of clinical phenotype into variant interpretation framework may be important for re-evaluating variant association with disease. When combined, these resources can allow the expert clinician within a multidisciplinary team that specializes in genetic CVDs to reinterpret the probability that a given variant may or may not be associated with disease.
Figure 2. Factors that influence the likelihood that an incidentally identified variant in a CVD-associated gene is associated with disease. Several factors (box) can increase or decrease the probability that an incidentally identified variant is associated with a cardiovascular disease (CVD). If a variant exceeds a 90% probability of being CVD associated, it is labeled likely pathogenic, whereas if a variant has >90% probability of being benign, it is labeled likely benign. Variants that do not exceed these thresholds are variants of uncertain significance (VUSs).

Posttest Probability of Disease Association: Determination of Clinical Management and Follow-Up

The posttest likelihood that an incidentally identified variant is associated with disease is based on the pretesting probability that the individual hosting the variant has disease and incorporation of the strength of the evidence that the identified variant is associated with the disease into a Bayesian framework. This assessment guides subsequent clinical management and follow-up, which can be performed by, or in consultation with, the specialty center. For example, identification of an incidental variant that is found to be strongly associated with risk of HCM, even in an individual without evidence of disease, should warrant continued longitudinal follow-up (intervals as per existing HCM guidelines) for evaluation of cardiomyopathy. Conversely, an incidentally identified variant in a gene not on the ACMG list and disputed by ClinGen as to whether it is disease associated found in an individual with a reassuring clinical evaluation may prompt infrequent follow-up or no further follow-up. Any variant found to be likely disease associated (LP/P) requires longitudinal follow-up of the individual to monitor for disease development and risk-predictive testing of first-degree family members to identify other individuals at risk of disease. This should be done regardless of whether there is clinical evidence of disease. Conversely, risk-predictive testing in the family should not be performed with a variant with an uncertain disease association, regardless of whether the individual hosting the variant is clinically affected by the disease in question.

Follow-Up of Variants Over Time

The appropriate interpretation of the pathogenicity of a genetic variant is crucial for translating genetic data into clinical practice. The classification of variant-disease pathogenicity is dynamic as a result of rapidly evolving research. Moreover, there is no consensus for how often variants should be re-evaluated. This is of special importance for variants classified as VUSs because most are designated as uncertain because of the strictness of ACMG recommendations and lack of available functional data.38 Recent work has highlighted that variants initially assigned an LP/P or likely benign/benign analysis can change from ≥1%/y to 8%/y per variant, often toward a VUS classification.19,39 Conversely, variants initially assigned as VUSs may change more frequently.40–42 Thus, continual follow-up of incidentally identified genetic variants is critical and should be part of the long-term clinical surveillance of anyone found to have such a variant. This follow-up should entail a reinterpretation of the genetic variant and the association of the gene and variant with disease according to new research and the consensus of the community, and follow-up should be conducted by experts in CVD genetics.43,44 When appropriate and applicable, the genetic follow-up should be paired with clinical follow-up to evaluate for evidence of the disease in question. Clinical follow-up provides an opportunity to re-evaluate personal and family history, to conduct a comprehensive evaluation of the individual, and to repeat clinical testing. Findings from both the genetic and clinical follow-up should be integrated to reassess the probability that the individual has the cardiac disease in question and the likelihood that the variant in question is associated with disease risk in the individual. The optimal frequency of this evaluation is every 1 to 3 years; however, timing should be individualized to the variant and the patient. Last, a discussion of the potential need for variant follow-up over time, even in the phenotype-negative individual, should be part of the pretest counseling before genetic testing.45 This way, the ability to perform longitudinal genetic testing follow-up should be established before broad ES or GS testing is considered.

Family Cascade Genetic Testing

Among heritable CVDs, cascade (ie, risk-predictive) genetic testing in a family is performed when an LP/P variant is identified in a proband that is felt to be associated with CVD risk. This variant can then be screened for in first-degree relatives of the proband to determine whether others in the family share that risk. This process can then be repeated such that first-degree relatives of genotype-positive individuals undergo variant-specific genetic testing to determine their own risk. This can be done regardless of whether they manifest evidence of disease. This principle applies to incidentally identified variants as well if, following the framework for evaluation detailed previously, the variant is determined to be LP/P. Although cascade testing can be done in the absence of evidence of the disease in question in the proband, suspicion for CVD risk of the variant should be high (ie, the variant assessed as LP/P). Cascade testing should not be performed on VUSs. Family members found to be genotype positive should be assessed with the same framework.

Other Important Considerations

Genetic Testing and Variant Adjudication in Diverse Populations

There are important considerations for genetic testing and variant adjudication in diverse racial and ethnic populations. Historically, most large GS studies have been performed in populations of European ancestry. Although there has been a rapid growth in genome-wide association studies from patient samples with Asian ancestry since 2009, samples from patients with African, Latin American, or native/indigenous ancestry are still woefully underrepresented.46 The continued bias toward European ancestry in genome-wide association studies has contributed to a slower development of databases that clearly define normal versus disease-associated genetic variation in diverse populations. Thus, the same framework for variant interpretation should be undertaken for incidentally identified variants in CVD-associated genes, with special attention given to variant re-evaluation and follow-up over time. VUSs identified in individuals of non-European descent are more common, and benign variants may be more likely to be misclassified as LP/P because of the inadequate diversity of sequence data available from control populations.46–48 Because accurate variant interpretation for diverse or admixed populations relies on the availability of information on variation in non-European cohorts, an urgent need remains to include diverse and underrepresented racial and ethnic populations in human genomics research.

Direct-to-Consumer Genetic Testing

Applying Bayesian principles to clinical tests aids in reducing unnecessary and inappropriate use, costs, and subsequent downstream tests based on an inaccurate report, with the safeguard of a clinician selecting hypothesis-driven tests. Direct-to-consumer genetic testing bypasses the clinician and allows patients to seek testing for a multitude of reasons ranging from recreational curiosity to self-diagnosis.49 Subsequent results of variants found in CVD genes can often be confusing to interpret, and primary care clinicians are typically called on to interpret these findings, although access to specialized CVD centers may be limiting. The majority of direct-to-consumer genetic testing does not undergo US Food and Drug Administration review for analytical reliability, clinical validity, and the companies’ claims. Furthermore, similarly labeled tests can have vastly different results from competing vendors. The ACMG has published guidance on minimum requirements for direct-to-consumer genetic testing.50 The emphasis is on appropriate counseling and expectations of results before testing, and when results are communicated, support should be provided by the vendor. When an LP/P variant is identified in an ACMG-recommended gene, referral to a center that specializes in inherited CVDs should be considered.

Pharmacogenomic Variants

Incidental findings after clinical pharmacogenomic testing are not uncommon. Although the test is obtained to evaluate for the presence of a variant that affects the response to a specific medication, at times, the variant is also associated with an unrelated phenotype.51 The Clinical Pharmacogenetics Implementation Consortium has published numerous guidelines for specific pharmacogenomic test results, and each has a section that describes potential unrelated phenotypes that may be identified. Unfortunately, these guidelines do not address how these incidental results should be reported, and there are no standards for the reporting of incidental findings identified at the time of clinical pharmacogenomic testing. Given that clinical pharmacogenomic testing is focused on a limited number of genes relevant to pharmacogenomics, lower numbers of incidental findings are expected to result from this type of testing compared with other methods of sequencing. Work from the National Institutes of Health Undiagnosed Diseases Program found that each subject within their cohort had at least 1 pharmacogenomic-related incidental finding and ≈1% had an incidental finding related to a medication that they were currently taking.52 Because clinical pharmacogenomic tests are often ordered without the patient meeting with a genetic specialist before testing, the patient may not have had any discussion about the possibility of an incidental finding being identified and may be unprepared for this possibility.51 These issues underscore the need for consistent pretest genetic counseling before testing is obtained. Moreover, creation of a list of reportable pharmacogenetic variants and uniform policies on reporting incidental findings resulting from clinical pharmacogenomic testing are needed.53,54

Variants in Pediatric Populations

Incidentally identified variants found in infants, children, and adolescents are a significant and growing consequence of expansive ES and GS diagnostic testing in this vulnerable population. At present, although they are rare, the frequency of these variants is markedly higher than the prevalence of the respective diseases in the general population, suggesting that not all variants will lead to highly penetrant disease.55 Thus, careful interpretation of these variants in a multidisciplinary setting is key. Parents/guardians of the pediatric patient undergoing ES or GS should be informed of the possibility of identifying variants in CVD-associated genes. Moreover, the potential ethical, social, legal, and financial implications of potentially finding a CVD-associated variant should be discussed before ES or GS in the pediatric patient.56 Children should be involved in the consent process to the extent possible, and assent (expression of approval and willingness to participate in the genetic testing) should be sought from the child if they are able to understand the rationale and implications of testing and finding an incidental variant.56 Adolescents should be offered the opportunity for private discussion without their parents present. Given the possibility of pediatric-onset disease, the availability of preventive measures and therapies to reduce the morbidity and mortality associated with genetic CVD, and the challenge in evaluating pediatric patients, pediatric patients with incidentally identified variants should be offered a timely referral to multidisciplinary centers that specialize in this evaluation.

What Every Patient and Family Should Know

When a patient or research participant presents with an incidental variant, a comprehensive and individualized clinical evaluation should be performed by a multidisciplinary team of experts in cardiovascular genetics and genetic cardiology. Even when patients are completely asymptomatic, each incidental variant finding should have a disease-specific evaluation to determine the best approach to long-term management and to identify the need for family cascade-based targeted variant testing. This includes planning for both patient and variant follow-up because variant reclassification can change medical management recommendations.18

Conclusions

Interpretation of incidentally identified variants in CVD-associated genes is challenging and is best performed within a framework of evaluation that incorporates an individualized clinical assessment of the patient and careful evaluation of the variant in question (Table 2). This framework should leverage a probabilistic model whereby the clinical evaluation of the patient and variant determines the likelihood that the variant is disease associated and informs the scope and duration of follow-up. This is best done in partnership with a specialized, multidisciplinary team that can optimize the evaluation of the patient and provide ongoing support for both patient and genetic follow-up as the field of cardiovascular genetics continues to rapidly evolve.
Table 2. Summary of Key Points in the Interpretation of Incidentally Identified Variants in CVD-Associated Genes
Only incidentally identified variants predicted to be associated with CVD (LP/P) should be communicated to the patient who has agreed to learning about these results before gene testing was conducted.
The initial interpretation of a variant as CVD associated is not always accurate and can change over time.
A framework should be established for interpretation of incidentally identified variants in CVD genes that includes (1) a patient-specific comprehensive evaluation for the CVD in question and (2) re-evaluation of the variant/gene association with the CVD in question to arrive at (3) a determination of variant risk of being associated with CVD development.
This framework of variant risk assessment determines appropriate clinical management and follow-up of the patient and their family.
The framework for interpreting incidentally identified variants in CVD genes should be conducted at a center that specializes in heritable CVD through a multidisciplinary team-based approach.
CVD indicates cardiovascular disease; and LP/P likely pathogenic/pathogenic.
Article Information

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Circulation: Genomic and Precision Medicine
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Published online: 27 March 2023
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Keywords

  1. AHA Scientific Statements
  2. aortic diseases
  3. cardiomyopathies
  4. cardiovascular diseases
  5. channelopathies
  6. dyslipidemias
  7. genomics
  8. patient care team

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Anwar A. Chahal, MBChB, PhD, MRCP, Vice Chair
Michael J. Ackerman, MD, PhD
Dianna M. Milewicz, MD, PhD
Alanna A. Morris, MD, MSc, FAHA
Georgia Sarquella-Brugada, MD, PhD
Christopher Semsarian, MBBS, PhD, MPH, FAHA
Svati H. Shah, MD, MHS, FAHA
Amy C. Sturm, MS, LCGC
on behalf of the American Heart Association Data Science and Precision Medicine Committee of the Council on Genomic and Precision Medicine and Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Hypertension; Council on Lifelong Congenital Heart Disease and Heart Health in the Young; Council on Peripheral Vascular Disease; and Stroke Council

Notes

The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on December 5, 2022, and the American Heart Association Executive Committee on January 24, 2023. A copy of the document is available at https://professional.heart.org/statements by using either “Search for Guidelines & Statements” or the “Browse by Topic” area. To purchase additional reprints, call 215-356-2721 or email [email protected].
The American Heart Association requests that this document be cited as follows: Landstrom AP, Chahal AA, Ackerman MJ, Cresci S, MD; Milewicz DM, Morris AA Sarquella-Brugada G, Semsarian C, Shah SH, Sturm AC; on behalf of the American Heart Association Data Science and Precision Medicine Committee of the Council on Genomic and Precision Medicine and Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Hypertension; Council on Lifelong Congenital Heart Disease and Heart Health in the Young; Council on Peripheral Vascular Disease; and Stroke Council. Interpreting incidentally identified variants in genes associated with heritable cardiovascular disease: a scientific statement from the American Heart Association. Circ Genom Precis Med. 2023;16:e000092. doi: 10.1161/HCG.0000000000000092
The expert peer review of AHA-commissioned documents (eg, scientific statements, clinical practice guidelines, systematic reviews) is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit https://professional.heart.org/statements. Select the “Guidelines & Statements” drop-down menu, then click “Publication Development.”
Permissions: Multiple copies, modification, alteration, enhancement, and distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at https://www.heart.org/permissions. A link to the “Copyright Permissions Request Form” appears in the second paragraph (https://www.heart.org/en/about-us/statements-and-policies/copyright-request-form).

Disclosures

Writing Group Disclosures
Writing group memberEmploymentResearch grantOther research supportSpeakers’ bureau/honorariaExpert witnessOwnership interestConsultant/advisory boardOther
Andrew P. LandstromDuke University School of Medicine, Duke University Medical CenterNIH (grant: K08 PI, R01 PI, R01 co-I that provides salary and research funds); Doris Duke Charitable Foundation (grant PI with research and salary support); Additional Ventures (grant PI with research and salary support); The Hartwell Foundation (grant PI with research)NoneNoneNoneNoneNoneNone
Anwar A. ChahalUniversity of Pennsylvania School of Medicine; Center for Inherited Cardiovascular Diseases, WellSpan HealthNoneNoneNoneNoneNoneNoneNone
Michael J. AckermanMayo ClinicNoneNoneNoneNoneAlive Cor; Anumana*; ARMGO Pharma; Pfizer; Thryv Therapeutics*Abbott*; Boston Scientific*; Daiichi Sankyo*; Invitae*; Medtronic*; Bristol Myers Squibb; UpToDateNone
Sharon CresciWashington University School of MedicineNoneNoneNoneNoneNoneNoneNone
Dianna M. MilewiczUniversity of Texas Health Science Center at HoustonNIH; GADA Canada; AHA; John Ritter FoundationNoneNoneNoneNoneNoneNone
Alanna A. MorrisEmory University School of MedicineNoneNoneNoneNoneNoneNoneNone
Georgia Sarquella-BrugadaHospital Sant Joan de Deu (Spain)NoneNoneNoneNoneNoneNoneNone
Christopher SemsarianUniversity of Sydney (Australia)NoneNoneNoneNoneNoneNoneNone
Svati H. ShahDuke UniversityNoneNoneNoneNoneNoneNoneNone
Amy C. SturmGeisinger Genomic Medicine InstituteNIH (NHLBI R01 on FH)*NoneNoneNone23andMe23andMe*23andMe (director)
This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $5000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $5000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.
*
Modest.
Significant.
Reviewer Disclosures
ReviewerEmploymentResearch grantOther research supportSpeakers’ bureau/honorariaExpert witnessOwnership interestConsultant/advisory boardOther
Elijah R. BehrSt George’s University of London (United Kingdom)NoneNoneNoneNoneNoneNoneNone
Prince J. KannankerilVanderbilt University Medical SchoolNIH (PI for Vanderbilt Integrated Center of Excellence in Maternal and Pediatric Precision Therapeutics)NoneNoneNoneNoneNoneNone
Luisa MestroniUniversity of Colorado Anschutz Medical CampusNIH (R01); John Patrick Albright Foundation*NoneNoneNoneNoneNoneNone
Shaine A. MorrisTexas Children’s Hospital/Baylor College of MedicineMarfan Foundation (on a no-cost extension through 2022 for a pilot trial of exercise on cardiovascular outcomes in Marfan syndrome)NoneNoneNoneNoneAytu BiopharmaBaylor College of Medicine (employer is a vendor for many types of genetic testing)
This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $5000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $5000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.
*
Modest.
Significant.

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  1. Implementing a New Algorithm for Reinterpretation of Ambiguous Variants in Genetic Dilated Cardiomyopathy, International Journal of Molecular Sciences, 25, 7, (3807), (2024).https://doi.org/10.3390/ijms25073807
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  8. Clinical impact of genetic testing for lipid disorders, Current Opinion in Cardiology, 39, 3, (154-161), (2024).https://doi.org/10.1097/HCO.0000000000001133
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  9. Predicted Deleterious Variants in Cardiomyopathy Genes Prognosticate Mortality and Composite Outcomes in the UK Biobank, JACC: Heart Failure, 12, 5, (918-932), (2024).https://doi.org/10.1016/j.jchf.2023.07.023
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  10. Interpreting the actionable clinical role of rare variants associated with short QT syndrome, Human Genetics, 143, 12, (1499-1508), (2024).https://doi.org/10.1007/s00439-024-02713-x
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