Color Atlas and Synopsis of Electrophysiology, 1st Ed.


Amy C. Sturm, MS, CGC


A 17-year-old boy was referred to the Inherited Arrhythmia Clinic after suffering an aborted sudden cardiac death episode while running at school. The patient’s past medical history was significant for epilepsy diagnosed at 6 years of age. A teacher reported the patient had no pulse and was not breathing during the event, and an automated external defibrillator detected a shockable rhythm, which was converted with a shock from the device. The baseline ECG was normal, an echocardiogram showed a structurally normal heart with normal left ventricular systolic function, and a stress test documented exercise-induced ventricular ectopy. Because of the patient’s presentation, he underwent implantation of an implantable cardioverter defibrillator (ICD) for secondary prevention, and β-blocker therapy was initiated.

During the arrhythmia clinic appointment, a genetic counselor constructed a three-generation pedigree (Figure 52-1). The family history was significant for sudden death in a maternal uncle, but no other relatives had a concerning history. Given the family history and documentation of exercise-induced ventricular ectopy, catecholaminergic polymorphic ventricular tachycardia (CPVT) was considered a possible diagnosis, and genetic testing was discussed with the family. Informed consent was obtained, and a blood sample was collected for CPVT genetic testing. The patient tested positive for a novel, likely pathogenic mutation in the RYR2 gene (c.6916G>C; Val2306Leu). This result confirmed the diagnosis of autosomal-dominant CPVT in the patient and also allowed for subsequent cascade genetic testing in his at-risk relatives. His mother was identified to have the RYR2 mutation while his father and sister both tested negative; this allowed the patient’s paternal relatives to learn they were not at increased risk for CPVT. During follow-up visits, it was noted that the patient was suffering from insomnia and depression; his prior career goal before his diagnosis was to become a police officer, and he was having a difficult time adjusting to the idea that he would no longer be able to pursue such a path.


FIGURE 52-1 Pedigree of patient with catecholaminergic polymorphic ventricular tachycardia (CPVT). This three-generation pedigree utilizes standard pedigree symbols (men are represented by squares; women are represented by circles). The pedigree was constructed by the genetic counselor during the proband’s first appointment in the Inherited Arrhythmia Clinic. A major “red flag” for risk assessment was present in the pedigree; the proband’s maternal uncle died suddenly at 38 years of age. Genetic testing in the proband identified a causative mutation in the RYR2 gene. Subsequently, the proband’s first-degree at-risk relatives (parents and sister) underwent cascade genetic testing, and his mother was identified to also have the RYR2 mutation.


Genetic testing was able to confirm a diagnosis of CPVT in a patient with a prior, likely misdiagnosis of epilepsy. Genetic counseling is recommended for all patients with CPVT (and other inherited heart diseases) and their at-risk relatives in the Heart Rhythm Society/European Heart Rhythm Association expert consensus statement on genetic testing for channelopathies and cardiomyopathies.1 Through a multidisciplinary clinical approach that included genetic counseling, the patient and his family were able to:

• Receive an accurate diagnosis and appropriate management.

• Determine their risk status through cascade, mutation-specific genetic testing.

• Receive information regarding the inheritance pattern of CPVT and recurrence risk.

• Learn about future reproductive options.

• Receive psychosocial support and resources.


Genetic Counseling

Genetic counseling is the process of helping individuals and their families understand and adapt to the medical, psychological, and familial implications of a genetic condition.2 The genetic counseling process for patients with inherited heart disease includes multiple components, listed and explained in further detail below. Genetic counseling is indicated regardless of the availability of genetic testing for a specific cardiac disorder.

• Collection of ≥3 generation family medical history information, with special attention to “red flags” for inherited heart disease (Table 52-1).

TABLE 52-1 “Red Flags” in Pedigree That May Signify Underlying Inherited Cardiovascular Disease


Images Includes confirmation with medical records, autopsy reports, and death certificates.

• Performance of risk assessment utilizing medical and family history information.

• Analysis and discussion of inheritance patterns and recurrence risk.

• Facilitation of genetic testing process.

Images Pre- and posttest genetic counseling.

• Facilitation of family-based care.

Images Cascade genetic testing (Figure 52-2).

Images Coordination of family clinical screening.

• Discussion of reproductive options.

• Provision of written documentation of medical, genetic, and counseling information to referring health care providers and patients, including family letters.

• Provision of psychosocial counseling and anticipatory guidance.

• Provision of education, resources, and advocacy to patients and families.

• Discussion of available genetics research study options.

• Discussion of the availability of DNA banking, when applicable.


FIGURE 52-2 Implementation of cascade genetic testing in a large family with long QT syndrome (LQTS). This pedigree shows a large family with long QT syndrome (LQTS). The proband, designated by an arrow, is a 56-year-old woman who presented to the Inherited Arrhythmia Clinic due to her previous clinical diagnosis of LQTS after her 8-year-old son died suddenly while swimming. The genetic counselor met with the proband as part of her multidisciplinary consultation and this four-generation pedigree was constructed. Genetic testing had not been performed in the family to date, so the genetic counselor explained the potential benefits and limitation of LQTS genetic testing to the proband, who decided to proceed with full panel LQTS genetic testing. A pathogenic KCNQ1 mutation was identified in the proband, which allowed predictive genetic testing to be offered to her at-risk relatives. Both of her daughters tested negative for the mutation, which meant her granddaughter was not at risk for LQTS. The proband utilized a family letter provided by the genetic counselor to inform the rest of her at-risk siblings and their children about the option of cascade genetic testing. Multiple additional individuals in the family were able to determine their accurate risk level based on the genetic testing information. Several additional individuals, marked with question marks, could still benefit from this predictive genetic testing information.

Genetic Counselors

Genetic counselors are health care professionals with specialized graduate degrees and expertise in medical genetics and counseling. Many genetic counselors work as members of a health care team and provide information and support to families with inherited conditions. Cardiovascular genetic counselors are an important resource and integral health care team members for patients and families with inherited heart disease, including those families who have suffered a sudden death in a young person.3 It has been suggested that a master’s-trained, board-certified genetic counselor, preferably with specialized training in cardiovascular genetics, be part of the multidisciplinary team involved in the care of families with heritable cardiovascular diseases.4 The types of patients that should be referred to for cardiovascular genetic counseling and potentially genetic testing are listed in Table 52-2. Genetic counselors can be located by utilizing the “Find a Genetic Counselor” tool on the National Society of Genetic Counselors Web site,

TABLE 52-2 Indications for Referral for Cardiovascular Genetic Counseling and Testing


Patients with a suspected or definite diagnosis or family history of the following:

Inherited arrhythmias and channelopathies

• Long Qt syndrome

• Short Qt syndrome

• Brugada syndrome

• Catecholaminergic polymorphic ventricular tachycardia

• Familial atrial fibrillation

• Familial conduction system disease

• Idiopathic ventricular fibrillation


• Hypertrophic cardiomyopathy

• Idiopathic or familial dilated cardiomyopathy

• Arrhythmogenic right ventricular cardiomyopathy

• Left ventricular noncompaction cardiomyopathy

• Restrictive cardiomyopathy

Hereditary conditions affecting the aorta and other blood vessels

• Marfan syndrome

• Loeys-Dietz syndrome

• Ehlers-Danlos syndrome

• Familial thoracic aortic aneurysm and dissections

• Premature coronary artery disease (<55 years of age in a man; <65 years of age in a woman)

• Familial hypercholesterolemia

• Congenital heart disease

• Family history of sudden cardiac (or unexplained) death <50 years of age


A careful family history for at least three generations should be collected and assessed for all patients with potential hereditary heart disease. The individual collecting the family history should actively inquire about the presence of “red flags” while constructing the pedigree since the patient themselves may not know to offer certain information important to risk assessment (eg, the presence of sudden infant death syndrome [SIDS] in a blood relative may represent the presence of a cardiac ion channel gene mutation). For a list of “red flags” and what inherited heart condition they may represent, see Table 52-1. The collection of family history is imperative in (1) aiding diagnosis, (2) identifying at-risk relatives, (3) selecting the most informative family member for genetic testing initiation, and (4) determining inheritance pattern.

While most inherited cardiac diseases follow an autosomal-dominant pattern of inheritance, there are important exceptions, and this information is necessary for the provision of accurate recurrence risks. Also complicating matters is the fact that many inherited cardiac conditions, especially the heritable arrhythmia syndromes including long QT syndrome, Brugada syndrome, and arrhythmogenic right ventricular cardiomyopathy, display both incomplete and age-related penetrance and variable expressivity of clinical signs and symptoms. Small, or limited, family structures may also mask a genetic pattern of disease (eg, smaller sibships including only children may limit the number of affected individuals in the family; higher number of female relatives in a family can hide an X-linked disease). Because patients’ self-reported family history information can have both reduced sensitivity and specificity, it is important to collect medical records, including autopsy reports, whenever possible so that diagnoses can be confirmed. In some cases, it is not until clinical screening commences through a family that a familial, or genetic, condition is able to be diagnosed, as has recently been shown with isolated atrioventricular block.5 Also, family history is not static, but changes over time, and should therefore be updated periodically.


Technological advances and cardiovascular genetics research discoveries have steadily and rapidly increased the number of clinically available genetic testing options for patients and their families with heritable heart diseases.6Because of the dramatic locus (multiple genes involved) and allelic (multiple mutations within a gene) heterogeneity observed in almost every heritable cardiac condition, most cardiovascular genetic tests involve multigene DNA sequencing panels that have been developed by commercial genetic testing laboratories. Most laboratories utilize next-generation DNA sequencing technologies, which provide fast and more cost-efficient analyses of multiple genes at one time. Up-to-date information on clinical and research genetic testing options can be located in two main online genetic testing databases: the National Institutes of Health Genetic Testing Registry ( and GeneTests (

While great strides have been made in the field of cardiovascular genetics, the fact that not all disease loci and genes associated with heritable cardiac conditions have been discovered means that currently available genetic tests have incomplete clinical sensitivities. Therefore, when currently available clinical disease-specific genetic testing panels (ie, Brugada syndrome gene panel) fail to identify the cause for a patient’s likely genetic condition, health care providers can (1) consider large-scale genomic sequencing tests for their patients (ie, whole exome or whole genome sequencing) and (2) should inform the patient and potentially their family members about the option of participating in research studies focused on novel gene discovery.

The Clinical Utility and Value of Diagnostic and Predictive Genetic Testing

The clinical utility of genetic testing for multiple inherited cardiac diseases is now well recognized,1 with applications including diagnostic confirmation, “phenocopy” identification which may target treatment (eg, Fabry disease, a phenocopy of hypertrophic cardiomyopathy, is treated with enzyme replacement therapy), therapeutics (eg, β-blocker initiation for the management of most long QT syndrome patients; implantable cardioverter defibrillator versus pacemaker consideration in patients with a LMNA mutation causing conduction system disease and dilated cardiomyopathy7), predictive genetic testing for at-risk relatives when the causative familial mutation(s) is identified, and the ability to provide patients with family planning information and reproductive options, including preimplantation and prenatal genetic diagnosis. Preimplantation genetic diagnosis allows couples the option to select mutation-negative embryos for implantation after in vitro fertilization. Prenatal genetic testing involves testing a sample of fetal DNA to determine whether the fetus carries the disease-associated mutation. Genetic counseling in these clinical settings is essential for the discussion of available testing options, risks (including miscarriage with certain prenatal sampling techniques), and to facilitate decision-making through supportive and nondirective counseling.

One of the main values of diagnostic genetic testing in an affected proband is that once their causative mutation(s) has been identified, all living first-degree relatives (parents, siblings, and children) can undergo predictive genetic testing. As additional mutation-positive individuals in the family are identified, genetic testing should continue to proceed in a stepwise, cascade fashion, moving through the pedigree in sequential steps until all at-risk relatives have been identified: this is termed cascade genetic testing (Figure 52-2). Predictive genetic testing also identifies those individuals in the family who did not inherit the genetic predisposition and therefore do not require serial clinical screening. This approach (using predictive genetic testing compared to serial lifetime clinical screening alone) has been shown to be highly cost-effective in families with hypertrophic cardiomyopathy.8 Further, cascade genetic screening in families with inherited arrhythmia syndromes including long QT syndrome, Brugada syndrome, and CPVT through genetic testing and follow-up cardiac testing has been shown to result in treatment initiation with drugs and/or cardiac devices as well as counseling regarding lifestyle and drugs to avoid.9

The cardiac phenotype in some patients is due to the presence of multiple mutations; therefore, the best approach to genetic testing includes ordering the first, most comprehensive genetic testing panel on the most severely affected person in the family, since this will provide the highest likelihood of identifying all of the family’s disease-associated mutations and will allow for the most accurate risk assessment and predictive genetic testing for at-risk relatives.10

Interpretation of Genetic Testing Results

Genetic testing results interpretation can be complex and challenging in many cases, with novel variants frequently identified whose clinical significance is not often clear. Variants identified through clinical genetic testing may be highly penetrant disease-causing mutations, lower penetrance modifiers of the clinical phenotype, or benign polymorphisms. Laboratories consider multiple factors in the interpretation of genetic testing results and whether a variant is actually pathogenic or not; this classification may change over time as new knowledge regarding the variant is gained. In order to fully realize the benefits and value of predictive genetic testing, accurate interpretation and application of genetic testing results is of the utmost importance, as clinicians must be sure they are testing at-risk relatives for the causative mutation and not a benign variant, especially when the stakes are high as with these inherited cardiovascular diseases that have risks for sudden cardiac death. In the absence of in vivo and/or in vitro models to examine these variants’ functional significance, additional approaches, including analyzing cosegregation of the variant with the phenotype through large kindreds, amino acid conservation across species, variant frequency in large, ethnically matched control populations, and the use of in silico prediction tools, can be utilized. Variants with the highest likelihood of pathogenicity are those that cosegregate with the phenotype, are highly conserved, located in significant protein domains, and absent from matched controls.

Pretest Genetic Counseling

Pretest genetic counseling should include information on the indications for genetic testing as well as a discussion regarding the benefits, limitations, familial implications, and potential risks of genetic testing to insure informed decision-making. Pretest counseling should also include a discussion anticipating all possible results scenarios, including positive, negative, and/or uninformative genetic testing results and what each type of result would mean for the patient and his/her family. Pretest probabilities and clinical sensitivities should be shared with the patient (eg, a patient with a clinical diagnosis of Brugada syndrome should be informed that the current clinical sensitivity, or chance to find the disease-causing mutation, is approximately 25% to 40%). Possible psychological ramifications of genetic testing as well as baseline levels of risk perception, anxiety, and health beliefs should be assessed.11Questions regarding genetic discrimination are raised by many patients, and providers should therefore be prepared to discuss the protections afforded by, yet also the limitations of, the Genetic Information Nondiscrimination Act (GINA), which was signed into law on May 21, 2008. This federal law prohibits health insurers and employers from discriminating against individuals on the basis of their genetic information; however, life, disability, and long-term care insurance discrimination are not covered under GINA.

Posttest Genetic Counseling

Posttest genetic counseling should include a full discussion of genetic testing results and their implications for the index patient as well as at-risk relatives. Information regarding “duty to warn” should also be communicated; index patients should be counseled to inform their relatives of their risk as well as clinical screening recommendations. Family letters have been shown to be an effective tool to inform relatives of their risk and promote screening; these letters should include information about the family’s diagnosis, inheritance pattern, risks, genetic testing, clinical screening, and preventative options.12 If a pathogenic mutation is identified through clinical genetic testing, then family-specific single-site genetic testing is recommended for all living at-risk first-degree relatives. If genetic testing does not identify a causative mutation or if a variant of uncertain clinical significance is identified, the index patient should be informed that his/her condition may have an undetected underlying genetic/familial cause, that additional genetic testing may be warranted in the future as clinical sensitivities continue to improve, and that while at-risk relatives cannot pursue predictive genetic testing at this time, they should undergo clinical screening evaluations.

During posttest genetic counseling, an assessment of the psychological and emotional response to results should also be performed.11 A positive result in a clinically affected individual may eliminate doubt and uncertainty, but for those who test positive through predictive testing (ie, they are genotype-positive, phenotype-negative) it may have potential negative impacts including feelings such as increased worry, distress, anxiety, anger, fear of discrimination, alteration of self-esteem, and elimination of autonomy.11 Genetic testing results can also impact family dynamics and relationships. Parents in particular may have feelings of guilt related to passing their mutation to their children. In this situation, it may be helpful to emphasize the benefits provided by this type of genetic information (ie, knowledge is power); specifically, clinicians can utilize this information to initiate clinical screening that may lead toward the earliest possible detection of disease and that may provide the opportunity for prophylactic treatment and lifestyle modifications.13 Because many of the heritable cardiovascular conditions have inherent risks for arrhythmias and sudden cardiac death, the implications of positive predictive genetic testing can also include alteration of the ability to participate in competitive sports and other athletic activities, as well as additional lifestyle restrictions and modifications, which can be difficult for patients to cope with.

A negative genetic testing result can provide reassurance to patients regarding their personal risk level and that of their children and can also eliminate their need for follow-up cardiac screening. Patients in this category should be counseled that while they may have tested negative for their family’s specific mutation, they can still develop heart disease, so they should not ignore or minimize cardiac symptoms they may have in the future. Patients who test negative may also experience feelings of so-called “survivor guilt,” particularly in families where other siblings are clinically affected or have tested positive and are at risk.11,13 It has been proposed that follow-up counseling within 3 to 6 months time to assess for persistent or amplified levels of distress over results should be offered to families with inherited cardiovascular diseases.11


Family member clinical screening is recommended for relatives who test positive via predictive genetic testing, those whose genetic status is unknown, and also for at-risk relatives in families where genetic testing has not identified the underlying molecular cause of a likely heritable disease. It is crucial for at-risk relatives to understand that a one-time normal echocardiogram, electrocardiogram, or other cardiac test does not clear them from the risk to develop the signs and symptoms, including sudden cardiac arrest or death, of a heritable cardiovascular disease in the future due to reduced and age-related penetrance and variable expressivity. For this reason, it must be communicated to the index patient that their at-risk relatives should undergo clinical screening, likely in a serial fashion, with personalized recommendations for follow-up from their health care providers. Similarly to cascade genetic testing, clinical screening should commence in a cascade fashion until all the first-degree relatives of affected individuals have undergone screening. Guidelines including recommended clinical screening approaches, modalities, and frequencies are available for certain inherited cardiac conditions.7


An integrated, structured, multidisciplinary clinical approach to the care of families with inherited cardiac disease and sudden death has been recommended and should include the expertise of cardiologists, genetic counselors, clinical geneticists, nurses, pathologists, clinical and research molecular genetic testing centers, psychologists, and patient support groups.3 Such multidisciplinary clinics need not require the actual physical presence of each and every subspecialty during every patient encounter, but instead involve strong, collaborative working relationships and communication between disciplines. Specialized cardiac genetics clinics have been shown to lead to better patient adjustment and less worry.14 Many academic medical centers have established multidisciplinary inherited arrhythmia clinics as well as general cardiovascular genetic medicine clinics; community hospitals and other settings are also beginning to adopt this approach and are including genetic counseling and testing as part of their clinical service offerings. A timely American Heart Association policy statement on genetics and cardiovascular disease strongly advocates for the involvement of physicians and centers with expertise in cardiovascular genetics to guide the appropriate initiation, interpretation, and implementation of genetic testing.15 Master’s trained genetic counselors have been recommended as a solution to incorporate genetic medicine by providing genetic counseling and testing to applicable patients and by working in concert with subspecialty cardiovascular medicine physicians, such as electrophysiologists.16


The past 10 years have been witness to an explosion of discovery in the field of cardiovascular genetics. This, along with the development of novel DNA sequencing technologies, has led to a steep increase in the number of clinical genetic testing options available to patients with, or at risk for, hereditary cardiovascular diseases. Patients have much better access to clinical genetic testing, with many health insurance companies and federally funded insurance plans covering genetic testing for their beneficiaries; practice guidelines and position statements also now exist that recommend genetic counseling and genetic testing and provide best practice approaches for the patient and family with a cardiovascular genetic condition.

With the costs of DNA sequencing continuing to drop, the $1000 whole genome sequence may very well be right around the bend for use in standard clinical care, and may even supersede the use of disease-specific gene panels. The health care provider, a cardiovascular genomic counselor, and the patient could potentially utilize information from each of the 3 billion nucleotides in the genetic code to personalize care (eg, tailored drug therapy) and more precisely predict future cardiovascular health status (ie, patient X will develop Y condition at 23 years of age without Z intervention). Future research will hopefully lead toward additional discoveries that could ameliorate or prevent these conditions altogether. This is the goal, and the promise, of individualized cardiovascular genetic medicine.


1. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. This document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm. 2011;8(8):1308-1339.

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12. Van Der Roest WP, Pennings JM, Bakker M, Van Den Berg MP, Van Tintelen JP. Family letters are an effective way to inform relatives about inherited cardiac disease. Am J Med Genet A. 2009;149A(3):357-363.

13. Ingles J, Zodgekar PR, Yeates L, Macciocca I, Semsarian C, Fatkin D. Guidelines for genetic testing of inherited cardiac disorders. Heart Lung Circ. 2011;20(11):681-687.

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15. Ashley EA, Hershberger RE, Caleshu C, et al. Genetics and cardiovascular disease: a policy statement from the American Heart Association. Circulation. 2012;126(1):142-157.

16. Hershberger RE. Cardiovascular genetic medicine: evolving concepts, rationale, and implementation. J Cardiovasc Trans Res. 2008;1(2):137-143.