2 Cv Genetics

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2: Cardiovascular Genetics

Overview

Understanding the genetic underpinnings of CV disease has assumed greater importance in patient care. This chapter reviews

prototypical Mendelian CV disorders such as Marfan syndrome, hypertrophic cardiomyopathy, and long QT syndromes. There is

additional discussion of coagulation disorders and complex CV disease genetics, such as those pertaining to coronary artery

disease.

Authors

Patrick T. O'Gara, MD, FACC

Editor-in-Chief

Thomas M. Bashore, MD, FACC

Associate Editor

James C. Fang, MD, FACC

Associate Editor

Glenn A. Hirsch, MD, MHS, FACC

Associate Editor

Julia H. Indik, MD, PhD, FACC

Associate Editor

Donna M. Polk, MD, MPH, FACC

Associate Editor

Sunil V. Rao, MD, FACCAssociate Editor


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2.1: Cardiovascular Genetics

Author(s):

Svati H. Shah, MD, FACC

Learner Objectives

Upon completion of this module, the reader will be able to:

1. Recognize the clinical presentation of Mendelian cardiovascular (CV) disorders to identify patients for referral to genetic

clinics, facilitate genetic counseling and testing, and initiate appropriate therapies, and thereby prevent adverse events.

2. Differentiate between Mendelian and common complex CV diseases (CVDs) to prioritize patients who should be referredfor possible genetic testing for diagnosis, screening, and risk prediction.

3. Recognize the role of genetic testing in identifying high-risk patients with a family history of coronary artery disease (CAD)

for primary prevention of CVD events.


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Introduction

Since the advent of the Human Genome Project (http://www.genome.gov/12011238 ), a large number of studies have

focused on seeking to understand the genetic basis underlying many CVDs and related risk factors. While clinicians

involved in the routine clinical care of patients with CVD may not need extensive knowledge of the vast literature, it is

important to understand basic genetic concepts and the key findings in CV genetics research as it applies to patient care.

This chapter will provide a brief overview of important genetic concepts, and will detail clinically relevant and applicable

findings in CV genetics research.


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Overview

The Human Genome Project documented the entire nucleotide sequence (three billion base pairs) of the human

genome through sequencing in a small number of individuals. The HapMap Project ( http://www.hapmap.org )

subsequently determined the common variation that exists in this sequence in a larger number of individuals, and

importantly, evaluated diversity of this variation by race/ethnicity. These projects set the foundation for a large number of

studies that have related this genetic variation to disease risk.

Mendelian Versus Common, Complex Diseases

Prior to the Human Genome Project, human genetics research primarily focused on Mendelian diseases. These rare

diseases are characterized by clear genetic models of risk transmission (i.e., autosomal dominant, autosomal

recessive, or X-linked). They are caused by mutations in one or a few genes, which usually produce gross perturbation in

the protein product of the gene and show a large relative risk of disease.

Examples of Mendelian CVDs include hypertrophic cardiomyopathy (HCM), long QT syndrome (LQTS), and Marfan

syndrome. However, it is also well-documented that common atherosclerotic CVD has a heritable component, with family

history being a strong risk factor the risk increases in the relative when there is an earlier onset of the disease. 1

In contrast to Mendelian CVDs, atherosclerotic CVD is more appropriately termed a "common, complex" disease with

regard to its genetic component. Such diseases are characterized by: 1) multiple genes conferring risk, with only modest

effects 2) variable penetrance (i.e., if the individual has a genetic mutation, that does not necessarily mean he or she will

develop the disease) 3) no clear model of risk transmission and 4) often having multiple gene-gene and gene-

environment interactions. It is important for clinicians to understand these distinctions, as it can influence clinicaldecisions related to the utility of genetic testing, disease screening, and counseling.

Genetic Nomenclature and Technologies

A full review is beyond the scope of this chapter. However, a few key concepts are germane to understanding CVD

genetics. While 99% of the human genome is the same in all humans, it contains single nucleotide changes that are

common in the population (i.e., >1% frequency), so-called "single nucleotide polymorphisms" (SNPs).

There are >3 million SNPs throughout the human genome, in protein coding regions of genes (exons), nonprotein-

coding regions in genes (introns), and in intergenic regions between genes. Most Mendelian CVDs are due to more rare

genetic changes (i.e.,


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Mendelian Cardiovascular Genetic Diseases(1 of 3)

There are several genetic CVDs that demonstrate Mendelian inheritance. Although

these diseases are relatively rare, CV clinicians will no doubt encounter individuals

either with diagnosed or undiagnosed disease, as well as individuals at risk of

disease due to a family history, who require careful screening for disease. Thus, it is

important to recognize the key clinical features of these diseases, the underlying

genetic models, and guidelines for screening of family members. This knowledge

will facilitate prompt identification of at-risk individuals for diagnostic testing and

referral to specialty care for genetic counseling and potential genetic testing.

Marfan Syndrome

Marfan syndrome is a connective tissue disorder characterized by CV (aortic

dilatation and dissection, mitral and tricuspid valve prolapse, and pulmonary artery

dilatation) and noncardiac (ocular lens displacement, retinal detachment, early

cataracts, joint laxity, long bone overgrowth, scoliosis, pectus excavatum or

carinatum) manifestations. Marfan syndrome is one of the most common Mendelian

disorders, with a prevalence of 1 in 3,000-5,000 individuals.3 The diagnosis of

Marfan syndrome is made clinically, incorporating family history and presence of

clinical manifestations of disease in multiple organ systems. Figure 1 displays a

patient with the typical phenotypic manifestations of Marfan syndrome. Clinicaldiagnostic criteria, including the Ghent criteria, have been published. 4, 5

Marfan syndrome is inherited in an autosomal dominant fashion and is caused by

mutations in the fibrillin-1 extracellular matrix protein gene (FBN1), although up to

30% of cases do not have affected parents and thus presumably represent de novo

mutations.3 Genetic testing is available and the likelihood of finding a causative

mutation is 95%. Marfan syndrome needs to be clinically distinguished from other

similar genetic disorders including familial ectopia lentis, MASS phenotype (mitral

valve prolapse, aortic root diameter at upper limits of normal, stretch marks, and

skeletal conditions), and familial aortic aneurysm, all of which may also have

mutations in FBN1,3 as well as more rare, but related genetic disorders caused by

other genes such as Loeys-Dietz syndrome and Ehlers-Danlos syndrome (EDS),

vascular type.

As with many Mendelian disorders, genetic testing is indicated not for confirming

diagnosis in the index case (which is made clinically), but to focus genetic testing in

other family members. These results can help determine whether they need to have

longitudinal clinical monitoring or whether they can be reassured that they have not

inherited the pathologic mutation.3

There are several Mendelian CV genetic disorders with manifestations that can

present similarly to Marfan syndrome. For example, the vascular type of EDS (EDS

type IV) is an autosomal dominant disorder characterized by joint laxity, translucent

skin, easy bruising, wide and dystrophic scars, visceral organ rupture, and a

predilection towards aneurysm and/or dissection of medium to large arteries,

without predilection for involvement of aortic root.4 EDS, vascular type, is caused by

mutations in the collagen COL3A1 gene.

A much more rare disorder, Loeys-Dietz syndrome, is transmitted in an autosomal

dominant fashion and shares many features with Marfan syndrome (craniofacial

abnormalities, pectus deformity, arachnodactyly, joint laxity, dural ectasia, and aortic

root aneurysm with dissection).4 Unique features of Loeys-Dietz include

hypertelorism, broad or bifid uvula, cleft palate, Chiari I malformation, blue sclerae,

translucent skin, easy bruising, and the syndrome is particularly notable for a

propensity for diffuse and aggressive vascular disease including arterial tortuosity

and aneurysms with dissections. Loeys-Dietz is caused by mutations in the

TGFBR1 orTGFBR2genes.4

Familial Dilated Cardiomyopathy

Figure 1

Table 1

Figure 2


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Familial dilated cardiomyopathy (DCM), also often called hereditary or idiopathic

DCM, manifests clinically as left ventricular (LV) systolic dysfunction and dilatation in

the absence of other causes of cardiomyopathy, and predisposes patients to

congestive heart failure, arrhythmias, and sudden cardiac death. It accounts for up to

50% of cases of DCM. Familial DCM often displays an age-dependent penetrance,

with patients manifesting disease in their fourth to sixth decades. 6 The diagnosis is

usually made when two or more closely related family members meet a diagnosis

for idiopathic DCM.5 The prevalence of familial DCM has been estimated at

~1:2,700, but this is likely underestimated. Pathologic evaluation reveals myocyte

death and myocardial fibrosis.7

Familial DCM is overall a very heterogeneous genetic disease, characterized by

variable presentation and age of onset, reduced penetrance, and different modes of

inheritance, depending on the gene/mutation involved. Autosomal dominant is the

most commonly seen pattern of inheritance.7 Mutations in 33 genes encoding a

wide variety of components of the myocyte, including two X-linked genes, have been

implicated in familial DCM (Table 1 Figure 2). In total, they only account for 30-35%

of genetic causes of the disease.6 It is important to note that classification based on

the underlying genetic mutation should not override diagnosis based on clinical

findings, since different mutations in different genes can cause different CV

disorders. For example, mutations in the -myosin heavy chain cause either

hypertrophic cardiomyopathy or familial DCM.7

The role of genetic testing in familial DCM is unclear, since the diagnostic yield in

identifying a causative mutation is relatively low and this knowledge does notchange management for the affected patient. However, this knowledge could help

with counseling at-risk family members and could help determine the need and

frequency of clinical evaluations. In addition, in patients with concomitant significant

conduction disease, familial DCM due to mutations in the LMNA gene should be

considered, and if confirmed by genetic testing, use of an implantable cardioverter-

defibrillator (ICD) should be considered.7

Clinical screening of first-degree relatives of patients with familial DCM should be

pursued, with history, physical exam, ECG, and echocardiogram. However, given the

variable age-of-onset, a baseline normal ECG and echo does not rule out familial

DCM, and longitudinal follow-up should be performed. With a new diagnosis of

DCM, clinical screening of first-degree family members will reveal DCM in 20-35% of

family members.6


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Typical Phenotypic Manifestations of Marfan Syndrome

Figure 1

Typical phenotypic manifestations of Marfan syndrome including (a) pectus carinatum, (b) pectus excavatum, (c and d) joint hypermobility, (e)

protrusio acetabulae (medial displacement of the femoral head into the pelvic cavity), and (f) stretch marks.

Reproduced with permission from Canadas V, Vilacosta I, Bruna I, Fuster V. Marfan syndrome. Part 1: pathophysiology and diagnosis. Nat Rev

Cardiol 20107:256-65.


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Genes Implicated in Familial Dilated Cardiomyopathy

Table 1

DCM = dilated cardiomyopathy N/A = not applicable N = no Y = yes.

Adapted with permission from Hershberger RE, Siegfried JD. Update 2011: clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll

Cardiol 201157:1641-9.


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Diagram of a Cardiac Myocyte With Annotation of Genes Causing Dilated and/or Hypertrophic Cardiomyopathy

Figure 2

Displayed are key structures of the cardiac myocyte (extracellular matrix, sarcolemma, sarcomere, mitochondrion, sarcoplasmic reticulum, and

nucleus) and their key individual components. Within the extracellular matrix (top of diagram in medium blue) are found components of integrins

(which bind the myocyte to the extracellular matrix and basement membrane), the sarcoglycan complex, and ion channels (all of which span the

sarcolemma membrane).

Intracellularly (in light blue), resides the sarcomere (the fundamental contractile unit of the myocyte) it is composed of thin filaments (actin) and

thick filaments (myosin), along with other fundamental proteins of the contractile apparatus including myosin, tropomyosin, and the troponin

complex. The sarcoplasmic reticulum (in dark blue) is an intracellular membrane network that handles regulation of cytosolic calcium. Genes that

have been shown to cause dilated and/or hypertrophic cardiomyopathy that encode these cardiac myocyte components are annotated in italics.


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Familial Hypertrophic Cardiomyopathy

HCM is a genetic disorder characterized by LV hypertrophy (LVH) without LV dilation,

particularly of the interventricular septum, in the absence of other predisposing

conditions such as hypertension or valvular disease. It is a relatively common

genetic disease, with a 1 in 500 prevalence by echocardiography in the general

population.8

The clinical diagnosis is typically made with echocardiography. Twenty-five percent

of patients with HCM have a detectable obstructive gradient, and even more have a

gradient with provocation.9 The presence and degree of LVH can be age related

thus, the importance of serial longitudinal follow-up in at-risk individuals. HCM can

cause diastolic dysfunction and LV outflow tract obstruction, and a predisposition to

increased risk of heart failure and sudden cardiac death. In fact, HCM is the most

common cause of sudden death in young individuals.8

Pathologic evaluation often reveals disarray of cardiac myocytes with fibrosis.

Treatment can involve beta-blockers or calcium channel blockers, antiarrhythmics,

alcohol septal ablation, or surgical myomectomy. An ICD should be considered in

individuals with prior cardiac arrest or those deemed at increased risk (i.e., familyhistory of sudden cardiac death, ventricular ectopy on Holter monitoring, unexplained

syncope, extreme LVH [>3 cm], or a drop in blood pressure with exercise).

Familial HCM is a Mendelian genetic disorder with autosomal dominant inheritance

caused by one of >900 identified mutations in one of 14 genes that encode

components of the sarcomere (Figure 2). Mutations in MYH7(-myosin heavy chain)

and MYBPC3 (encoding cardiac myosin binding protein C) are the most common,

with each attributable to 40% of HCM cases. 7 The remaining seven genes account

for


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strong family history of HCM should be screened, and even mild LVH that does not

meet diagnostic criteria (i.e., septal wall thickness >15 mm) should be further

evaluated.11

Guidelines for the screening of clinically unaffected, at-risk family members have

been proposed,12 including repeat evaluation with physical exam, and ECG, every

12-18 months for family members ages 12-18 years, and every 3-5 years for ages

>18-21 years (or in response to any change in symptoms).

Screening in children


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course is influenced by genotype.14,15 As well, genetic testing in the index individual

is helpful for guiding genetic testing and clinical screening in at-risk family

members.

Romano-Ward syndrome (RWS) is the most common form of inherited LQTS, with a

prevalence of 1:3,000 to 1:7,000.16 RWS includes LQT1, LQT2, LQT3, LQT5, and

LQT6, and manifests as a cardiac disorder without other systemic manifestations.

Symptoms of syncope usually occur during exercise (LQTS1 and LQTS2), times of

high stress (LQTS), or during sleep (LQTS2 and LQTS3), and usually occur during

the adolescent years through the second decade of life. RWS is inherited in an

autosomal dominant fashion, with approximately 70% of families identifiable as

having one of the known disease-causing mutations.

Five genes are known to cause RWS, and clinical genetic testing is available for all

of them: KCNQ1 (LQT1, 58% of RWS is attributable to mutations in this gene),

KCNH2(LQT2, 35%), SCN5A (LQT3, 5%), KCNE1 (LQT5, 1%), and KCNE2(LQT6,

1%).16 There is a correlation between the type of genetic mutation and clinical

presentation and therapy. LQTS1 and LQTS2 are usually treated with beta-blockers

if symptomatic and can be considered for some asymptomatic individuals

prophylactic ICD can be considered for those who have resistant symptoms and/or

history of cardiac arrest. An ICD should be considered for symptomatic LQT3

individuals. Patients with RWS should be counseled to avoid intense physical

activity, emotional stress, and drugs that could further prolong the QT interval. Other

genes have been implicated in LQTS:ANK2(LQTS4), KCNJ2(LQT7), and mutations

in CAV3 (LQT9) have been associated with LQTS,16

and thus, are proposed asadditional genes for RWS.

Several disorders are genetically related to RWS. Jervell and Lange-Nielsen

syndrome presents with congenital bilateral sensorineural hearing loss and

prolonged QT interval, which is associated with an increased risk of ventricular

arrhythmias and sudden cardiac death. Jervell and Lange-Nielson syndrome is

inherited in an autosomal recessive pattern and is caused by mutations in the

KCNQ1 (LQT1) orKCNE1 (LQT5) genes. Brugada syndrome (described later), is

caused by mutations in SCN5A (LQT3) and is associated with polymorphic

VT/ventricular fibrillation and sudden death. Acquired LQTS is characterized by

prolongation of the QT interval in the context of treatment with an offending drug

some individuals with acquired LQTS have a genetic predisposition caused by a

mutation in one of the known RWS genes.

Andersen-Tawil syndrome manifests as a triad of periodic paralysis, high-frequency

bidirectional VT, and prolonged QT interval, and also shows other noncardiac

features. It is caused by one mutation in KCNJ2, with approximately 70% of

individuals with Andersen-Tawil having this mutation, and has been proposed as

LQT7, but there is uncertainty about where there is true QT prolongation in this

syndrome or whether the large U waves are precluding accurate measurement.16

Timothy syndrome (LQT8) can present with cardiac defects (prolonged QT and other

congenital cardiac defects), syndactyly and facial and neurodevelopmental changes,

and is caused by a mutation in the Cav 1.2 calcium channel gene CACNA1C.16

LQT4 is very rare and is caused by mutations in the ankyrin (ANK2) gene. LQT4

shows variable penetrance with only a minority of individuals with a mutation

showing QT prolongation, and atrial arrhythmias being a prominent manifestation,including sinus bradycardia and atrial fibrillation.1 6


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Diagram of a Cardiac Myocyte With Annotation of Genes Causing Dilated and/or Hypertrophic Cardiomyopathy

Figure 2

Displayed are key structures of the cardiac myocyte (extracellular matrix, sarcolemma, sarcomere, mitochondrion, sarcoplasmic reticulum, and

nucleus) and their key individual components. Within the extracellular matrix (top of diagram in medium blue) are found components of integrins

(which bind the myocyte to the extracellular matrix and basement membrane), the sarcoglycan complex, and ion channels (all of which span the

sarcolemma membrane).

Intracellularly (in light blue), resides the sarcomere (the fundamental contractile unit of the myocyte) it is composed of thin filaments (actin) and

thick filaments (myosin), along with other fundamental proteins of the contractile apparatus including myosin, tropomyosin, and the troponin

complex. The sarcoplasmic reticulum (in dark blue) is an intracellular membrane network that handles regulation of cytosolic calcium. Genes that

have been shown to cause dilated and/or hypertrophic cardiomyopathy that encode these cardiac myocyte components are annotated in italics.


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Genes Implicated in Hypertrophic Cardiomyopathy

Table 2

HCM = hypertrophic cardiomyopathy N = no Y = yes.

Adapted with permission from Hershberger RE, Siegfried JD. Update 2011: clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll

Cardiol 201157:1641-9.


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Clinical Characteristics and Genetic Mutations Associated With Long QT Syndrome

Table 3

JLNS = Jervell and Lange-Nielsen syndrome RWS = Romano-Ward syndrome.

Modified with permission from Vincent GM. Romano-Ward syndrome. In: Pagon RA, Bird TD, Dolan CR, Stephens K, eds. GeneReviews. Seattle:

University of Washington, Seattle 1993, and Goldenberg I, Zareba W, Moss AJ. Long QT Syndrome. Curr Probl Cardiol 200833:629-94.


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Typical Electrocardiogram in Long QT Syndrome

Figure 3

Reproduced with permission from Brugada R. Sudden death: managing the family, the role of genetics. Heart 201197:676-81.


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Brugada Syndrome

Brugada syndrome is characterized by RV conduction abnormalities and coved-type

ST-segment elevation in the anterior right precordial leads (V1-V3) on ECG (Figure

4), and leads to ventricular fibrillation and sudden cardiac death at an early age. 17

Brugada syndrome is relatively rare, affecting an estimated 3 in 10,000 people. It

displays an autosomal dominant inheritance pattern with variable penetrance and

expressivity, ranging from asymptomatic individuals to sudden cardiac death during

the first year of life.18

Most mutations causing Brugada syndrome occur in genes within or related to the

sodium channel (SCN5A), which cause 20-25% of Brugada syndrome, although

other ion channels have been implicated.17 In addition, several genes encoding

auxiliary proteins of the cardiac sodium channel have been linked to Brugada

syndrome, including SCN5A, -1-subunit of the cardiac sodium channel (SCN1B), -

3-subunit of the cardiac sodium channel (SCN3B), and glycerol 3 phosphate

dehydrogenase 1-like (GPDL1),17 as well as mutations involving the L-type calcium

channel -subunit (CACNA1C) and -subunit (CACNB2B) implicated in almost 10%

of Brugada syndrome cases.18

Clinical genetic testing is available for many of these mutations

(http://www.ncbi.nlm.nih.gov/sites/GeneTests/ ) however, the diagnostic yield is low,

with up to 65% of patients not having an identifiable mutation on genetic testing. 18

Genetic testing in Brugada syndrome can help with risk stratification in the proband,

as some mutations demonstrate a more deleterious molecular deficit and, thus, a

more severe phenotypic presentation, although the primary utility is for diagnostic

confirmation in the proband and testing in first-degree family members to help guide

screening.18

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

ARVD/C is a genetic disorder characterized by cardiomyopathy predominantlyaffecting the right ventricle that pathologically consists of fibrofatty replacement of

cardiomyocytes,19 resulting in an increased risk of sudden cardiac death due to

ventricular arrhythmias at a young age. The clinical diagnosis is made based on the

presence of two major criteria, or one major and two minor criteria, or four minor

criteria.

Major criteria include: 1) severe RV dilatation or localized RV aneurysm 2) fibrofatty

infiltration of the RV myocardium on biopsy 3) Epsilon waves or localized

prolongation of the QRS complex in V1-V3 or 4) family history of ARVD/C confirmed

on autopsy or surgery. Minor criteria include: 1) mild global RV dilation or regional

RV hypokinesia 2) late potentials on signal-averaged ECG 3) inverted T waves in

leads V1-V3 (in the absence of right bundle branch block) 4) left bundle branch

block-type VT or frequent premature ventricular contraction or 5) family history of

ARVD/C based on clinical diagnosis or family history of premature sudden death

due to suspected ARVD/C.19

Two related diseases include: 1) Naxos disease, characterized by ARVD/C with

woolly hair and palmoplantar keratoderma, and 2) the Carvajal syndrome,

characterized by a similar dermatologic presentation as Naxos disease, but with

predominantly LV involvement.7

ARVD/C is a hereditary disease, with an autosomal dominant mode of

transmission, but the genetic penetrance is low and there is high variability in the

clinical presentation. Mutations in genes encoding proteins of the cardiac

desmosome, important for mechanical cell-to-cell adhesion, are responsible for

ARVD/C, Naxos disease, and Carvajal syndrome.

Figure 4


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Mutations in the desmosomal protein plakophilin 2 (PKP2) are present in up to 43%

of cases. Other genes involved include desmocollin-2 (DSC2), desmoplakin (DSP),

desmoglein-2 (DSG2), and plakoglobin (JUP).19 Two non-desmosomal genes have

also been implicated in ARVD/C: transforming growth factor 3 ( TGF-3) and

transmembrane protein 43 (TMEM43).6 Clinical testing is available for all of the

desmosomal gene mutations however, given low yields, high background noise,

and unclear clinical implications for the proband, the role of genetic testing in

ARVD/C is not well established.18

It is important to note that mutations have been identified in only 50% of cases.

Thus, a "negative" genetic test for ARVD does not rule out the presence of the

disease. Genetic testing for ARVD/C is often for identification of family members at

risk for the disease. Genetic testing in ARVD/C, in general, should not be used to

confirm the diagnosis, as clinical imaging and other clinical evaluations have

greater diagnostic utility.19

Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic VT (CPVT) is characterized by a normal resting

ECG, sometimes with bradycardia and U waves, which presents with significant

ventricular ectopy including bidirectional VT with treadmill or catecholamine stress

testing, and like LQT1, is associated with swimming precipitating an arrhythmia.18

Patients with CPVT generally have a structurally normal heart, but have a very strong

risk for sudden cardiac death.

CPVT is a heritable disorder caused by mutations in genes encoding components

of the intracellular calcium release channel complex within the sarcoplasmic

reticulum of the cardiac myocyte, with mutations in the cardiac ryanodine receptor

2/calcium release channel gene (RYR2) causing 50-60% of cases.18 Clinical

genetic testing is available (http://www.ncbi.nlm.nih.gov/sites/GeneTests/ ) however,

there is currently no consensus about the utility of a comprehensive screen of all

105 RYR2exons, or whether more targeted genetic testing would be sufficient.

Interestingly, almost 30% of possible or atypical LQTS cases (corrected QT interval


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Typical Electrocardiogram Findings in Brugada Syndrome

Figure 4


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Genetics of Coagulation and Bleeding

Coagulation and hemostasis are the delicate balance of a complex interrelationship of coagulation factors, platelets, and

fibrinolytic proteins. Genetic variants associated with changes in these factors may cause derangement of this

coordinated system, resulting in abnormal coagulation or fibrinolysis and increased risk of thrombosis. Until the early

1990s, only three single gene disorders had been identified that resulted in increased risk of thromboembolism:

antithrombin and protein C and protein S deficiencies, which together occur in only 15% of families with familial venous

thromboembolism (VTE). For arterial thrombosis, few genetic variants had been reproducibly associated with increased

risk.

One must keep in mind that the pathophysiology of most thrombosis is fundamentally linked to acquired nongenetic

factors that interact with a background of inherited genetic risk to produce disease. The following is a brief review of the

currently available knowledge of the genetics of human thrombosis, but there remains a large amount of unexplained

variation in the genetic, molecular, and clinical manifestations of this disease.

Factor V Leiden (Activated Protein C Resistance)

Activated protein C (APC) resistance predisposes to VTE, and approximately 90% of cases of VTE due to APC resistance

are caused by a SNP in the factor V gene known as factor V Leiden. Factor V Leiden is the most common genetic cause

of VTE, responsible for up to 50% of cases, with a prevalence of up to 6% in Caucasians and a frequency of homozygosity

of 1:5,000. Factor V Leiden shows variable penetrance and expressivity and is transmitted in an autosomal dominant

fashion, although individuals homozygous for the mutation have a much greater thrombotic risk than heterozygotes who

have a slightly increased risk.22 The risk for VTE varies from a threefold increased risk in individuals carrying one copy,

increasing to a 10-fold increased risk in individuals carrying two copies (i.e., homozygotes), and up to 18-fold increased

risk for homozygotes from thrombophilic families.22

Factor V Leiden does not appear to be consistently associated with risk of arterial thrombosis, although there are data to

suggest that it may contribute to myocardial infarction (MI) in younger patients and patients with other CVD risk factors. 22

The presence of factor V Leiden in conjunction with another thrombotic defect can result in increasing the thrombotic risk

up to threefold in comparison with risk of a single defect.

In patients with factor V Leiden who suffer a first thromboembolic event, in addition to standard guidelines for treatment,

long-term oral anticoagulation should be considered in patients with: 1) recurrent VTE, 2) multiple thrombophilic

disorders, 3) concomitant risk factors, or 4) homozygous status for factor V Leiden. 22 In heterozygous individuals,

prophylactic anticoagulation is not routinely recommended, although a short course could be considered when other risk

factors are present.22 Women who carry the factor V Leiden polymorphism should be counseled to avoid oral

contraceptives and smoking.

Factor V Leiden is diagnosed by either a coagulation screening test (APC resistance assay) or by DNA analysis of the

factor V gene (F5).22 Genetic testing should be considered in individuals with: 1) a first unprovoked VTE at any age,

especially at younger ages 2) history of recurrent VTE 3) VTE at unusual sites or 4) VTE during pregnancy or associated

with the use of hormone replacement therapy or oral contraceptives.22 Genetic testing may also be considered in

individuals with unexplained fetal loss, female smokers 50 years old with

a first VTE in the absence of malignancy or intravascular device, asymptomatic adult family members of individuals with a

factor V Leiden mutation (especially those who are pregnant or considering pregnancy or oral contraceptive use), and

children with noncatheter-related unexplained VTE or stroke.22

Antithrombin III, Protein C, and Protein S Deficiencies

Although antithrombin III, protein C, and protein S deficiencies are strong risk factors for VTE (stronger than factor VLeiden), they are relatively rare disorders, accounting individually for


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manner and is caused by one of >100 genetic mutations in the protein C gene. The prevalence of heterozygous protein C

deficiencies is up to 1:200 in the general population and up to 5% in patients with VTE. Protein C deficiency is diagnosed

by a variety of immunologic and functional assays. Homozygous protein S or protein C deficiency is rare, and usually

associated with neonatal or fetal death.24 Genetic testing is not indicated for any of these deficiencies.

Prothrombin 20210A

This genetic variant in the prothrombin (factor II) gene has been associated with up to a threefold increased risk of VTE

and is the second most frequent prothrombotic polymorphism. The transmission is autosomal dominant, with a

prevalence of 2% in the general population, 6% in patients presenting with a first deep venous thrombosis, and present

in up to 18% of individuals who have already had a thrombotic event or have a family history of thrombosis. 22

It has been suggested that this variant results in increased thrombosis risk only in patients who have additional risk

factors such as other prothrombotic genetic variants. For example, the frequency of individuals carrying both a factor V

Leiden allele and the prothrombin gene mutation is 1:1,000 in the general population and 1-5% in individuals with VTE.22

As with the other prothrombotic genetic variants, the role of this mutation in arterial thrombosis is inconsistent. Clinical

genetic testing is available for this variant.

Hyperhomocysteinemia

Homocystinuria is a rare genetic disease transmitted in an autosomal recessive pattern and manifests as

thromboembolic disease and premature atherosclerosis. In contrast, hyperhomocysteinemia is relatively common, with

up to 7% of the population showing homocysteine elevations to a lesser degree than that seen with the Mendelian

disease of homocystinuria. Although debated, elevated total homocysteine levels have been shown to be associated with

an increased risk of thromboembolic disease including atherosclerotic disease (see review by Di Minno et al. 25)

however, these associations are confounded by many factors. There are many clinical variables that can cause mild-

moderate elevations in homocysteine levels, including nutritional deficiencies, medications, chronic kidney failure and

smoking, and genetic factors also appear to play a role.

A relatively common variant in the MTHFR(5,10-methylenetetrahydrofolate reductase) gene, which encodes an enzyme

that catalyzes the conversion of homocysteine to methionine, has been associated with elevated homocysteine levels in

individuals with low folate intake.22 However, the data implicating the prothrombotic role of this polymorphism are

conflicting, and in general, it is not thought to be a significant contributor to prothrombotic risk. Thus, genetic testing for

the MTHFRvariant is not clinically indicated, and routine measurement of homocysteine levels is not indicated. However,

although there are no clear data supporting this approach, given the absence of other modifiable biomarkers for risk

assessment, measurement of plasma homocysteine levels may be considered in patients presenting with very early

onset thrombotic events (including atherosclerosis) and treatment with vitamins B6, B12, and folate initiated for elevated

levels.


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Complex Disease Genetics: Genetics of Atherosclerosis

CAD and related atherosclerotic traits are heritable in nature, as are many CAD-related risk factors. Early studies have

shown that having a first-degree relative with CAD increases an individual's risk of CAD, with increasing risk the younger

the age of onset of that relative.26 Despite this strong heritability, the genetic architecture of CAD and atherosclerosis

remains incompletely understood. This is most likely because of the complex, polygenic risk model including gene-

environment and gene-gene interactions, underlying not only CAD, but also CAD-related risk factors. Regardless, given

that currently available clinical risk models do not completely predict risk of CAD and CV events, there has been great

hope that genetic studies would identify markers that would improve clinical risk models.

Hundreds of candidate gene studies have been published with inconsistent and often modest findings. In these studies,

single or multiple SNPs in genes in known CAD/atherosclerosis biological pathways are tested for association with

presence of disease. Furthermore, while some have demonstrated statistical significance, the majority of these studies

have not assessed independent and incremental association with CVD. While a comprehensive review of genes

implicated as associated with CAD or CV events is beyond the scope of this chapter, some of the most relevant genes

implicated in CAD/CVD pathogenesis include genes involved in low-density lipoprotein cholesterol metabolism (APOB,

APOE, LDLR, HMGCR, ABCA1, and PCSK9), genes involved in high-density lipoprotein cholesterol metabolism (LIPC,

LPL, and CETP), and other genes (ACE,MTHFR, and eNOS).27

In addition, application of a relatively new technology, GWAS, has enabled an agnostic "unbiased" approach to

understanding genetic risk for atherosclerosis. These studies have consistently identified a region on chromosome 9p21

to be associated with CAD.28 However, these variants are very common (~20% of the population is homozygous), have

unknown functional consequences with unclear biology of disease mediation, and confer only modest risk of CAD (oddsratios, 1.2-1.6). Thus, it is believed that much of the genetic risk of atherosclerosis remains to be elucidated. More recent

GWAS have identified more variants that may explain some of this unexplained risk. 27

While testing for some of these genetic variants is available on a research basis, and has begun to be offered by

commercial entities, it is not currently indicated for general clinical management. In fact, the best "genetic" test currently

available for assessing risk of CAD/atherosclerosis is a detailed family history with subsequent initiation of primary

preventive therapies, as indicated.

Novel genetic technologies including epigenetics (heritable changes in the expression of a gene that are caused by

mechanisms other than actual changes in the DNA sequence, i.e. DNA methylation), copy number variation (abnormal

number of copies of sections of DNA as opposed to single changes seen with SNPs), and DNA resequencing to identify

more rare genetic variants that may be associated with disease. Once this genetic architecture is clarified and shown to

be incremental to clinical risk models for disease, genetic testing may be appropriate in order to target more aggressive

treatment of CAD risk factors.


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Complex Disease Genetics: Arrhythmias

While Mendelian genetic arrhythmic disorders have been previously covered, with the shift in focus to common complex

diseases, there has been a growing interest in understanding the genetics of arrhythmic disorders such as sudden

cardiac death. These disorders, which appear to have a genetic component, are characterized by an unclear mode of

transmission and are probably the result of gene-environment interactions that remain to be elucidated. For example,

genetic variants that have a relatively high frequency in the population (i.e., >5% prevalence), either within known genes

that cause Mendelian genetic disorders (i.e., ion channel genes) or within other genes, could increase the risk of

ventricular arrhythmias in the context of reduced LV function.

This notion is supported by recent GWAS that have identified common variants within these ion channel genes as well as

within novel genes, which are associated with higher QT intervals in a general population not enhanced for long QT.

Given the known association of longer QT intervals (even within the normal range) with increased risk of sudden cardiac

death, it could be hypothesized that these same genetic variants could increase risk of ventricular arrhythmias and

sudden cardiac death. While genetic testing is not clinically indicated in the management of these complex disorders,

with the growing accumulation of studies in these disorders, clinical decision making may include genetic testing in the

future.


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Cardiovascular Pharmacogenomics

"Pharmacogenomics" can be defined as the study of genetic variation in drug response. 29 In the era of "personalized

medicine," pharmacogenomics holds promise for enabling more judicious decisions about which drug and what dose to

use in a given patient. In CVD, this paradigm is supported by several key examples of genetic variants that have been

associated with differential response to, or complications from, commonly used medications.

Warfarin

Warfarin shows marked heterogeneity in time to, and dosage of, final therapeutic dose. It is metabolized predominantlyby a cytochrome P-450 enzyme CYP2C9 two common variants in the CYP2C9 gene result in reduced enzymatic activity

(12% forCYP2C9*2and 5% forCYP2C9*3).29 Patients harboring one of these common genetic variants required a

lower final dose for therapeutic anticoagulation with warfarin and are at increased risk of bleeding complications. In

combination, CYP2C9 and another gene, vitamin K epoxide reductase complex subunit 1 (VKORC1) genotypes, explain

30-40% of the total variation in the final warfarin dose.29

Observational studies have suggested that addition of these genotypes to a clinical algorithm results in improved

outcomes,29 which have been supported by results of clinical trials. 30 In fact, the Food and Drug Administration (FDA)

has revised the label on warfarin and now provides ranges of doses based on genotype with the suggestion that genetic

testing be considered when prescribing the drug.29 Genetic testing for these polymorphisms is clinically available, and

online algorithms are available to help the clinician determine the best warfarin dose when genotype data are available

(http://www.warfarindosing.org). Clinical trials of pharmacogenomic warfarin dosing algorithms are ongoing. However,

emerging alternative oral anticoagulants with fixed dosing may preclude further development of warfarin algorithms.

Clopidogrel

Many patients suffer recurrent events despite therapy with clopidogrel, a mainstay antiplatelet agent for a variety of CV

disorders, suggesting a syndrome of clopidogrel resistance. Clopidogrel is an inactive prodrug requiring hepatic

activation via cytochrome p450 enzymes including CYP2C19. A number of different alleles of the gene encoding this

enzyme have been identified (CYP2C19*2being the most common), which result in loss of enzymatic activity. Patients

carrying those alleles have reduced formation of clopidogrel's active metabolite and consequently reduced platelet

inhibition.29 Studies have confirmed the clinical implications of this reduced platelet inhibition carriers of at least one

CYP2C19*2allele experience a 1.5-fold increase in risk of CV death, MI, and stroke in the year of follow-up after receiving

percutaneous coronary intervention (PCI) for acute coronary syndrome and treatment with clopidogrel, as compared with

noncarriers.31

Carriers also have up to a sixfold increased risk of stent thrombosis. These findings prompted the FDA to add a "boxed

warning" to clopidogrel, stating that individuals with a CYP2C19 variant associated with a low rate of metabolism might

require dose adjustment or use of a different drug.29 Similarly, the American College of Cardiology Foundation and

American Heart Association (ACCF/AHA) have issued a joint statement suggesting that CYP2C19 genotyping be

considered for patients treated with clopidogrel who are at moderate or high risk for CV events.29,32

Unfortunately, the data regarding use of alternative agents are somewhat conflicting. A large genetic substudy within

the PLATO (PLATelet inhibition and patient Outcomes) trial of ticagrelor versus clopidogrel found that ticagrelor resulted

in superior outcomes to clopidogrel regardless ofCYP2C19 genotype. There was a higher event rate in carriers

randomized to clopidogrel compared with noncarriers within 30 days of initiation of therapy, but this difference did not

bear out over the longer term.33

Clinical genetic testing forCYP2C19 variants is available, and should be considered in moderate- or high-risk patients.

However, it still does not have widespread use due to uncertainty about how to treat carriers of the variant and uncertaintyabout the clinical utility of genotyping in reducing the incidence of CV events.29 Further studies are ongoing.

Statins

There exists heterogeneity in the response to statins, suggesting a role for genetic factors. A GWAS has uncovered a

polymorphism in the SLCO1B1 gene, encoding an organic anion transporter regulating the hepatic uptake of statins,

which is strongly associated with risk of statin-induced myopathy.34 While clinical trials to assess the clinical application

of this genetic variant are ongoing, this variant could prove to be helpful in determining which individuals are at risk of

developing myopathy prior to placing them on a statin.

Studies have also been done to understand possible genetic variation underlying the heterogeneity in response to

statins with regard to efficacy. Data have suggested that a variant in the kinesin-like family 6 ( KIF6) gene (Trp719Arg) is

associated with incident CVD and a more beneficial response to therapy with statins, and that atorvastatin may be


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superior to pravastatin in patients with acute coronary syndrome who are carriers of the variant. 35

Such data prompted development of a widely used commercially available test. However, the test has not yet been

approved by the FDA due to insufficient data to demonstrate the safety and effectiveness of the test for use in CV risk

assessment. Subsequent nested studies within clinical trials have shown no difference in efficacy of certain statins by

KIF6genotype.35 Further, the biological mechanisms have not been well elucidated. Thus, the clinical utility ofKIF6

genetic testing remains unclear.


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Complex Disease Genetics: Nongenetic Biomarkers

Work continues to more thoroughly define the genetic underpinnings of "common" atherosclerotic CVD, but it is important

to note that genetic variants are immutable and static throughout a lifetime. The presence of a gene or gene variant does

not necessarily specify that a disease phenotype will be observed clinically. Some genes are constitutively expressed

while for others, regulation is sensitive to the environment and exposures (e.g., dietary, stress, hormonal, smoking, etc.).

Thus, an individual's genotype alone will be unlikely to provide risk stratification for CVD events that would be sufficient to

guide individualized treatment strategies. As such, a growing number of studies have identified novel CVD biomarkers

using emerging molecular technologies, including transcriptomics, proteomics, and metabolomics.

RNA expression patterns reflect active transcription of genetic information at a given point in time and may be more

reflective of disease state and activity than DNA-based genetic markers. Thus, gene expression may be more predictive

of clinical events in the near-term. These RNA levels can be measured in biological tissues and in peripheral blood

through use of commercially available gene expression chips, which represent tens of thousands of genes, so-called

"transcriptomics." By comparing one clinical state to another (e.g., event vs. no event), one can identify RNA markers

associated with disease as well as facilitating biological pathway discovery. While work to identify RNA markers

predicting future CV events is ongoing, studies have revealed that a 23-gene RNA signature reporting on many

inflammatory genes measured in peripheral blood is associated with the presence and severity of CAD in nondiabetic

patients,36 and has been developed as a commercially available test (Corus CAD, CardioDX, Palo Alto, CA).

Metabolomics is the study of the small-molecule metabolites that are byproducts of cellular metabolism and is an

emerging discipline that may be particularly useful for diagnosis of human diseases because changes in metabolite

levels provide an integrated phenotypic "read-out" of genomic, transcriptomic, and proteomic variation. Metabolomics hasbeen used to successfully identify novel metabolic biomarkers independently associated with insulin resistance and

prediction of diabetes,37 and for CAD and CV events.38 None of these markers are available for clinical testing, but

demonstrate the utility of this approach for biomarker discovery.

While these novel RNA and metabolic-based biomarkers are not FDA approved or routinely indicated for the general care

of patients, health care providers will likely see a greater integration of such tests into clinical practice. Future studies will

no doubt identify additional novel biomarkers and importantly, will need to assess the incremental utility of these

biomarkers on top of more easily measureable clinical factors for diagnosis or risk prediction. Validation of genetic

discoveries, along with integration of the information they convey with established clinical models as well as new clinical

biomarkers derived from these novel molecular technologies, will be essential to establish utility of genetics and other

such technologies in clinical practice.


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Human Genetic Resources

The explosion of human genetics research both in common complex and Mendelian

genetic disorders can seem overwhelming, but health care providers need to be

knowledgeable about the basics of these diseases, in order to appropriately identify

and refer high-risk patients and their families, and for facilitating critical review of the

large number of studies that continue to emerge, suggesting new genomic markers

for potential clinical use. Several public genetic website resources are available to

aid the clinician and researcher in these endeavors (Table 4).

Table 4


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Publicly Available Human Genetic Website Resources

Table 4


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Conclusions and Future Directions

The Human Genome Project and other genetic endeavors have fueled major advances in our understanding of the

genetics of CVD. CV health care providers need to have a basic knowledge of human genetic concepts, and clinical

presentations and screening implications for family members for Mendelian CV disorders, in order to identify at-risk

individuals and their families and refer to appropriate subspecialty genetics clinics for genetic counseling and

consideration of genetic testing. This knowledge will also help CV health care providers interpret the ongoing work on

genetic and other biomarkers for common, complex CAD and CV events where the role of genetic testing is less clear.

Future studies will need to establish that DNA- or RNA-based tests for diagnosis of CAD or risk prediction for CV eventsprovide information above and beyond that provided by conventional risk factors. Further, as the genetic architecture of

common CVD is clarified, integration with nongenetic molecular biomarkers will likely be necessary to produce a robust

model for CVD risk prediction and for understanding the molecular mechanisms underlying this risk mediation.


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Key Points

Mendelian CVDs include HCM, LQTS, Marfan syndrome, and familial DCM. These diseases are characterized by

a clear mode of inheritance and one or a few genes causing the disease, with mutations within the genes

showing strong association with the disease and marked phenotypic effects.

Genetic testing of the affected individual is often indicated in these Mendelian CV genetic diseases, not for

diagnostic purposes (diagnosis is usually a clinical diagnosis), but for facilitating genetic testing and screening in

at-risk family members.

When performing genetic testing in most Mendelian CV genetic diseases, the best approach is usually to perform

a full screen of all available genetic variants in the index case, and then perform focused testing of only that

genetic variant in at-risk family members.

Marfan syndrome is a connective tissue disorder inherited in an autosomal dominant fashion, with 95% of cases

caused by mutations in the fibrillin-1 extracellular matrix protein gene (FBN1), and predisposes to aortic

aneurysms and dissections.

Familial DCM is a heterogeneous genetic disease, with variable presentations, reduced penetrance, and different

modes of inheritance. It is caused by mutations in 33 known genes, but these account for only 30-35% of cases

thus, the role of genetic testing is unclear.

Familial HCM is a relatively common genetic disease showing an autosomal dominant mode of inheritance

caused by mutations in 1 of 14 genes encoding components of the sarcomere, with genetic testing identifying one

of these mutations in 50-75% of cases. Thus, genetic testing can be useful in helping to confirm a diagnosis and

for guiding screening in at-risk family members.

Familial HCM needs to be differentiated from LV hypertrophy resulting from other genetic disorders such as Fabry

disease, amyloidosis, or other metabolic cardiomyopathies, especially in younger individuals.LQTS is typically autosomal dominant but with variable penetrance, and is subdivided into 12 types based on the

underlying causative gene. Genetic testing will identify a known LQTS mutation in approximately 75% of cases,

and thus, can help with diagnosis and for guiding screening in at-risk family members.

Factor V Leiden is a genetic variant that causes APC resistance and is the most common genetic cause of VTE,

causing up to 50% of cases. It is transmitted in an autosomal dominant fashion, and genetic testing for this

genetic variant is indicated in certain patients with a VTE.

Warfarin metabolism is determined partially by genetic variants in two genes, the hepatic cytochrome p450

enzyme CYP2C9 and VKORC1, which explain 30-40% of the total variation in final warfarin dose. Genetic testing

for these variants may help with achieving optimal warfarin doses more quickly, and for improving outcomes.

Clopidogrel activation is mediated partially through a hepatic cytochrome p450 enzyme coded by the gene

CYP2C19, and variants in this gene have been associated with reduced platelet inhibition and worse clinical

outcomes in patients treated with clopidogrel. The ACCF and AHA suggest testing for these CYP2C19 variants

may be indicated for patients treated with clopidogrel who are at moderate or high risk for CV events.

Common CVDs such as CAD, MI, and atrial fibrillation demonstrate a more complex model of genetic risk thus,genetic testing is not currently routinely indicated in these diseases.

Novel genomic technologies including epigenetics, copy number variation testing, and DNA resequencing will

hopefully help refine the genetic architecture of these common CVDs and facilitate creation of a robust risk

prediction model.


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2. Kao WH, Arking DE, Post W, et al. Genetic variations in nitric oxide synthase 1 adaptor protein are associated with

sudden cardiac death in US white community-based populations. Circulation 2009119:940-51.

3. Keane MG, Pyeritz RE. Medical management of Marfan syndrome. Circulation 2008117:2802-13.

4. Dietz HC. Marfan syndrome. In: Pagon RA, Bird TD, Dolan CR, Stephens K, eds. GeneReviews. Seattle: University

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5. Canadas V, Vilacosta I, Bruna I, Fuster V. Marfan syndrome. Part 1: pathophysiology and diagnosis. Nat Rev

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6. Hershberger RE, Siegfried JD. Update 2011: clinical and genetic issues in familial dilated cardiomyopathy. J Am

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7. Watkins H, Ashrafian H, Redwood C. Inherited cardiomyopathies. N Engl J Med 2011364:1643-56.

8. Maron BJ, Towbin JA, Thiene G, et al. Contemporary definitions and classification of the cardiomyopathies: an

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9. Maron MS, Olivotto I, Zenovich AG, et al. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular

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10. Ho CY. Genetics and clinical destiny: improving care in hypertrophic cardiomyopathy. Circulation 2010122:2430-

40.11. Kim L, Devereux RB, Basson CT. Impact of genetic insights into mendelian disease on cardiovascular clinical

practice. Circulation 2011123:544-50.

12. Maron BJ, Seidman JG, Seidman CE. Proposal for contemporary screening strategies in families with

hypertrophic cardiomyopathy. J Am Coll Cardiol 200444:2125-32.

13. Lehnart SE, Ackerman MJ, Benson DW Jr, et al. Inherited arrhythmias: a National Heart, Lung, and Blood Institute

and Office of Rare Diseases workshop consensus report about the diagnosis, phenotyping, molecular

mechanisms, and therapeutic approaches for primary cardiomyopathies of gene mutations affecting ion channel

function. Circulation 2007116:2325-45.

14. Goldenberg I, Zareba W, Moss AJ. Long QT Syndrome. Curr Probl Cardiol 200833:629-94.

15. Brugada R. Sudden death: managing the family, the role of genetics. Heart 201197:676-81.

16. Vincent GM. Romano-Ward syndrome. In: Pagon RA, Bird TD, Dolan CR, Stephens K, eds. GeneReviews. Seattle:

University of Washington, Seattle 1993.

17. Wilde AA, Brugada R. Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac

sodium channel. Circ Res 2011108:884-97.18. Tester DJ, Ackerman MJ. Genetic testing for potentially lethal, highly treatable inherited

cardiomyopathies/channelopathies in clinical practice. Circulation 2011123:1021-37.

19. Awad MM, Calkins H, Judge DP. Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular

dysplasia/cardiomyopathy. Nat Clin Pract Cardiovasc Med 20085:258-67.

20. Mahida S, Lubitz SA, Rienstra M, Milan DJ, Ellinor PT. Monogenic atrial fibrillation as pathophysiological

paradigms. Cardiovasc Res 201189:692-700.

21. Sinner MF, Ellinor PT, Meitinger T, Benjamin EJ, Kaab S. Genome-wide association studies of atrial fibrillation:

past, present, and future. Cardiovasc Res 201189:701-9.

22. Kujovich JL. Factor V Leiden Thrombophilia. In: Pagon RA, Bird TD, Dolan CR, Stephens K, eds. GeneReviews.

Seattle: University of Washington, Seattle 1993.

23. Patnaik MM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia 200814:1229-39.

24. Dahlback B. Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood 2008112:19-

27.25. Di Minno MN, Tremoli E, Coppola A, Lupoli R, Di Minno G. Homocysteine and arterial thrombosis: Challenge and

opportunity. Thromb Haemost 2010103:942-61.

26. Scheuner MT. Genetic evaluation for coronary artery disease. Genet Med 20035:269-85.

27. Humphries SE, Drenos F, Ken-Dror G, Talmud PJ. Coronary heart disease risk prediction in the era of genome-

wide association studies: current status and what the future holds. Circulation 2010121:2235-48.

28. Helgadottir A, Thorleifsson G, Manolescu A, et al. A common variant on chromosome 9p21 affects the risk of

myocardial infarction. Science 2007316:1491-3.

29. Wang L, McLeod HL, Weinshilboum RM. Genomics and drug response. N Engl J Med 2011364:1144-53.

30. Epstein RS, Moyer TP, Aubert RE, et al. Warfarin genotyping reduces hospitalization rates: results from the MM-

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31. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J

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33. Wallentin L, James S, Storey RF, et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on

outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the

PLATO trial. Lancet 2010376:1320-8.

34. Link E, Parish S, Armitage J, et al., on behalf of the SEARCH Collaborative Group. SLCO1B1 variants and statin-

induced myopathy--a genomewide study. N Engl J Med 2008359:789-99.

35. Ridker PM, Macfadyen JG, Glynn RJ, Chasman DI. Kinesin-like protein 6 (KIF6) polymorphism and the efficacy of

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36. Rosenberg S, Elashoff MR, Beineke P, et al. Multicenter validation of the diagnostic accuracy of a blood-basedgene expression test for assessing obstructive coronary artery disease in nondiabetic patients. Ann Intern Med

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1.

Which of the following is the most common genetic cause of VTE?

A. Protein S deficiency.

B. Prothrombin 20210A.

C. Factor V Leiden.

D. MTHFRgenetic variant.

2.

In which of the following CVDs is genetic testing often indicated?

A. CAD.

B. Familial DCM.

C. LQTS.

D. Atrial fibrillation.

3.

Which of the following is the most likely cardiac cause of exercise-induced syncope

in a 16-year-old patient?

A. Coronary artery anomaly.

B. LQTS.

C. Familial DCM.

D. HCM.

Chapter 2 Exam

Visit the online version of the product to see the correct answer and commentary.

Please visit the online version to engage in this Exam.

1. The correct answer is C. Factor V Leiden is responsible for up to 50% of cases of VTE,

making it the most common genetic cause of VTE. It is relatively common in Caucasian

populations, with a frequency of up to 6%.

Although protein S deficiency, which is caused by mutations in the protein S gene, does cause

VTE, this is not a common cause of disease (prevalence up to 0.1% in the general population

and up to 7.3% in patients with VTE). The prothrombin 20210A variant is a relatively common

variant in the population, with a prevalence of up to 18% in individuals with a thrombotic event or

with a family history of thrombosis it is the second most common genetic cause of VTE. A

relatively common variant in the MTHFRgene has been associated with arterial and venous

thrombosis however, data are conflicting and at best, it confers only modest risk of VTE.

2. The correct answer is C. Genetic testing will identify a known LQTS mutation in approximately


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75% of cases, and thus, can help with diagnosis (especially in individuals with "borderline"

corrected QT intervals) and can guide screening in at-risk family members.

While studies have uncovered hundreds of genetic variants as associated with CAD, there are no

genetic tests currently indicated for routine evaluation of patients with CAD. This may change in

the future as studies evaluate multiple genes as part of a "gene score" and more genetic variants

are uncovered through novel genetic technologies.

There are 33 known genes that have been implicated in familial DCM, but in total, they account

for only 30-35% of cases. The role of routine genetic testing in familial DCM is unclear given this

low yield and no change in clinical management based on genetic testing (although if a genetic

mutation is identified in a family, it can help with at-risk family members to help determine theirscreening regimen, i.e., if an at-risk family member does not carry the familial mutation, then

he/she does not need further longitudinal screening).

Atrial fibrillation is heritable in nature, and while there are some forms of Mendelian, monogenic

atrial fibrillation, most atrial fibrillation is characterized by a more complex genetic architecture,

and there is no current role for genetic testing of the genetic variants that have been identified.

3. The correct answer is D. HCM is a relatively common disorder (present in 1:500 people in

the general population), and is the most common cause of sudden death in young individuals.

The remainder of the answers can have exercise-induced syncope as a presenting symptom,

but are all less common in adolescents than HCM.

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