Download A Clinical Approach to Common Cardiovascular Disorders When

A Clinical Approach to Common Cardiovascular
Disorders When There Is a Family History
A Clinical Approach to a Family History of Sudden Death
Boon Yew Tan, MD; Daniel P. Judge, MD
S
Downloaded from http://circgenetics.ahajournals.org/ by guest on May 13, 2017
ir William Osler reportedly once said, “Varicose veins
are the result of an improper selection of grandparents.” Indeed, our family history strongly influences many
aspects of our cardiovascular system, with the magnitude
of effect ranging from very strong for autosomal dominant
genetic disorders to more subtle in the setting of complex multigenic diseases like coronary atherosclerosis and
hypertension. Accordingly, the standard evaluation of any
new patient who presents to a physician includes assessment of their family history. Unfortunately, the family
history may sometimes be discounted as noncontributory
without detailed review. This can be exacerbated by busy
office schedules with declining amounts of time available
for comprehensive evaluations. A few minutes saved might
seem to justify the lack of focus on an aspect of history
that is sometimes deemed not to be particularly useful.
However, a thorough assessment of family history also
may provide the key diagnostic information to determine
the cause of an illness, to determine who else is at risk of
disease within the family, to add useful prognostic information, and to help for family planning and reproductive
decisions.
A family history of sudden death should prompt consideration of a wide range of heritable cardiovascular conditions,
including many monogenic disorders (Table). However, the
terms used by the lay public to describe sudden death may not
adequately explain the cause of death on initial consideration.
For instance, the phrase “heart attack” may be used to describe
sudden death of any etiology. Further questioning may help
one to discern whether there was a history of heart failure,
cardiomyopathy, coronary artery disease (or its risk factors),
aortic aneurysm, or features of syndromic disorders that are
associated with sudden death.
medical history (Figure 1A). His mother is well at age 63
years of age. He has a younger brother and sister who are
well, and 2 children 5 and 7 years of age who are well. He
consumes approximately 4 alcoholic beverages weekly and
does not use tobacco.
This scenario is seen commonly in medical practice.
This 40-year-old man undoubtedly is considering strongly
his father’s sudden death at a similar age, but healthcare
providers do not always recognize the significance, the
range of potential contributing factors, and the latest technologies that are impacting the approach to improve the
diagnosis. His palpitations are nonspecific, and his paucity of other symptoms does not exclude coronary disease,
cardiomyopathy, inherited arrhythmic disease, or aortic
aneurysm. Although genetic analysis in a clearly affected
proband would be ideal, DNA is usually not available
from people who died in the remote past. As such, clues
to target the phenotypic assessment of subsequent generations may be obtained from a carefully obtained family
history.
From an extended discussion of his father’s sudden death,
it would be clear that he had heart failure prior to his sudden
death in the absence of coronary atherosclerosis risk factor
(Figure 1B). The proband’s paternal grandmother has unexplained dilated cardiomyopathy (DCM), and 3 of her 4 siblings also had unexplained DCM, 2 of whom died suddenly
at younger ages. This additional historical information helps
target the proband’s assessment now and serially for his risk
of inheriting the genetic predisposition for DCM that runs
in his family, and importantly it also helps to identify other
family members who are at risk of sudden cardiac death
(SCD) or DCM. In such a family, all offspring of an affected
individual carry a 50% chance of inheriting a genetic predisposition to DCM.
Typical Case
Adequate Family History
A 40-year-old man presents to a physician for evaluation
of palpitations. These occur briefly about once per month
without dizziness or lightheadedness, and he is otherwise
without symptoms. He exercises twice weekly, running
approximately 2 miles, and he is not limited by unexpected
dyspnea or chest discomfort. His past medical history is
negative. On discussion of his family history, he notes that
his father died suddenly at age 41 years without antecedent
When possible, one should obtain at least 3 generations of
antecedent family history. Several factors may complicate its
assessment. An autosomal dominant pattern of inheritance of
sudden death due to a monogenic disorder in a large family
cannot be recognized with only limited questioning. Agedependent phenotypes, small families, and the inability to
track down accurate antecedent family history can limit the
From the Johns Hopkins University, Division of Cardiology, Center for Inherited Heart Disease, Baltimore, MD (B.Y.T., D.P.J.); Department of
Cardiology, National Heart Centre, Singapore (B.Y.T.); and Université Paris Descartes, Sorbonne Paris Cité, Paris, France (D.P.J.).
Correspondence to Dr Daniel P. Judge, Center for Inherited Heart Disease, Johns Hopkins University, Ross 1049, 720 Rutland Avenue, Baltimore, MD
21205, E-mail [email protected].
(Circ Cardiovasc Genet. 2012;5:697-705.)
© 2012 American Heart Association, Inc.
Circ Cardiovasc Genet is available at http://circgenetics.ahajournals.org
697
DOI: 10.1161/CIRCGENETICS.110.959437
698 Circ Cardiovasc Genet December 2012
Table. Monogenic Disorders Associated With Sudden Death
Long QT syndrome
Noonan syndrome
Brugada syndrome
Fabry disease
Short QT syndrome
Danon disease
Timothy syndrome
Andersen-Tawil syndrome
Catecholaminergic polymorphic
VT
Dilated cardiomyopathy
Hypertrophic cardiomyopathy
Restrictive cardiomyopathy
Marfan syndrome
Loeys-Dietz syndrome
Ehlers Danlos syndrome (notably
type IV)
Nonsyndromic familial thoracic aortic
aneurysm
Limb-girdle muscular dystrophies
Dystrophin-related muscular
dystrophies
Noncompaction cardiomyopathy
Friedreich ataxia
Arrhythmogenic right ventricular
cardiomyopathy
Mitochondrial myopathies
Downloaded from http://circgenetics.ahajournals.org/ by guest on May 13, 2017
Naxos syndrome
Carvajal syndrome
Myofibrillar myopathies
Cavernous cranial malformations
VT indicates ventricular tachycardia.
proper recognition of Mendelian conditions. For instance, in
the case presented, if further questions led to the discovery of
a paternal sibling or cousin with aortic aneurysm or long QT
syndrome (LQTS) instead of DCM, one would have a much
different perspective regarding the cause of death of the proband’s father.
Other patterns of inheritance also should be considered.
Recessive disorders are harder to recognize from family history unless there is clear consanguinity. Although cultural
norms may lead to difficulty with discussions of consanguinity (defined as mating between second cousins or closer),
its worldwide prevalence has been estimated to be 10.4%
with prominent regional variation.1 One should also keep in
mind that consanguinity is certainly not required for a recessive disorder to occur. An X-linked form of inheritance can
be excluded if male-to-male transmission is observed, and
a mitochondrial pattern (due to mtDNA mutations) can be
excluded if any male transmission of the trait is found. Clues
that suggest a family history of chromosomal abnormality
include recurrent miscarriages, unexplained developmental
delay, or multiple congenital abnormalities.2 Ethnicity should
be assessed, as certain ethnicities carry increased risk of specific genetic forms of heart disease.
A family history of sudden death is a risk factor for sudden
death. This was first reported in the Paris Prospective study,
which followed 7079 men employed by the city of Paris 43
to 52 years of age for an average of 23 years.3 There were
2083 deaths, among which 603 were cardiovascular: 118 were
sudden deaths (19.6%), 192 were fatal myocardial infarctions
(31.8%), 31 deaths were attributed to heart failure (5.1%),
110 deaths were attributed to other cardiac causes (18.2%),
100 deaths were caused by strokes (16.6%), and 52 deaths
resulted from other vascular causes (8.6%). The relative risk
(RR) for sudden death of having 1 parent die from sudden
death was 1.89, and the RR of having 2 parental histories of
sudden deaths was 9.44 (P<0.01). In this prospective study, a
parental history of myocardial infarction was also a risk factor
for the occurrence of fatal myocardial infarction (RR, 2.09;
95% CI, 1.36–3.20).3
Sudden Cardiac Death Associated With
Coronary Atherosclerosis
In attempting to categorize the cause of antecedent sudden
death, it is important to consider the possibility of coronary
atherosclerosis and ischemic cardiomyopathy. A history of
chest pain, a confluence of coronary disease risk factors, or
a prior history of coronary disease and myocardial infarction readily help to assign sudden cardiac death to ischemic
arrhythmia in this setting. The age of the deceased should
be considered in this context. Although the majority of SCD
cases do not occur in individuals with a prior history of coronary disease or ischemic cardiomyopathy, the prevalence of
SCD among individuals with these conditions makes SCD
more likely for them.4
Several trials have investigated the genetic contribution
to SCD among individuals with coronary artery disease.
In a study cohort of people after ST-elevation myocardial
infarction (MI), Dekker et al5 demonstrated that a family
history of SCD occurred more frequently among primary
ventricular fibrillation (VF) survivors after their first MI as
compared with controls without VF who were matched for
age, gender, and infarct size (OR, 2.72, 95% CI, 1.84–4.03).
Figure 1. A A pedigree representing this
individual’s family members. Circles indicate females and squares indicate males.
The arrow identifies the proband in the text.
A diagonal line indicates family members
who are deceased. Circles or squares with
white filling are without known cardiac disease. Those with the left half in black have
experienced sudden death, and those with
the right half in black have known dilated
cardiomyopathy. B A more extended pedigree. Circles indicate females and squares
indicate males. The arrow identifies the
proband in the text. A diagonal line indicates family members who are deceased.
Circles or squares with white filling are
without known cardiac disease. Those with
the left half in black have experienced sudden death, and those with the right half in
black have known dilated cardiomyopathy.
Tan and Judge Family History of Sudden Death 699
Downloaded from http://circgenetics.ahajournals.org/ by guest on May 13, 2017
Similarly, Kaikkonen et al6 reported a higher incidence of
SCD among first degree relatives of SCD acute MI victims
compared with acute MI survivors (OR, 1.6, CI 95%, 1.2–
2.2, P<0.01).
These studies have led to further investigation for specific
genetic variants that confer SCD risk. A chromosomal locus
in close proximity to NOS1AP that is associated highly with
QT duration has been linked to SCD.7 More recently, genomewide analysis of 515 Dutch individuals with MI and VF compared with 457 controls with MI but without VF identified a
highly associated chromosomal locus in close proximity to
CXADR, encoding the human coxsackie virus and adenovirus receptor.8 Although SCD is often difficult to definitively
characterize, this investigation benefitted greatly by use of a
highly refined clinical phenotype. Recognition of the genetic
basis for the heritability of sudden death is the first step in the
complex but critical process of improving our understanding
of disease pathogenesis so that novel targeted therapies can be
designed and tested.
The utility of clinical genetic testing for these conditions
seems low at this point. Atherosclerosis is a complex genetic
disorder that is influenced strongly by environmental factors
and other heritable traits, such as hyperlipidemia, hypertension, and diabetes mellitus. The chromosomal locus 9p21 has
been very highly associated with coronary atherosclerosis and
acute myocardial infarction, but it is associated only with a
1.5 to 2.0 fold increase in relative risk of coronary disease.9,10
While a high-risk genotype for these 9p21 markers may help
with either preventative therapy or closer phenotypic evaluation, a low risk genotype does not exclude other genetic
or environmental contributors to atherosclerosis. The use of
NOS1AP or CXADR single nucleotide polymorphism analysis is only theoretical, as variations in the coding sequence or
expression of these genes have not yet been reported to associate with the noncoding single nucleotide polymorphisms in
their proximity that are linked to SCD risk.
Sudden Death From Cardiomyopathy
Dilated Cardiomyopathy
Dilation of the left ventricle with normal wall thickness along
with systolic dysfunction, with or without right ventricular involvement, is the hallmark of DCM. The prevalence in
adults has been reported to be 1 in 2500 individuals, with an
incidence of 7 per 100 000 per year.11 Familial dilated cardiomyopathy accounts for 20% to 48% of cases in studies that
used echocardiography to assess first degree relatives of an
individual with unexplained DCM.12–14
A family history of unexplained sudden death prior to the
age of 35 years is considered a criterion for familial DCM.15
Indeed, if an individual presents with unexplained DCM,
assessment of family members for the same condition is
a class I recommendation by American Heart Association
(AHA)/American College of Cardiology (ACC)/American
Society of Echocardiography guidelines.16 Within families who have a familial form of cardiomyopathy, the risk
of arrhythmia is influenced strongly by family history of
SCD.17,18 Current ACC/AHA/Heart Rhythm Society (HRS)
guidelines recommend implantable cardioverter-defibrillator
(ICD) therapy in nonischemic cardiomyopathy patients with
an ejection ­fraction (EF) ≤35% (New York Heart Association
class II or III) as a class I indication, provided a reversible
cause of left ventricular (LV) dysfunction has been excluded.19
However, some of the studies that were used to establish these
criteria excluded individuals with familial DCM associated
with a family history of SCD, with the expectation that ICD
already was justified on that basis.20 In such families, one need
not wait for the EF to be [ltequ]35% before recommending
an ICD.
Several syndromic disorders are associated with familial
DCM, and such details should be considered when assessing a family history that may involve 1 of these conditions.
The most common association with familial DCM is skeletal
myopathy or muscular dystrophy. A severe form of skeletal
myopathy, such as Duchenne muscular dystrophy where use
of a wheelchair in early teenage years is common, is typically much more obvious than many of the limb girdle muscular dystrophies. For X-linked disorders (such as Duchenne
and Becker), female carriers may only manifest with DCM,
sometimes obscuring the connection to the condition of their
affected male relatives.
Mitochondrial gene mutations can cause DCM.21,22
Mutations in mtDNA genes can present with isolated nonsyndromic cardiomyopathy, or may be associated with systemic
features, such as early hearing loss, visual problems, diabetes,
skeletal myopathy, lactic acidosis or elevated lactate-to-pyruvate ratio, or cognitive impairment.21,22 An mtDNA mutation
can be excluded as the sole cause of disease in a family if any
offspring of an affected male also are affected, because we
inherit our mtDNA from our mothers. Variability in severity or
phenotypic expression may depend on the percentage (heteroplasmy) of the mtDNA that carry a specific mutation.
Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is characterized by
unexplained left ventricular hypertrophy (LVH), a disorder
that occurs in 1 in 500 individuals on population screening.23
It is one of the most common causes of sudden death among
athletes.24 Histologically, there is myocyte disarray and myocardial replacement with scar. HCM typically is caused by a
mutation in 1 of the genes encoding an element of the cardiac
sarcomere, although nonsarcomere gene mutations also may
result in left ventricular hypertrophy.25 Prospective randomized trials designed to determine who should receive an ICD
for primary prevention of SCD have not been reported. The
standard criteria used to determine risk of arrhythmia include
substantial septal wall thickness, history of unexplained syncope, nonsustained ventricular tachycardia (VT), decline in
blood pressure with exercise, and family history of SCD.26
Additional criteria include delayed contrast enhancement on
cardiac magnetic resonance imaging, LV aneurysm, LV outflow tract gradient, and occasionally a specific gene mutation
from which arrhythmia risk can be inferred.27–30 For instance,
mutations in TNNT2 encoding cardiac troponin T are known
to carry increased risk of arrhythmia despite a relative paucity
of left ventricular hypertrophy.31
A few syndromic disorders can present with HCM, and
family history may help to recognize some of them.32 Fabry
700 Circ Cardiovasc Genet December 2012
Downloaded from http://circgenetics.ahajournals.org/ by guest on May 13, 2017
disease is an X-linked disorder of glycogen storage that often
involves renal dysfunction, corneal dystrophy, hypohidrosis,
and angiokeratomas of the skin.33 A cardiac variant also has
been reported.34 Female carriers often manifest disease.35
Danon disease is another X-linked syndromic disorder with
HCM.36 Affected males usually also have skeletal myopathy
and developmental delay or cognitive impairment and retinal impairment. Female carriers typically manifest disease,
though not as young as affected males.37 Noonan syndrome
is a heterogeneous disorder often associated with HCM,
together with short stature, characteristic facial appearance,
and pectus deformities of the chest.38 HCM does not occur
often with skeletal myopathy, and when both are present, several genes that could have mutations to explain this include
TTN, MYH7, FHL1, CAV3, or LAMP2. Barth syndrome is an
X-linked disorder in which affected males typically present
with childhood onset of cardiomyopathy, LVH, neutropenia,
muscle weakness, and delayed growth.39
Cardiac amyloidosis can mimic HCM. Although the most
common cause in the United States is related to monoclonal
light chain immunoglobulin overproduction, genetic forms of
cardiac amyloidosis also occur.40 In particular, TTR mutations
can cause syndromic features along with cardiac amyloidosis, including carpal tunnel syndrome, peripheral neuropathy,
autonomic insufficiency, and gastroenteritis.40 TTR amyloidosis has strong ethnic associations. For instance, 3% to 4%
of African-Americans carry a specific mutation, p.Val122Ile,
that is known to cause late-onset cardiac amyloidosis, and the
p.Val30Met mutation often is seen in Portugal and Japan.41,42
Arrhythmogenic Right Ventricular Dysplasia/
Cardiomyopathy
Arrhythmogenic right ventricular dysplasia/cardiomyopathy
(ARVD/C) is an inherited form of cardiomyopathy with an
estimated prevalence of 1 in 5000 individuals.43 The typical age of diagnosis is within the second and third decade of
life, though very early and very late diagnoses do occur.44,45
Tragically, the first manifestation is often SCD, with the diagnosis made on autopsy. In many affected patients, a preceding history of symptoms, including syncope, often occurs. It
is usually possible to discern a period when right ventricular
(RV) dilation and dysfunction is present prior to the onset of
symptoms. This has been described as the “concealed phase.”44
For reasons that are not clear, many people with this condition are highly trained athletes, particularly those who engage
in long-distance aerobic activities. Indeed, murine models of
ARVD/C can be induced to develop RV cardiomyopathy with
exercise.46
Arrhythmogenic right ventricular dysplasia/­cardiomyopathy
is a disease that often is caused by a mutation in genes encoding the desmosome proteins in the heart, resulting in electric
and mechanical uncoupling of cardiomyocytes.43 This leads to
cell death with fibro-fatty replacement, primarily affecting the
right ventricle but sometimes extending to the left ventricle.
A similar condition, termed arrhythmogenic left ventricular
cardiomyopathy (or simply arrhythmogenic cardiomyopathy), also has been reported.47 Focal ventricular scar becomes
a substrate for VT. In 1 study, up to one half of patients with
ARVD/C presented with malignant or potentially malignant
ventricular arrhythmia.44
A family history of sudden death occurring during athletic
activity suggests either ARVD/C or HCM, particularly if the
death occurs in the 2nd or 3rd decade of life. Although rare,
some people with ARVD/C also have skin or hair abnormalities. Naxos syndrome first was reported in 1986 as a curious
disorder on the Greek island of Naxos, in which affected
individuals had cardiomyopathy, palmoplantar keratoderma,
wooly hair, VT, and sudden death.48 Carvajal syndrome subsequently was reported with similar syndromic features involving both hair and skin, along with RV cardiomyopathy in the
setting of fibro-fatty scar in the heart.49
Other Forms of Familial Cardiomyopathy
Forms of cardiomyopathy typically are classified based on
the appearance of the heart, yet overlap certainly exists. For
instance, HCM can “burn out” with loss of systolic LV function and LV dilation. Noncompaction cardiomyopathy (also
known as LV hypertrabeculation) can mimic either HCM or
DCM. At least 1 form of ARVD/C is predominantly a left ventricular cardiomyopathy.50 These patients with overlapping
phenotypes, in particular, may not fit into the standard guidelines for receiving an ICD. This group of individuals would
benefit from assessment in a center with expertise in the management of inherited heart diseases.
Genetic Testing for Familial Cardiomyopathies
The use of genetic analysis for individuals with monogenic
forms of familial cardiomyopathy is far greater than with complex genetic disorders, such as coronary disease. It should be
considered to help determine the cause of a condition, to assess
for syndromic manifestations, to facilitate cascade screening
within the family (particularly in the context of sudden death),
and to assist with family planning.51 Such testing should be
restricted initially to a family member who is unequivocally
affected. If more than 1 is available, those with the youngest
age of onset typically are assessed with the most comprehensive panel of genetic testing, as compound heterozygosity and
digenic inheritance occur in about 5% of cases, and cascade
screening in the family may need to assess for more than 1
mutation or rare genetic variant. If a definite mutation is recognized, analysis in additional family members who are at
risk but without phenotypic features can be performed. One
cost-effectiveness analysis compared the use of serial echocardiographic assessment for family members who were at
risk of HCM with family screening that was guided by genetic
analysis.52 The use of genetic testing to guide investigation of
phenotypic manifestations within families was lower in cost
than serial screening alone without genetic testing in this
model.52 A recent report shows the high use of cascade family
member evaluations in the setting of sudden death associated
with ARVD/C.53 This same report also demonstrates certain
cases when the genetic test results can be ambiguous or uncertain. Published guidelines for the use of genetic testing in cardiomyopathy by 2 different expert committees are available,
and both emphasize the importance of referral to specialized
centers with genetic counseling.54,55
Tan and Judge Family History of Sudden Death 701
Downloaded from http://circgenetics.ahajournals.org/ by guest on May 13, 2017
Sudden Death From Aortic Dissection
Sudden Death From Ion Channel Disorders
Both syndromic and nonsyndromic forms of familial aortic
aneurysm should be considered in the differential diagnosis
for unexplained sudden death. The criteria used to assign
a diagnosis of Marfan syndrome are based on cardiovascular, skeletal, ophthalmologic, pulmonary, and integumentary systems, along with family history or genetic data.56
When considering an individual who had unexpected sudden death, historical questions should interrogate features
of disproportionate long bone overgrowth (arm span:height
ratio >1.05, arachnodactyly, dolichostenomelia, wrist, and
thumb signs) and pectus deformities of the chest.56 Pictures
may help to assess for facial characteristics of Marfan syndrome, such as dolichocephaly, malar hypoplasia, downslanting palpebral fissures, and retrognathia. With regard
to ophthalmologic manifestations of Marfan syndrome,
myopia is widely prevalent and nonspecific, but its presence along with ocular lens dislocation in the setting of
aortic aneurysm or sudden death strongly suggests Marfan
­syndrome.56 Other notable aspects of Marfan syndrome
include spontaneous pneumothorax, scoliosis, unexplained
dermal striae, pes planus (flat feet), and myxomatous mitral
valve prolapse.
A related disorder, known as Loeys-Dietz syndrome, more
recently was reported to have features similar to Marfan syndrome.57 It is associated with higher rates of death from aortic
dissection, often occurring at smaller aortic dimension.58 Its
hallmark features include arterial tortuosity and midline facial
abnormalities, such as hypertelorism (widely spaced eyes),
cleft palate, or bifid uvula. Marked arterial tortuosity can
be present among any medium or large arteries, sometimes
involving the cranial vessels.57 Additional characteristics of
Loeys-Dietz syndrome that may be present include easy bruising, thin skin, blue sclerae, and joint hypermobility. Mutations
in the genes encoding components of the TGFβ-receptor complex (TGFBR1 and TGFBR2) are responsible.57
Nonsyndromic aortic aneurysm is a more difficult disorder to recognize by historical questioning. By its very nature,
it typically is not associated with systemic manifestations,
though a subtle abnormality of the skin, livedo reticularis, has
been reported.59 Known genetic causes include mutations in
ACTA2 and MYH11 encoding smooth muscle actin and myosin, components of the smooth muscle sarcomere.59,60
The diagnosis of syndromic aortic diseases, such as
Marfan syndrome, typically is established by phenotypic
criteria. A proposed modification of the diagnostic criteria
recently was published to include FBN1 mutation analysis.61
Such testing within a family initially should be restricted
to an individual who is unequivocally affected. Cascade
screening of at-risk family members then can be performed
if a definite mutation is identified. Because many families
with Marfan syndrome have their own unique mutation, a
rare nonpathogenic DNA variant may be difficult to distinguish from a pathogenic mutation. When a DNA variant
of unknown significance (VUS) is identified, other definitively affected family members should be tested for this
variant, and its absence in an unequivocally affected family
member would exclude it as the sole cause of the condition
in the family.
There are several related disorders that fit into this category,
and this review will focus on 3 distinct phenotypes: long QT
syndrome, Brugada syndrome, and catecholaminergic polymorphic VT. The general concepts that are outlined for these
conditions also apply to related phenotypes such as short
QT syndrome, J-wave syndrome, idiopathic VT, and early
repolarization syndrome, all of which share similar pathogenesis involving abnormalities in ion channel genes with
a paucity of structural heart disease. Similarities and differences among these specific disorders are well described
elsewhere.62
Long QT Syndrome
Long QT syndrome is a genetically heterogeneous disorder
with a reported prevalence of 1 in 2500 people.63 While a
diagnosis of LQTS is apparent in an individual with persistent
severe prolongation of the corrected QT (QTc) interval (> 500
ms), its diagnosis can be challenging in borderline cases. This
in part is due to, (1) the overlap in the QTc duration between
LQTS patients and unaffected individuals, (2) individual variability in QTc length for people with this condition, and (3)
miscalculation of QTc. The Bazett formula, for example, consistently underestimates the QTc in low heart rates, and overestimates it in high heart rates. The QT interval also may be
measured erroneously in the presence of U waves or complex
T waves.64
Unexplained drowning or sudden death while swimming
should suggest either LQTS or catecholaminergic polymorphic ventricular tachycardia (CPVT).65 A history of seizures
or recurrent syncope in the absence of structural heart disease
should suggest the possibility of LQTS. One study reported
a presumed diagnosis of seizures among approximately one
third of patients with LQTS.66 While arrhythmic syncope
sometimes is attributed erroneously to seizures, attempts
to link the 2 phenotypes of LQTS and seizures has led to
a recent report of brain expression of KCNQ1 and KCNE1,
2 genes in which mutations are known to cause LQTS.67
In addition, mice carrying knock-in missense mutations in
Kcnq1 developed QTc prolongation and both partial and generalized seizures.67
Rare syndromic conditions may occur with LQTS. Jervell
and Lange-Nielsen syndrome is a recessive disorder characterized by congenital deafness, QT prolongation, and recurrent syncope with SCD caused by mutations in KCNQ1.68
Andersen-Tawil syndrome is a multisystemic autosomal
dominant disorder with variable penetrance.69 Features that
suggest Andersen-Tawil include QT prolongation with potassium-sensitive periodic paralysis, short stature, clinodactyly,
and characteristic facial features, including a broad forehead,
malar hypoplasia, low set ears, and hypertelorism.70 Timothy
syndrome is a multisystemic disorder caused by dominant
de novo mutations in CACNA1C.71 Affected individuals have
congenital prolongation of the QT interval along with webbing
of fingers and toes, autism, developmental delay, intermittent
hypoglycemia, abnormal teeth, and immune deficiency.71
Some affected individuals also have congenital cardiac malformations, such as patent ductus arteriosus, patent foramen
ovale, and ventricular septal defects.71
702 Circ Cardiovasc Genet December 2012
Downloaded from http://circgenetics.ahajournals.org/ by guest on May 13, 2017
Brugada Syndrome
Brugada syndrome (BrS) is a genetically heterogeneous
disorder with a reported prevalence of 0.5% to 0.7% and
male preponderance.72,73 It is thought to account for up to
4% of all SCD and up to 20% of SCD in structurally normal
hearts.74 The ECG manifestations of ST elevation in BrS
can occur spontaneously, or in the presence of a sodiumchannel blocker. More detailed electrophysiological manifestations and patterns of ST elevation in BrS have been
reviewed elsewhere.75 The ACC/AHA/HRS 2008 guidelines
have designated ICD implantation as a class IIa indication
(level of evidence C) for BrS patients who present with syncope, or have documented VT that has not resulted in cardiac arrest.19
The differential diagnosis for a BrS-like pattern of ST elevation on ECG includes acute myocardial infarction, electrolyte
abnormalities, myopericarditis, and ARVD/C. In the absence
of diagnostic ECG findings, suspicion for BrS should arise in
the setting of unexplained SCD without structural heart disease. It is not associated with syndromic or systemic manifestations. Asian ethnicity may indicate a higher likelihood
of BrS, as several reports have indicated higher prevalence of
this condition or “sudden unexplained nocturnal death syndrome” among different Asian groups.76–78 One important
factor contributing to BrS among Asians was reported by
Bezzina and colleagues.78 They identified a haplotype within
the SCN5A promoter that results in lower gene expression. It
was present with an allele frequency of 22% among Japanese
individuals in 2 cohorts and was absent among individuals of
Caucasian or black African ancestry.78 This corresponds to 5%
of this population with homozygosity for this haplotype and
approximately 35% having 1 copy, assuming normal HardyWeinberg equilibrium. The presence of this SCN5A promoter
haplotype also influenced the response to sodium channel
blocking drugs, but its presence alone was not sufficient to
result in BrS.78
Catecholaminergic Polymorphic Ventricular Tachycardia
Catecholaminergic polymorphic ventricular tachycardia is a
rare disorder of stress-related bidirectional VT in the absence
of structural heart disease or resting ECG abnormalities.
Autosomal dominant CPVT is caused by heterozygous mutation of the cardiac ryanodine receptor gene, and an autosomal
recessive form is caused by mutations in CASQ2, encoding
the calsequestrin-2 gene.79,80 The typical age of onset for both
forms is childhood or adolescence. Syncope in the setting of
exercise or emotional stress is common among affected individuals.81 One study reported a family history of unexplained
SCD ≤40 years of age among 33% of affected individuals.81
Noncardiac or systemic manifestations are not known to occur
with CPVT.
Sudden Infant Death Syndrome
Sudden infant death syndrome (SIDS) is the sudden death of
an infant <1 year of age that remains unexplained after thorough investigation. Its cause remains unknown, and there are
probably many different disorders that present with this same
end result. Its incidence is declining, and it now occurs in
about 0.5 per 1000 live births in the United States. Although
rare, it is the leading cause of death among infants age 1 to 12
months, and it is the third-leading cause overall of infant mortality in the United States (http://www.cdc.gov/sids). Research
into the genetic basis of SIDS has focused on genes in which
mutations cause LQTS or CPVT.82 Currently, it is estimated
that ≈10% of cases of SIDS are caused by mutations in these
genes, whereas sudden unexplained death in those >1 year of
age is estimated to be caused by a LQTS or CPVT gene mutation in 25% to 30% of cases.82
Postmortem Genetic Investigation
At the time of the decedent’s death, an autopsy may represent the best and last opportunity to make a proper diagnosis.83 To facilitate genetic investigation within families,
the use of molecular techniques has been recommended in
recent guidelines for autopsy investigation of sudden death
by the Association for European Cardiovascular Pathology.84
Unclotted blood may be obtained from the heart, or frozen tissue may be used. The isolation of DNA from formalin-fixed,
paraffin-embedded tissue is generally poor because DNA
becomes fragmented in this process, though one report shows
promise along these lines.85 Although a broad range of testing using large gene panels may not be possible from fixed
tissue, small amounts of fragmented DNA may be perfectly
acceptable for testing for a known mutation that is recognized
in another family member, or perhaps more importantly, for
investigating cosegregation of a novel DNA sequence VUS.
Another practical consideration for postmortem genetic testing is that medical insurance is unlikely to pay for the decedent’s subsequent genetic characterization. Guidelines for the
use of genetic testing for monogenic arrhythmias and postmortem testing for sudden cardiac death recently have been
published.54
DNA Banking
Despite extensive efforts, the cause of death sometimes may
not be discernible. Genetic testing may or may not be feasible
at that point. Long-term storage of DNA, either premortem
or postmortem, is a low-cost method of facilitating the availability of DNA for future generations to access and use. This
can be particularly helpful if a VUS is recognized in another
family member with a familial form of cardiovascular disease.
Targeted testing for this VUS in a deceased family member
whose phenotypic characterization found the same features can
allow determination of cosegregation of the VUS and disease
in the family. In instances where sudden death of unknown
cause occurs and genetic testing for ion channel disorders is
negative, remaining DNA can be transferred from a Clinical
Laboratory Improvement Amendments (CLIA)-certified testing laboratory to a long-term DNA storage facility for future
use. As the molecular genetic characterization of the numerous
monogenic cardiovascular diseases improves, access to DNA
from deceased affected family members may be very helpful.
Next-Generation DNA Sequencing
Improvements in technology have led to lower cost and higher
throughput for DNA sequence analysis. The determination
of DNA sequence on radiolabeled polyacrylamide gels was
Tan and Judge Family History of Sudden Death 703
Downloaded from http://circgenetics.ahajournals.org/ by guest on May 13, 2017
laborious, costly, and slow. It was readily replaced by dideoxy
(Sanger) sequencing, which may now be considered the gold
standard. However, “next-generation sequencing” methods,
such as pyrosequencing, sequencing by oligonucleotide ligation and detection, and true single molecule sequencing use
massively parallel short sequence reads to efficiently assess
enormous regions of DNA at relatively very low cost.86 For
instance, the complete sequencing of the first human genome
was estimated to cost $100 000 000 to $300 000 000 using
dideoxysequencing.87,88 Later reports of whole human genome
sequencing were estimated at $500 000, followed by $50 000
just a few years later.89–91 Naturally, this technology has been
applied to clinical genetic testing with the inevitable development of larger panels of genes in which mutations can cause
monogenic cardiovascular diseases. Such panels can contain
>50 such genes covering enormous portions of the genome, or
one may sequence the entire “exome.”92 The challenge inherent in these approaches is to catalogue the many rare missense alleles that will be identified with unclear association
to the disorder under investigation, and with subsequent need
to determine their significance. The feasibility of appropriate
handling of such large quantities of DNA sequence recently
has been demonstrated, yet it remains tedious and difficult for
most researchers, and it is beyond the scope of clinical practice at this point.93
Conclusion
A family history of sudden death is a well-recognized risk
factor for sudden death in many different cardiovascular conditions. A thorough family history should be obtained, with
emphasis on features that could suggest an underlying disorder causing the sudden death, including coronary artery
disease, cardiomyopathy, an inherited arrhythmia syndrome,
or aortic disease. The pattern of inheritance within a family
helps to determine others who are at risk for the condition.
Improvements in DNA sequence analysis are leading to lower
costs for genetic testing, and efforts to obtain or bank DNA for
future use should help to determine genetic contributions to
sudden death, with an ultimate goal of preventing subsequent
sudden deaths within a family.
None.
Disclosures
References
1. Bittles AH, Black ML. The impact of consanguinity on neonatal and infant health. Early Hum Dev. 2010;86:737–741.
2. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter
NP, et al. Consensus statement: chromosomal microarray is a first-tier
clinical diagnostic test for individuals with developmental disabilities or
congenital anomalies. Am J Hum Genet. 2010;86:749–764.
3.Jouven X, Desnos M, Guerot C, Ducimetiere P. Predicting sudden
death in the population: the Paris Prospective Study I. Circulation.
1999;99:1978–1983.
4.Myerburg RJ, Kessler KM, Castellanos A. Sudden cardiac death.
Structure, function, and time-dependence of risk. Circulation.
1992;85:I2-10.
5. Dekker LR, Bezzina CR, Henriques JP, Tanck MW, Koch KT, Alings MW,
et al. Familial sudden death is an important risk factor for primary ventricular fibrillation: a case-control study in acute myocardial infarction
patients. Circulation. 2006;114:1140–1145.
6. Kaikkonen KS, Kortelainen ML, Linna E, Huikuri HV. Family history and
the risk of sudden cardiac death as a manifestation of an acute coronary
event. Circulation. 2006;114:1462–1467.
7. Kao WH, Arking DE, Post W, Rea TD, Sotoodehnia N, Prineas RJ, et al.
Genetic variations in nitric oxide synthase 1 adaptor protein are associated
with sudden cardiac death in US white community-based populations.
Circulation. 2009;119:940–951.
8. Bezzina CR, Pazoki R, Bardai A, Marsman RF, de Jong JS, Blom MT,
et al. Genome-wide association study identifies a susceptibility locus
at 21q21 for ventricular fibrillation in acute myocardial infarction. Nat
Genet. 2010;42:688–691.
9.Helgadottir A, Thorleifsson G, Magnusson KP, Gretarsdottir S,
Steinthorsdottir V, Manolescu A, et al. The same sequence variant on 9p21
associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet. 2008;40:217–224.
10. Helgadottir A, Thorleifsson G, Manolescu A, Gretarsdottir S, Blondal T,
Jonasdottir A, et al. A common variant on chromosome 9p21 affects the
risk of myocardial infarction. Science. 2007;316:1491–1493.
11.Codd MB, Sugrue DD, Gersh BJ, Melton LJ III. Epidemiology of
­idiopathic dilated and hypertrophic cardiomyopathy. A population-based
study in Olmsted County, Minnesota, 1975–1984. Circulation. 1989;80:
564–572.
12. Michels VV, Moll PP, Miller FA, Tajik AJ, Chu JS, Driscoll DJ, et al. The
frequency of familial dilated cardiomyopathy in a series of patients with
idiopathic dilated cardiomyopathy. N Engl J Med. 1992;326:77-82.
13.Grunig E, Tasman JA, Kucherer H, Franz W, Kubler W, Katus HA.
Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll
Cardiol. 1998;31:186–194.
14. Baig MK, Goldman JH, Caforio AL, Coonar AS, Keeling PJ, McKenna
WJ. Familial dilated cardiomyopathy: cardiac abnormalities are common
in asymptomatic relatives and may represent early disease. J Am Coll
Cardiol. 1998;31:195–201.
15. Mestroni L, Maisch B, McKenna WJ, Schwartz K, Charron P, Rocco
C, et al. Guidelines for the study of familial dilated cardiomyopathies.
Collaborative Research Group of the European Human and Capital
Mobility Project on familial dilated cardiomyopathy. Eur Heart J.
1999;20:93-102.
16. Cheitlin MD, Armstrong WF, Aurigemma GP, Beller GA, Bierman FZ,
Davis JL, et al. ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography: summary article: a report of the
American College of Cardiology/American Heart Association Task Force
on Practice Guidelines. Circulation. 2003;108:1146–1162.
17.Becane HM, Bonne G, Varnous S, Muchir A, Ortega V, Hammouda
EH, et al. High incidence of sudden death with conduction system and
myocardial disease due to lamins A and C gene mutation. Pacing Clin
Electrophysiol. 2000;23:1661–1666.
18. van Tintelen JP, Van Gelder IC, Asimaki A, Suurmeijer AJ, Wiesfeld AC,
Jongbloed JD, et al. Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missense mutation in
the DES gene. Heart Rhythm. 2009;6:1574–1583.
19. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NAM III, Freedman
RA, Gettes LS, et al. ACC/AHA/HRS 2008 Guidelines for device-based therapy of cardiac rhythm abnormalities. Circulation.
2008;117:e350–e408.
20. Kadish A, Dyer A, Daubert JP, Quigg R, Estes NA, Anderson KP, et al.
Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med. 2004;350:2151–2158.
21. Grasso M, Diegoli M, Brega A, Campana C, Tavazzi L, Arbustini E. The
mitochondrial DNA mutation T12297C affects a highly conserved nucleotide of tRNA(Leu(CUN)) and is associated with dilated cardiomyopathy.
Eur J Hum Genet. 2001;9:311–315.
22. Wallace DC. Mitochondrial defects in cardiomyopathy and neuromuscular disease. Am Heart J. 2000;139:S70-85.
23. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE.
Prevalence of hypertrophic cardiomyopathy in a general population
of young adults: echocardiographic analysis of 4111 Subjects in the
CARDIA study. Circulation. 1995;92:785–789.
24.Maron BJ. Sudden death in young athletes. N Engl J Med.
2003;349:1064–1075.
25. Morita H, Seidman J, Seidman CE. Genetic causes of human heart failure.
J Clin Invest. 2005;115:518–526.
26. Maron BJ, Spirito P, Shen WK, Haas TS, Formisano F, Link MS, et al.
Implantable cardioverter-defibrillators and prevention of sudden cardiac
death in hypertrophic cardiomyopathy. JAMA. 2007;298:405–412.
704 Circ Cardiovasc Genet December 2012
Downloaded from http://circgenetics.ahajournals.org/ by guest on May 13, 2017
27. Maron MS, Finley JJ, Bos JM, Hauser TH, Manning WJ, Haas TS, et
al. Prevalence, clinical significance, and natural history of left ventricular apical aneurysms in hypertrophic cardiomyopathy. Circulation.
2008;118:1541–1549.
28. Elliott PM, Gimeno JR, Tome MT, Shah J, Ward D, Thaman R, et al. Left
ventricular outflow tract obstruction and sudden death risk in patients with
hypertrophic cardiomyopathy. Eur Heart J. 2006;27:1933–1941.
29. Adabag AS, Maron BJ, Appelbaum E, Harrigan CJ, Buros JL, Gibson
CM, et al. Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy in relation to delayed enhancement on cardiovascular magnetic resonance. J Am Coll Cardiol. 2008;51:1369–1374.
30.Judge DP, Rouf R. Use of genetics in the clinical evaluation and
management of heart failure. Curr Treat Options Cardiovasc Med.
2010;12:566–577.
31. Baudenbacher F, Schober T, Pinto JR, Sidorov VY, Hilliard F, Solaro RJ,
et al. Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice. J Clin Invest. 2008;118:3893–3903.
32. Arad M, Maron BJ, Gorham JM, Johnson WH Jr., Saul JP, Perez-Atayde
AR, et al. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med. 2005;352:362–372.
33. Desnick RJ, Brady R, Barranger J, Collins AJ, Germain DP, Goldman M,
et al. Fabry disease, an under-recognized multisystemic disorder: expert
recommendations for diagnosis, management, and enzyme replacement
therapy. Ann Intern Med. 2003;138:338–346.
34. Hagege A. Cardiac manifestations of Anderson-Fabry disease and efficacy
of enzyme replacement therapy. Rev Med Interne. 2010;31:S238–242.
35. Chimenti C, Pieroni M, Morgante E, Antuzzi D, Russo A, Russo MA, et
al. Prevalence of Fabry disease in female patients with late-onset hypertrophic cardiomyopathy. Circulation. 2004;110:1047–1053.
36. Nishino I, Fu J, Tanji K, Yamada T, Shimojo S, Koori T, et al. Primary
LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature. 2000;406:906–910.
37. Boucek D, Jirikowic J, Taylor M. Natural history of Danon disease. Genet
Med. 2011;13:563–568.
38. Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME,
et al. Noonan syndrome: clinical features, diagnosis, and management
guidelines. Pediatrics. 2010;126:746–759.
39. Johnston J, Kelley RI, Feigenbaum A, Cox GF, Iyer GS, Funanage VL,
et al. Mutation characterization and genotype-phenotype correlation in
Barth syndrome. Am J Hum Genet. 1997;61:1053–1058.
40.Falk RH. Diagnosis and management of the cardiac amyloidoses.
Circulation. 2005;112:2047–2060.
41. Jacobson DR, Pastore RD, Yaghoubian R, Kane I, Gallo G, Buck FS, et
al. Variant-sequence transthyretin (Isoleucine 122) in late-onset cardiac
amyloidosis in black Americans. N Engl J Med. 1997;336:466–473.
42. Saraiva MJ. Transthyretin mutations in health and disease. Hum Mutat.
1995;5:191–196.
43. Awad MM, Calkins H, Judge DP. Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Nat
Clin Pract Cardiovasc Med. 2008;5:258–267.
44.Dalal D, Nasir K, Bomma C, Prakasa K, Tandri H, Piccini J, et al.
Arrhythmogenic right ventricular dysplasia: a United States experience.
Circulation. 2005;112:3823–3832.
45. Tan BY, Jain R, den Haan AD, Chen Y, Dalal D, Tandri H, et al. Shared
desmosome gene findings in early and late onset arrhythmogenic
right ventricular dysplasia/cardiomyopathy. J Cardiovasc Transl Res.
2010;3:663–673.
46. Kirchhof P, Fabritz L, Zwiener M, Witt H, Schafers M, Zellerhoff S, et
al. Age- and training-dependent development of arrhythmogenic right
ventricular cardiomyopathy in heterozygous plakoglobin-deficient mice.
Circulation. 2006;114:1799–1806.
47. Norman M, Simpson M, Mogensen J, Shaw A, Hughes S, Syrris P, et
al. Novel mutation in desmoplakin causes arrhythmogenic left ventricular
cardiomyopathy. Circulation. 2005;112:636–642.
48. Protonotarios N, Tsatsopoulou A, Patsourakos P, Alexopoulos D, Gezerlis
P, Simitsis S, et al. Cardiac abnormalities in familial palmoplantar keratosis. Br Heart J. 1986;56:321–326.
49. Carvajal-Huerta L. Epidermolytic palmoplantar keratoderma with woolly
hair and dilated cardiomyopathy. J Am Acad Dermatol. 1998;39:418–421.
50.Merner ND, Hodgkinson KA, Haywood AF, Connors S, French VM,
Drenckhahn JD, et al. Arrhythmogenic right ventricular cardiomyopathy
type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense
mutation in the TMEM43 gene. Am J Hum Genet. 2008;82:809–821.
51. Judge DP. Use of genetics in the clinical evaluation of cardiomyopathy.
JAMA. 2009;302:2471–2476.
52. Wordsworth S, Leal J, Blair E, Legood R, Thomson K, Seller A, et al.
DNA testing for hypertrophic cardiomyopathy: a cost-effectiveness model. Eur Heart J. 2010;31:926–935.
53. Quarta G, Muir A, Pantazis A, Syrris P, Gehmlich K, Garcia-Pavia P, et
al. Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria. Circulation.
2011;123:2701–2709.
54. Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H,
et al. HRS/EHRS expert consensus statement on the state of genetic
testing for the channelopathies and cardiomyopathies. Heart Rhythm.
2011;8:1308–1339.
55. Hershberger RE, Lindenfeld J, Mestroni L, Seidman CE, Taylor MRG,
Towbin JA. Genetic evaluation of cardiomyopathy—a heart failure society of America practice guideline. J Card Fail. 2009;15:83-97.
56. Judge DP, Dietz HC. Marfan’s syndrome. Lancet. 2005;366:1965–1976.
57. Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, et al.
A syndrome of altered cardiovascular, craniofacial, neurocognitive and
skeletal development caused by mutations in TGFBR1 or TGFBR2.
Nat Genet. 2005;37:275–281.
58. Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, et
al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N
Engl J Med. 2006;355:788–798.
59. Guo DC, Pannu H, Tran-Fadulu V, Papke CL, Yu RK, Avidan N, et al.
Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic
aneurysms and dissections. Nat Genet. 2007;39:1488–1493.
60. Zhu L, Vranckx R, Khau Van Kien P, Lalande A, Boisset N, Mathieu F,
et al. Mutations in myosin heavy chain 11 cause a syndrome associating
thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus.
Nat Genet. 2006;38:343–349.
61.Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J,
Devereux RB, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47:476–485.
62. Wilde AA, Ackerman MJ. Exercise extreme caution when calling rare genetic variants novel arrhythmia syndrome susceptibility mutations. Heart
Rhythm. 2010;7:1883–1885.
63.Ackerman MJ. Cardiac channelopathies: it’s in the genes. Nat Med.
2004;10:463–464.
64. Johnson JN, Ackerman MJ. QTc: how long is too long? Br J Sports Med.
2009;43:657–662.
65.Choi G, Kopplin LJ, Tester DJ, Will ML, Haglund CM, Ackerman
MJ. Spectrum and frequency of cardiac channel defects in swimming-­
triggered arrhythmia syndromes. Circulation. 2004;110:2119–2124.
66. Johnson JN, Hofman N, Haglund CM, Cascino GD, Wilde AA, Ackerman
MJ. Identification of a possible pathogenic link between congenital long
QT syndrome and epilepsy. Neurology. 2009;72:224–231.
67. Goldman AM, Glasscock E, Yoo J, Chen TT, Klassen TL, Noebels JL.
Arrhythmia in heart and brain: KCNQ1 mutations link epilepsy and sudden unexplained death. Sci Transl Med. 2009;1:2ra6.
68. Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J.
1957;54:59-68.
69. Tawil R, Ptacek LJ, Pavlakis SG, DeVivo DC, Penn AS, Ozdemir C, et al.
Andersen’s syndrome: potassium-sensitive periodic paralysis, ventricular
ectopy, and dysmorphic features. Ann Neurol. 1994;35:326–330.
70.Tristani-Firouzi M, Jensen JL, Donaldson MR, Sansone V, Meola G,
Hahn A, et al. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest.
2002;110:381–388.
71. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, et
al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder
including arrhythmia and autism. Cell. 2004;119:19-31.
72. Brugada P, Brugada J. Right bundle branch block, persistent ST segment
elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. J Am Coll Cardiol. 1992;20:1391–1396.
73. Miyasaka Y, Tsuji H, Yamada K, Tokunaga S, Saito D, Imuro Y, et al.
Prevalence and mortality of the Brugada-type electrocardiogram in one
city in Japan. J Am Coll Cardiol. 2001;38:771–774.
74. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado
D, et al. Brugada syndrome: report of the second consensus conference.
Heart Rhythm. 2005;2:429–440.
75. Fowler SJ, Priori SG. Clinical spectrum of patients with a Brugada ECG.
Curr Opin Cardiol. 2009;24:74-81.
76. Sidik NP, Quay CN, Loh FC, Chen LY. Prevalence of Brugada sign and
syndrome in patients presenting with arrhythmic symptoms at a heart
rhythm clinic in Singapore. Europace. 2009;11:650–656.
Tan and Judge Family History of Sudden Death 705
Downloaded from http://circgenetics.ahajournals.org/ by guest on May 13, 2017
77.Kirschner RH, Eckner FA, Baron RC. The cardiac pathology of sudden, unexplained nocturnal death in Southeast Asian refugees. Jama.
1986;256:2700–2705.
78. Bezzina CR, Shimizu W, Yang P, Koopmann TT, Tanck MW, Miyamoto Y,
et al. Common sodium channel promoter haplotype in Asian subjects underlies variability in cardiac conduction. Circulation. 2006;113:338–344.
79. Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, et al. Mutations
in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic
polymorphic ventricular tachycardia. Circulation. 2001;103:196–200.
80. Lahat H, Pras E, Olender T, Avidan N, Ben-Asher E, Man O, et al. A
missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel. Am J Hum Genet.
2001;69:1378–1384.
81. Priori SG, Napolitano C, Memmi M, Colombi B, Drago F, Gasparini M, et
al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation. 2002;106:69-74.
82. Ackerman MJ. State of postmortem genetic testing known as the cardiac channel molecular autopsy in the forensic evaluation of unexplained sudden cardiac death in the young. Pacing Clin Electrophysiol.
2009;32:S86-89.
83. Basso C, Carturan E, Pilichou K, Rizzo S, Corrado D, Thiene G. Sudden
cardiac death with normal heart: molecular autopsy. Cardiovasc Pathol.
2010;19:321–325.
84. Basso C, Burke M, Fornes P, Gallagher PJ, de Gouveia RH, Sheppard
M, et al. Guidelines for autopsy investigation of sudden cardiac death.
Virchows Arch. 2008;452:11-18.
85.Carturan E, Tester DJ, Brost BC, Basso C, Thiene G, Ackerman MJ.
Postmortem genetic testing for conventional autopsy-negative sudden
unexplained death: an evaluation of different DNA extraction protocols
and the feasibility of mutational analysis from archival paraffin-embedded
heart tissue. Am J Clin Pathol. 2008;129:391–397.
86.Nagarajan N, Pop M. Sequencing and genome assembly using nextgeneration technologies. Methods Mol Biol. 2010;673:1-17.
87. Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, et al.
The sequence of the human genome. Science. 2001;291:1304–1351.
88.Bentley DR, Balasubramanian S, Swerdlow HP, Smith GP, Milton J,
Brown CG, et al. Accurate whole human genome sequencing using reversible terminator chemistry. Nature. 2008;456:53-59.
89. Wang J, Wang W, Li R, Li Y, Tian G, Goodman L, et al. The diploid
genome sequence of an Asian individual. Nature. 2008;456:60-65.
90. Wheeler DA, Srinivasan M, Egholm M, Shen Y, Chen L, McGuire A,
et al. The complete genome of an individual by massively parallel DNA
sequencing. Nature. 2008;452:872–876.
91.Lupski JR, Reid JG, Gonzaga-Jauregui C, Rio Deiros D, Chen DCY,
Nazareth L, et al. Whole-genome sequencing in a patient with CharcotMarie-Tooth neuropathy. N Engl J Med. 2010;362:1181–1191.
92.Biesecker LG. Exome sequencing makes medical genomics a reality.
Nat Genet. 2010;42:13-14.
93.Ashley EA, Butte AJ, Wheeler MT, Chen R, Klein TE, Dewey FE,
et al. Clinical assessment incorporating a personal genome. Lancet.
2010;375:1525–1535.
KEY WORDS: aorta ◼ arrhythmia ◼ cardiomyopathy ◼ death ◼ sudden ◼ genetics
A Clinical Approach to a Family History of Sudden Death
Boon Yew Tan and Daniel P. Judge
Downloaded from http://circgenetics.ahajournals.org/ by guest on May 13, 2017
Circ Cardiovasc Genet. 2012;5:697-705
doi: 10.1161/CIRCGENETICS.110.959437
Circulation: Cardiovascular Genetics is published by the American Heart Association, 7272 Greenville Avenue,
Dallas, TX 75231
Copyright © 2012 American Heart Association, Inc. All rights reserved.
Print ISSN: 1942-325X. Online ISSN: 1942-3268
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circgenetics.ahajournals.org/content/5/6/697
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation: Cardiovascular Genetics can be obtained via RightsLink, a service of the Copyright Clearance
Center, not the Editorial Office. Once the online version of the published article for which permission is being
requested is located, click Request Permissions in the middle column of the Web page under Services. Further
information about this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation: Cardiovascular Genetics is online at:
http://circgenetics.ahajournals.org//subscriptions/