Over the last several years, substantial progress has
been achieved in defining the molecular basis for several genetically
transmitted, nonatherosclerotic cardiovascular
diseases.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 These advances in molecular
biology have enhanced our understanding of the primary defects and
basic mechanisms responsible for the pathogenesis of these conditions
and their phenotypic expression, and in the process, new perspectives
on cardiac diagnosis have been formulated. In the course of this
scientific evolution, a certain measure of uncertainty has also arisen
regarding the implications of genetic analysis for clinical
diagnostic criteria.
New subgroups of genetically affected individuals without conventional
clinical diagnostic findings have been identified solely by
virtue of access to molecular laboratory techniques, creating a number
of medical and ethical concerns regarding the possible clinical
implications. Indeed, the extent to which such individuals should
receive sequential evaluations and/or therapy or be subjected to
employment or insurance discrimination, psychological harm, loss of
privacy, or unnecessary withdrawal from competitive athletics is
uncertain but remains a legitimate source of
concern.68 69 70 71
It is therefore particularly timely and appropriate to analyze
these issues in detail, specifically the extent to which molecular
biology has revised traditional diagnostic criteria. The
role of genetic testing in assessing prognosis and identifying
high-risk subgroups or in defining basic disease mechanisms and
pathophysiology is, however, largely beyond the scope of this
scientific statement. As models for the present critique, we
selected the 3 most common familial cardiovascular
diseases for which gene defects have been identified, each of which is
associated with autosomal dominant inheritance and a risk for sudden
cardiac death: hypertrophic cardiomyopathy (HCM),
long-QT syndrome (LQTS), and Marfan syndrome (MFS).
Hypertrophic Cardiomyopathy
Clinical Diagnosis (Phenotype)
Since the modern anatomic description of HCM by Teare in
1958,72 left ventricular
hypertrophy traditionally has been regarded as the gross
anatomic marker and the likely determinant of many of the clinical
features and consequences observed in most patients with this
disease.83 95 96 Because the left
ventricular cavity is usually small or normal in size,
increased left ventricular mass is due almost entirely to
increased wall thickness.83 95 97 98
Consequently, the clinical diagnosis of HCM has been based on the
identification by 2-dimensional echocardiography of
the most characteristic morphologically expressed feature of the
disease, ie, unexplained thickening of the left ventricular
wall (usually asymmetrical in distribution) associated with a
nondilated chamber, in the absence of another cardiac or systemic
disease capable of producing the magnitude of hypertrophy
evident (eg, systemic hypertension or aortic
stenosis)73 74 75 76 83 99
(Figure
Patients within the HCM disease spectrum show a broad range of left
ventricular wall thicknesses.83 The
magnitude of wall thickening usually encountered in a clinically
identified population (an average of 20 to 22 mm and up to 60
mm) generally permits unequivocal diagnosis, although more modest
degrees of hypertrophy (15 to 20 mm) are also
frequently encountered, particularly in the course of pedigree
mapping,10 13 23 100 or in subsets of elderly
patients.101 102 103 More subtle phenotypic
expression with borderline wall thicknesses (13 to 15 mm) in the
absence of outflow obstruction creates diagnostic ambiguity
and often clinical dilemmas. When such findings arise in highly trained
athletes, the differentiation from benign
physiological hypertrophy may be
difficult but potentially resolvable with noninvasive clinical
assessment or genetic testing.84 Not all
individuals who harbor a genetic abnormality for HCM show left
ventricular hypertrophy throughout
life.15 20 28 100 104 105 Left
ventricular wall thickening often does not appear until
adolescence, and phenotypic expression may not be complete until full
growth and maturation is achieved; therefore, many children with HCM
will not show left ventricular wall thickening identifiable
by 2-dimensional echocardiography before
adolescence.15 20 100 104 Although it appears
that the remodeling process is usually overtly complete by about age 18
years, a few genetically affected adults with variable penetrance
(and particular genetic defects, such as mutations in the gene for
cardiac myosin-binding protein C) have been reported to show little or
no hypertrophy (wall thickness <13
mm).28 Consequently it is possible that the
hypertrophic process can be delayed in onset until midlife or
beyond.23 28
Molecular Diagnosis (Genotype)
HCM can be caused by a mutation in any 1 of 5 genes that encode
proteins of the cardiac sarcomere: ß-myosin heavy chain (on
chromosome 14),1 7 18 19 20 21 cardiac troponin T
(chromosome 1),8 9 10 11 troponin I (chromosome
19),6
Available data suggest that mutations in the ß-myosin heavy chain
gene (myosin is the primary contractile protein in thick filaments of
myofibrils) may account for as much as 35% of familial HCM. All the
known genetic myosin defects have proved to be missense mutations.
Certain myosin mutations appear to carry more serious prognostic
implications than others; some may be associated with a largely benign
clinical course and near-normal life expectancy (eg,
Val606Met),3 4 7 18 whereas others have
been reported in a relatively small number of families showing
decreased survival either due to sudden catastrophic events or due to
heart failure (eg, Arg403Gln, Arg453Cys,
Arg719Trp).3 4 7 18 19
Cardiac troponin T mutations8 9 10 11 account for an
estimated 10% to 20% of familial HCM. Troponin T binds the troponin
complex to tropomyosin and plays a major role in calcium regulation of
cardiac contraction and relaxation. Several gene defects have been
identified, including missense mutations and small deletions. Despite
this diversity, the clinical manifestations of HCM associated with the
8 reported cardiac troponin T mutations are similar. Left
ventricular hypertrophy has been described as
relatively mild (subclinical in some adults), and life expectancy
appears to be reduced.
Mutations in the gene for
Mutations in the gene for myosin-binding protein
C14 15 16 17 28 (a structural component of the
sarcomere that does not participate in contractile function) may
account for an estimated 20% or more of familial HCM. This gene defect
appears to be associated with a relatively favorable clinical course,
as well as a substantial proportion of genetically affected adults
without phenotypic evidence of the disease on echocardiogram, ie, with
normal wall thicknesses in each segment of the left ventricle and often
with a normal 12-lead ECG.28 In addition, a
pattern is evident that is suggestive of penetrance increasing with
age, in which the initial phenotypic appearance of left
ventricular hypertrophy may occur later in
adulthood.
Although several disease-causing mutations have been defined for HCM,
the clinical consequences of these gene defects and their contribution
to disease incidence are not completely understood at present. All
the gene defects taken together account for about two thirds of the
pedigrees subjected to genotyping; however, other mutations involving
additional genes that cause HCM await identification. For example,
mutations in a gene on chromosome 7 remain to be
defined.24 Indeed, it is possible that many other
proteins implicated in filament assembly could account for familial HCM
at other loci. Nevertheless, the fact that all disease-causing
mutations for HCM defined to date involve genes that encode proteins of
the cardiac sarcomere represents a unifying principle to
explain the basic etiologic mechanisms responsible for this condition
and, at present, permits us to regard this diverse clinical
spectrum as a single disease entity and primary disorder of the
sarcomere.
Although the aforementioned mutations are regarded as causing
HCM, many of the primary structural abnormalities expressed as part of
the disease phenotype do not substantially involve sarcomere
proteins. These include mitral valve enlargement and elongation,
anomalous papillary muscle insertion directly into the anterior mitral
leaflet, abnormal intramural coronary arteries with thickened
walls and narrowed lumen, and an increased volume fraction of the
collagen matrix.86 87 88 90 91 92 Those observations,
as well as recognition that much or most of the left
ventricular wall is not involved by the hypertrophic
process in many patients with HCM83 95 and that
patterns of hypertrophy vary greatly within
families,13 89 suggest that penetrance and
variability in phenotypic expression are influenced importantly by
factors other than the mutant genes, eg, modifier genes (such as
angiotensin-I converting enzyme genotype
DD)107 108 or environmental variables,
including acquired traits such as lifestyle and exercise patterns.
Conclusions
In addition, the availability of DNA-based diagnosis has led to the
identification of increasing numbers of children and adults with a
preclinical diagnosis of HCM, usually in the context of genetic testing
in selected pedigrees. These individuals have a disease-causing genetic
mutation but no clinical or phenotypic manifestations of HCM such as
left ventricular wall thickening on echocardiogram or
cardiac symptoms (a variety of alterations, however, may be evident on
the 12-lead ECG). On the basis of the available data, it appears likely
that most such genotype-positive, phenotype-negative
children will develop left ventricular
hypertrophy while achieving full body growth and
maturation.
The lack of phenotypic expression of left ventricular
hypertrophy in genetically affected adults appears to be
relatively uncommon and is largely confined to nonmyosin mutations,
such as those reported in cardiac troponin T and particularly
myosin-binding protein C. The frequency or timing with which these
adults may subsequently develop the HCM phenotype is unknown.
At present, there is no available evidence to justify precluding
such genotype-positive, phenotype-negative individuals
from most employment opportunities or life activities; however, a
family history of frequent HCM-related death or the documentation of a
particularly malignant genotype may justify efforts at risk
stratification and possible restriction from competitive sports.
Long-QT Syndrome
Clinical Diagnosis (Phenotype)
LQTS is frequently unrecognized clinically, but it is an acknowledged
cause of sudden death in young, apparently healthy people, including
competitive athletes; indeed, because LQTS is unassociated with
anatomic cardiac markers identifiable during life or at autopsy, its
impact as a cause of premature death is probably underestimated. Even
when a 12-lead ECG is available for interpretation, measurement of the
QT-interval duration is subject to technical imprecision and
interobserver and spontaneous variability, as well as the effects of
age, sex, electrolyte alterations, central nervous system disorders,
and certain drugs.114 115 116 120 121 122 These
practical obstacles to reliable ECG measurement often make clinical
identification of the LQTS phenotype difficult and sometimes
elusive.
Diagnosis is easily confirmed when the QTc is markedly increased (eg,
Molecular Diagnosis (Genotype)
The first reported LQTS locus, on chromosome
11,35 responsible for
Ion channels consist of proteins that reside in the cell membrane and
form pores for entry and egress of ions. SCN5A mutations
appear to result in defective sodium channel
inactivation,30 31 32 33 45 46 whereas
KVLQT1 mutations (with or without coassembly with minK
mutations) and HERG mutations are responsible for impaired
outward potassium current.30 31 32 33 34 44 46 49 50
Therefore, both mechanisms result in reduced outward current during
repolarization, with secondary prolongation of cardiac action
potentials and lengthening of the QT-interval duration on the surface
ECG. It is believed that abnormalities in ion channel function are
likely to contribute importantly to
electrophysiological instability. Indeed,
it is now an aspiration to focus potential treatment strategies for
LQTS toward rectification of specific ion channel abnormalities.
Substantial intragenic heterogeneity has been
established for LQTS, with >30 total mutations (mostly missense) now
described in
Of particular note is the observation derived from genetic linkage
analysis studies in LQTS pedigrees that a wide range in QTc
values occurs in individual family members as a consequence of gene
mutations. Indeed,
Risk for adverse cardiac events appears to increase with greater QTc
values, and patients with the most substantial QT prolongation (QTc
>0.50 seconds) are those with the highest risk for subsequent cardiac
events, including sudden death.112 Although the
precise risks assumed by LQTS individuals with normal or borderline QTc
intervals are unresolved, their clinical course is not necessarily
innocent, because syncope and sudden cardiac death have occurred
in some of these patients. Of note, in subjects with normal to
borderline QTc, provocative tests such as treadmill or
bicycle exercise122 and isoproterenol or
epinephrine infusion have been advocated by some clinicians to
provide an additional measure of resolution to an otherwise equivocal
clinical diagnosis. However, this testing has not yet been validated
for the diagnosis of LQTS in all patients. For example, patients with
the SCN5A genotype appear to have a different
response to exercise than do those with the potassium ion
genotypes.
Conclusions
Marfan Syndrome
Clinical Diagnosis (Phenotype)
Classically, the clinical diagnosis of MFS has been made on the basis
of certain well-recognized and overt physical manifestations, most
prominently involving the skeletal, ocular, and
cardiovascular
systems.57 126 127 128 129 In addition, the advent of
echocardiography in the 1970s made identification
of structural and functional cardiovascular
abnormalities such as aortic dilatation, mitral valve prolapse, and
valvular regurgitation much more accessible.
Awareness of the true breadth of the MFS clinical spectrum has
gradually evolved, and it is now obvious that not all affected
individuals show classic features of the disease, that a diverse and
complex constellation of abnormalities that are variable in
severity (but difficult to measure) is consistent with this
vast clinical continuum, and that many of the physical findings
attributable to this disease are subtle or commonly encountered in the
general population.
As a consequence of such variability in expression and
diagnostic complexities, expert international panels have
been convened on 2 recent occasions to clarify the criteria necessary
for reliable identification of MFS.134 135 The
Berlin nosology developed in 1988 was the first concerted effort to
address this issue.134 Modifications proposed in
the more recent Ghent criteria of 1996135 attempt
to decrease the rate of false-positive diagnosis by increasing the
quantity and specificity of the physical manifestations needed for
diagnosis when a positive family history is present.
The Ghent formula for the clinical diagnosis of MFS uses major and
minor diagnostic criteria for each organ
system135 (Table 2
Accurate identification of MFS has important implications from a number
of clinical perspectives, particularly regarding
prophylactic medication, surgery, and lifestyle
restrictions. Consequently, a false-negative diagnosis is associated
with certain clinical risks.126 131 133 136
Furthermore, because a diagnosis of MFS confers a variety of social,
occupational, psychological, and economic consequences, a
false-positive diagnosis also has unfavorable implications. Of note,
the diagnosis of MFS may be facilitated by the consultative efforts of
a clinical geneticist.
Molecular Diagnosis (Genotype)
Linkage analysis has shown no locus
heterogeneity for MFS; the cause-and-effect relation
with the clinical Marfan phenotype has been confined to
fibrillin mutations.56 57 60 62 64 67
Nevertheless, substantial allelic heterogeneity is
evident, with 125 reported and unreported individual mutations (of
several types, but mostly of the missense variety); nearly every
genotyped family has a unique mutation in the fibrillin gene,
with the most common single mutation identified in just 4 unrelated
pedigrees.58 This intragenic
heterogeneity and the large size of the gene have
precluded the routine screening of mutations to establish the diagnosis
of MFS.58
Although patients with unequivocal phenotypic manifestations of MFS
show FBN1 mutations, such gene defects have also been
identified in individuals (or entire pedigrees) who do not satisfy
contemporary diagnostic criteria for the Marfan
phenotype or in patients with related but non-Marfan genetic
syndromes.58 60 62 64 65 At present, such
subjects are not regarded as affected by MFS in the absence of proven
MFS in another family member, and consequently such gene defects are of
uncertain clinical significance.135 Ultimately,
the greatest use of molecular testing will be to determine whether an
individual with the potential to develop symptoms or die suddenly has
inherited the genetic predisposition to develop the same Marfan
phenotype unequivocally documented in other family
members.67
Conclusions
Furthermore, the vast array of mutations in the fibrillin gene has made
genotype-phenotype correlations unrewarding. Therefore,
at present, genetic testing for MFS can only be regarded as an
adjunct to diagnosis; when available, molecular data can be considered
in conjunction with an assessment of the MFS phenotype and
assimilated into the ultimate diagnostic assignment.
Future Considerations for Molecular Diagnosis
Availability of laboratory DNA-based diagnosis of certain
genetically transmitted cardiovascular diseases has
influenced the landscape of clinical diagnosis. The historical
evolution of molecular biology over the last decade with regard to HCM,
LQTS, and MFS has progressed from the identification of the first
genetic defect to a much more complex phase in which substantial
genetic heterogeneity has become increasingly obvious.
In each instance, the molecular biology investigation has been
performed at a few academic research laboratories with a particular
interest in identifying new genes responsible for these diseases.
However, the variety of different mutations now apparent in HCM, LQTS,
and MFS, coupled with the time-intensive, demanding, and expensive
techniques required for genetic analysis (as well as competing
priorities for individual investigations), has created a circumstance
in which the available resources of the few involved laboratories have
become overwhelmed. Therefore, at present, DNA diagnosis of
cardiovascular diseases permits only research-oriented
genotyping of selected pedigrees and is not routinely available for
clinical practice.
Consequently, we are in a period in which access to clinically relevant
genetic diagnosis is limited. The impetus to produce widely available
DNA diagnosis for patients with cardiovascular disease
will probably require support from the commercial sector or
governmental programs. Further initiatives will undoubtedly be focused
on developing automated screening methods for rapid identification of
known genetic mutations. Such direct mutational analysis would
circumvent the classic but time-consuming methodology of linkage
analysis, which requires detailed study of multiple relatives
in large, informative pedigrees. Until these issues are resolved,
diagnosis in the vast majority of patients with HCM, LQTS, and MFS will
continue to be made largely by conventional clinical examination,
usually with the aid of noninvasive testing, and in association with
laboratory genetic analysis when such testing is selectively
available and appropriate.
Ethical Considerations
A number of complex and sensitive ethical questions have arisen by
virtue of the explosion of patient-related genetic data in many areas
of medicine, including those cardiovascular diseases
under discussion herein.68 69 70 137 138 139 140 141 142 The
potential concerns, pitfalls, and risks implicit in the results of
genetic testing include the following: (1) discrimination in employment
or other life activities and in health, life, and disability insurance;
(2) psychosocial difficulties and anxiety created by virtue of having a
genetic disease; (3) ambiguity regarding whether genetically affected
subjects without phenotypic expression should be regarded as having
cardiovascular disease solely on the basis of a
molecular abnormality; and (4) the unresolved clinical significance of
certain genetic laboratory data, particularly when effective preventive
measures are lacking. The concern about inadvertently
stigmatizing individuals and groups of patients through identification
of genetic defects must be weighed against the perspective that a
society founded on personal freedom and responsibility has the inherent
responsibility to create a fully informed public, including those
individuals with potentially relevant mutations.
Therefore, ethical considerations relevant to the diagnoses of the 3
familial cardiovascular disorders under discussion
herein should be viewed with respect to these issues. First, because
sufficient diagnostic findings are usually already evident
clinically, the ethical implications of a molecular diagnosis such as
MFS (and in many instances, HCM or LQTS) are not great and do not seem
to differ substantially from those in the premolecular era for these
patients. In such instances, the molecular DNA diagnosis is only
confirmatory of the clinical diagnosis. Schools, employers, and
insurance companies will have access to such information, if released
by the patient or family.
We acknowledge, however, certain ambiguous areas related to genetic
testing data in patients with HCM, LQTS, and MFS. Identifying a gene
mutation in family members without overt phenotypic evidence of a
disease usually provides information for which, at present, the
clinical consequences are unresolved. For example, recognition of a
disease-causing HCM mutation in a child or adult without left
ventricular hypertrophy (or, similarly, a
mutation in a member of a family with LQTS and normal QT interval) does
not per se have obvious therapeutic implications, nor are the risks for
adverse consequences known with certainty. There is also the potential
for misapplication of such data, whereby aggressive therapeutic
interventions (eg, implantable cardioverter-defibrillator) are
recommended to young people when such treatment may be unwarranted.
This gap between our ability to test for a mutation and subsequently
apply these data in a clinical context creates psychosocial and ethical
complexities. In clinical practice, concerns may arise when a genetic
test is obtained if the facts by which the results of that test may be
interpreted are lacking. The criteria used to determine whether a
diagnostic genetic test is appropriate in this context
depend on its potential to benefit the patient in his or her lifetime
to an equal or greater extent than other tests that are proposed.
Therefore, when subjects without overt evidence of cardiac disease
agree to enter a research protocol for the purpose of pedigree
genotyping, they should do so with sufficient informed consent in
collaboration with the physician and/or genetic counselor. The patient
and family should be counseled in advance regarding any limitations of
test result interpretation and advised not to embark on genetic testing
if they do not wish to know the results. If information gleaned from
genetic testing is not of use in patient management strategies, this
should be stated clearly and discussed with the patient within the
context of the doctor-patient relationship and informed consent.
Indeed, there is a potential risk for patients in interpreting genetic
data without access to formal counseling. In the case of minor
children, the situations can be more complex.70
However, because substantial medical benefit can accrue to the young
person if the diagnosis is certain, the parents should ultimately be
responsible for this decision-making process, although the competent
adolescent should be approached for consent. These ethical issues
arising in the context of genetic cardiovascular
diseases are perhaps not unlike some aspects of the debate currently
evolving over BRCA mutations and the risk for breast and
ovarian cancer.138 139 140 141 142
As molecular technology improves, laboratory testing for genetic
markers will become more available, and third parties (such as
employers and insurance carriers) will request genetic information with
increasing frequency. The number of genetically affected individuals
with little or no phenotypic evidence of disease is likely to increase
considerably, and such testing may be extended for the purpose of
stratifying the risk for premature death in family members. However,
there does not appear to be an obligation to provide such genetic
information, obtained largely for investigative scientific purposes, to
employers or to agencies such as schools, insurance carriers, and the
military unless specifically requested by the patient and/or family.
Indeed, genetic information can elicit powerful reactions, and even an
unproven perception of high-risk status may, for example, jeopardize
access to health insurance. However, some states have placed limits on
discriminatory practices in health insurance, and pending federal
legislation holds promise for greatly reducing such concerns for all
citizens. All these perspectives may well evolve over time as we come
to a better understanding of the clinical significance and implications
of the specific gene defects in diseases such as HCM, LQTS, and
MFS.
Final Perspectives
Hypertrophic cardiomyopathy, long-QT syndrome, and Marfan syndrome
are each inherited as a mendelian autosomal dominant trait and
demonstrate variable penetrance and expressivity. Although they are
relatively uncommon in the general population, each not infrequently
confers a predisposition for unexpected sudden cardiac death in the
young. Over the past 8 to 10 years, the application of molecular
biology and DNA-based technology to the study of genetically
transmitted cardiovascular diseases has provided a
measure of diagnostic clarification. Nevertheless, at
present, most adult patients with these conditions can still be
identified reliably by standard clinical diagnostic
techniques.
By virtue of linkage or mutational analysis in selected
pedigrees, genetically affected but phenotypically normal relatives
have been identified, particularly within the HCM and LQTS disease
spectrums. Indeed, it is the substantial proportion of relatives in
LQTS families with borderline (or normal) QTc values for whom molecular
diagnosis would potentially be most informative. Nevertheless, the
precise clinical significance of these patient subsets with little or
no phenotypic evidence of disease is currently uncertain, and
longitudinal clinical data will be required to more definitively
clarify the extent to which such individuals ultimately evolve
clinically overt disease manifestations and experience adverse cardiac
events.
At present, the clinical utility of genetic testing for HCM,
LQTS, and MFS is hampered by their substantial allelic
heterogeneity and the time-intensive and costly nature
of laboratory genotyping. Future initiatives directed toward molecular
diagnosis of HCM, LQTS, and MFS will likely result from improved
technology, gene sequencing, and the development of automated screening
methods for more rapid identification of mutations. Such direct
mutational analysis would have the distinct advantage of
obviating the complex and time-consuming process of classic linkage
analysis. In addition, with increased understanding of genetic
mechanisms, it may be possible to target therapy to mitigate genetic
defects or conceivably to correct molecular abnormalities. However,
given the large number of genes and mutations already evident in HCM,
LQTS, and MFS (and the realistic expectation for additional diversity),
the future design of comprehensive molecular screening tests and
therapy for these genetic cardiovascular diseases will
continue to be a challenge.
Glossary
Footnotes
This statement was approved by the American Heart Association Science Advisory and Coordinating Committee in May 1998. A single reprint is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Avenue, Dallas, TX 75231-4596. Ask for reprint No. 71-0151. To purchase additional reprints: up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies, call 214-706-1466, fax 214-691-6342, or
References
© 1998 American Heart Association, Inc.
AHA Medical/Scientific Statement
Impact of Laboratory Molecular Diagnosis on Contemporary Diagnostic Criteria for Genetically Transmitted Cardiovascular Diseases: Hypertrophic Cardiomyopathy, Long-QT Syndrome, and Marfan Syndrome
A Statement for Healthcare Professionals From the Councils on Clinical Cardiology, Cardiovascular Disease in the Young, and Basic Science, American Heart Association
Key Words: genetics • long-QT syndrome • cardiovascular diseases • cardiomyopathy, hypertrophic • Marfan syndrome • diagnosis
HCM is a primary and usually familial cardiac disease
characterized by complex pathophysiology and great
heterogeneity in its morphological, functional, and
clinical course.72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 This considerable
diversity is emphasized by the fact that HCM may present in all
phases of life, from the newborn to the elderly. The clinical course is
highly variable, with some patients remaining
asymptomatic throughout life and others developing severe
symptoms of heart failure; some die prematurely, either suddenly (often
in the absence of prior symptoms) or owing to progressive heart
failure.73 74 75 76 HCM appears to be a more benign
condition in unselected patient populations, which are more
representative of the overall disease
spectrum,79 80 81 93 than in those patients who are
part of preferentially selected and high-risk cohorts from a few
tertiary referral centers.93 Recent observations
suggest that the prevalence of HCM in the general population is
probably higher than previously thought (
0.2%, or 1 in
500).94 Therefore, HCM may be regarded as a
cardiomyopathy resulting from a relatively common
genetic defect. 
). Indeed, it is this
echocardiographically evident hypertrophy
that is conventionally regarded as the phenotypic expression of HCM and
that has been primarily used in classic linkage analyses to
define genetic loci.2 24 25 26 27 Because the
nonobstructive form of HCM is
predominant,73 75 76 the well-described clinical
features of dynamic obstruction to left ventricular outflow
(such as a loud systolic ejection murmur, systolic
anterior motion of the mitral valve, or partial premature closure of
the aortic valve) are not required for diagnosis.
View larger version (42K):
[in a new window]
Figure 1. Diagram summarizing the clinical and laboratory diagnosis of
hypertrophic cardiomyopathy (HCM). Although it is
possible to establish this diagnosis in the laboratory setting by
mutational analysis, in the vast majority of instances HCM is
identified clinically with 2-dimensional
echocardiographic imaging (by virtue of a hypertrophied
but nondilated left ventricle). Clinical diagnosis by this criterion
can be confounded by associated cardiovascular diseases
such as systemic hypertension or aortic valve stenosis, by
evolution to the end-stage (or dilated) phase of HCM in which left
ventricular wall thinning occurs, or if the subject is a
highly trained athlete in selected sporting disciplines.143
LV indicates left ventricle; LVH, left ventricular
hypertrophy; 2-D echo, 2-dimensional
echocardiographic imaging; and AS, aortic valve
stenosis. *Genotype-positive,
phenotype-negative adults are uncommon but appear to be more
frequently associated with certain genetic defects, such as mutations
in the gene for myosin-binding protein-C.14 28
It has been evident, even from the initial descriptions of the
disease, that HCM is usually inherited as a mendelian autosomal
dominant trait.100 Contemporary molecular genetic
approaches were first applied to familial HCM in the
mid-1980s.2 Over the last decade, molecular studies using
linkage analysis have mapped a number of genetic loci
responsible for HCM and in the process have provided insights into the
considerable clinical heterogeneity characteristic of
this disorder.3 4 5 8 14 15 The consequences of
these different gene defects for patients appear to differ greatly and
are not yet completely understood. 
-tropomyosin (chromosome
15),8 10 12 13 and cardiac myosin-binding protein
C (chromosome 11).14 15 16 17 28 In addition,
mutations in 2 genes encoding essential and regulatory myosin light
chains have been reported in what may be an extremely rare form of
HCM.22 This genetic diversity is further
compounded by intragenic heterogeneity, with a total of
more than 100 individual disease-causing mutations identified for these
genes; the majority represent missense mutations in which a
single amino acid residue is substituted with a different amino acid in
the globular head or head-rod junction regions of the myosin molecule.
Hence, it is apparent that the precise molecular defect responsible for
HCM usually proves to be different in unrelated individuals. -tropomyosin,8 10 12 13 106 a thin filament
component of the sarcomere that bridges troponin complex and actin
filaments, are uncommon. In contrast to other genes that cause HCM,
families with -tropomyosin thus far have demonstrated identical
Asp175Asn mutations in which a hot spot with increased susceptibility
to mutation has been observed at the nucleotide guanine
residue 579.13 The few -tropomyosin pedigrees
identified have shown favorable, near-normal life expectancies and
great variability in phenotypic appearance.
In most affected adult patients, the diagnosis of HCM is most
easily and reliably established by clinical examination, including
careful 2-dimensional echocardiographic imaging. In
those instances in which the clinical diagnosis is certain,
establishing the precise genetic defect responsible for this disease by
DNA analysis represents only a diagnostic
confirmation. Nevertheless, molecular studies have the potential to
enhance diagnostic reliability in HCM. Genotyping can play
an important role in resolving ambiguous diagnoses, such as in subjects
with a borderline or modest increase in left ventricular
wall thickness, including some trained athletes with
ventricular hypertrophy, and in patients with
systemic hypertension who are suspected of having HCM.
The long-QT syndrome (LQTS;
Romano-Ward)109 110 is an uncommon familial
disease transmitted as an autosomal dominant trait, causing a
predisposition to syncope and sudden cardiac death (often related to
emotional or physical stress, vigorous activity, or arousal stimuli).
Sudden collapse is mediated through ventricular
tachyarrhythmias such as polymorphic
ventricular tachycardia (torsade de pointes)
and ventricular
fibrillation.29 111 112 113 The principal
diagnostic and phenotypic hallmark of LQTS is abnormal
prolongation of ventricular repolarization, measured as
lengthening of the QT interval on the 12-lead ECG. This is usually most
easily identified in lead II or V1,
V3, or V5, but all 12 leads
should be examined and the longest QT interval used; care should also
be taken to exclude the U wave from the QT measurement. At present,
manual measurement of QT interval is preferred over automated
techniques because of the difficulties in detecting the end of the T
wave that are commonly encountered in this disease. The QT interval
should be adjusted for heart rate according to the Bazett formula (the
QTc).114 115 116 Other ECG alterations in LQTS
include bradycardia, increased QT dispersion,117
and a variety of T-wave forms that have been associated with particular
gene defects.115 118 119 
0.50 seconds), but often QTc values are more modestly
prolonged.29 114 Indeed, LQTS identification on
ECG is often unavoidably based on small differences in the quantitative
measurement of QT-interval duration. The "cutoff" value most
commonly used previously to define an abnormally prolonged QTc interval
was >0.44 seconds, but more recent genotype-phenotype
correlations indicate 0.46 seconds to be more
appropriate.29 In an effort to enhance
diagnostic reliability, an elaborate point score system has
been proposed that goes beyond QTc duration, incorporating other
hallmarks of LQTS such as syncope and a family history of this
condition (Table 1).114
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Table 1. LQTS Diagnostic
Criteria1
Since 1991, intensive laboratory investigation and a number of
published reports have established LQTS to be a molecular structural
disease with substantial genetic
heterogeneity36 38 as well as
complex pathophysiology involving several ionic
currents.33 At present, 4 mutant genes
encoding proteins of the cardiac ion channels have been identified as
responsible for LQTS30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 ; a fifth locus on
chromosome 4 has been reported,123 but this gene
has not yet been identified. These mutant genes are believed to account
for more than half of all patients with LQTS, and undoubtedly
additional genes will be identified to explain the remaining patients
affected with this disorder. 50% of
genotyped LQTS cases, has now been established as a mutant
KVLQT1 gene,39 40 41 which
encodes for the cardiac ion channel Iks.
Approximately 40% of genotyped families have mutations of the
-subunit of the HERG gene on chromosome 7, which encodes
for the cardiac potassium ion channel
Ikr.37 40 44 46 49 50
A small proportion of families (5%) have mutations of the sodium
ion channel SCN5A gene on chromosome
3.30 37 43 45 46 The fourth LQTS gene has been
identified on chromosome 21 as the potassium channel KCNE1
(minK) gene; this gene product coassembles in concert with KVLQT1
protein to generate the Iks
current.47 48 Most recently, KCNE1
(minK) and KVLQT1 mutations have also been shown to be
responsible for the Jervell-Lange-Nielsen form of the syndrome, in
which familial QT-interval prolongation is associated with congenital
sensorineural deafness (QT prolongation is an autosomal dominant trait,
with deafness transmitted as a recessive
trait).41 51 52 40 families, among which 1 mutational hot spot has been
observed in HERG.124 Nevertheless, the
recognition that mutations in 4 genes encode proteins formulating the
cardiac sodium and potassium ion channels has provided fundamental
insights into the genesis of arrhythmias. In addition, these
observations have established a unifying concept for the etiology and
pathophysiology of LQTS as a sarcolemmal ion channel defect affecting
repolarization.30 31 32 33 This is similar to the
circumstance that has evolved for HCM, in which the identification of
several mutant genes encoding proteins of the cardiac sarcomere has
created a working etiologic
hypothesis.1 3 4 7 8 13 14 15 16 40% of chromosome 7 and 11 gene carriers show
QTc values (0.41 to 0.47 seconds) that overlap with
noncarriers.29 In this QTc range, phenotypic
diagnosis from the ECG becomes imprecise. This segment of the LQTS
population includes a subgroup (comprising 5% to 15% of all gene
carriers), the majority of whom are males, who show false-negative QTc
values of 
0.44 seconds.29 Consequently, on the
basis of molecular genetic studies, it is reasonable to conclude that
QTc is not completely sensitive or specific for LQTS. When QTc 0.46
seconds is used, the positive predictive accuracy for LQTS is 96% in
women and 91% in men; almost 100% positive predictive accuracy for
LQTS can be achieved at QTc 0.47 seconds in males and QTc 0.48
seconds in females, in the absence of drugs or other conditions that
independently lengthen QT interval. Negative predictive accuracy of
almost 100% is present with a QTc 0.41 seconds in males and
0.44 seconds in females.29
Molecular diagnosis affords the potential to enhance
diagnostic reliability in LQTS. The role for DNA diagnosis
in this disease is substantial given the number of inherent
difficulties that exist in identifying the LQTS phenotype
solely from measurement of QT-interval duration on 12-lead ECG.
Available genotype-phenotype correlations in LQTS show
that a normal QTc does not exclude LQTS. Indeed, clinical diagnosis
with measurement of QTc may be uncertain in as many as 50% of family
members when false-negative, false-positive, and borderline values are
combined. It is this substantial proportion of relatives in LQTS
families for whom molecular diagnosis would potentially be most
informative. Indeed, gene carriers with false-negative or ambiguous
phenotypic diagnosis of LQTS are at some risk for clinical events. On
the other hand, a false-positive clinical diagnosis may create
unnecessary anxiety or result in inappropriate therapy. However, given
the marked genetic heterogeneity of LQTS involving 5
genes and a multitude of mutations (and the expectation of even greater
heterogeneity, with many mutations unique to single
families or rarely found in other pedigrees), the possibility of
comprehensive screening for LQTS genetic defects seems particularly
difficult.
Marfan syndrome (MFS) is a systemic connective tissue disorder
with autosomal dominant inheritance, first described in 1896 by Antoine
Marfan.125 Life expectancy may be reduced,
usually due to involvement of the cardiovascular system
with progressive aortic root dilatation, dissection and rupture, or
valvular
regurgitation.126 127 128 129 130 131 132 133 ). The most prominent major criteria
(ie, with high diagnostic specificity due to infrequent
occurrence in other conditions and in the general population) are as
follows: a constellation of skeletal manifestations, including pectus
carinatum or excavatum, reduced upper- to lower-segment ratio, or
arm-span–to-height ratio >1.05, scoliosis, and reduced elbow
extension; ectopia lentis; dilatation or dissection of the ascending
aorta; lumbosacral dural ectasia; and inheritance of a genotype
previously associated with classic MFS or an unequivocal family
history.
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Table 2. Requirements for Diagnosis of Marfan Syndrome (Ghent
Criteria)1
The primary defect responsible for MFS, first described in
1991, resides in a gene (FBN1) localized to the long arm of
chromosome 15 encoding the connective tissue protein
fibrillin-1.53 54 55 58 59 60 61 62 63 64 65 Fibrillin is a
structural glycoprotein component of microfibrils, which
are extracellular components that participate in the formation of
mature elastic fibers and which serve structural functions independent
of elastin.53 54 58 59 63 65
MFS fundamentally remains a clinical diagnosis, although in many
instances this assessment is fraught with considerable difficulty and
imprecision. No available genetic test can provide, in isolation, an
unequivocal assignment of either affected or unaffected status for
MFS.
-Tropomyosin and
cardiac troponin T mutations cause familial hypertrophic
cardiomyopathy: a disease of the sarcomere.
Cell. 1994;77:701–712.[Medline]
[Order article via Infotrieve]
-tropomyosin in hypertrophic
cardiomyopathy. N Engl J Med. 1995;332:1058–1064.
-tropomyosin that causes
hypertrophic cardiomyopathy.
Circulation. 1995;91:2302–2305.