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(Circulation. 1995;91:532-540.)
© 1995 American Heart Association, Inc.

Articles

Molecular Basis of Familial Cardiomyopathies

Ketty Schwartz, PhD; Lucie Carrier, PhD; Pascale Guicheney, PhD; Michel Komajda, MD

From the Unité de Recherches (K.S., L.C., P.G.), 153 de l'INSERM, and the Service de Cardiologie (M.K.), Groupe Hospitalier Pitié-Salpêtrière, Paris, France.

Correspondence to Ketty Schwartz, PhD, INSERM UR 153, Pavillon Rambuteau Groupe Hospitalier Pitié-Salpêtrière, 47 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France.

Key Words: hypertrophy • cardiomyopathy • genes

	Introduction

Top Introduction Evidence for the Existence... Disease Genes for FHC... Disease Genes for DCM... Phenotype/Genotype Relation Clinical Implications References

 
Cardiomyopathies represent a variety of cardiac diseases that are an important cause of morbidity and mortality throughout the world in children and adults and whose definition and classification have evolved since the middle of this century. Currently, they are defined as "heart muscle diseases of unknown etiology" and are classified as dilated, hypertrophic, or restrictive, depending on the type of functional impairment.¹ The dilated forms (dilated cardiomyopathy, DCM) are the most common variety. They are characterized by a marked ventricular dilation, poor systolic function, the development of progressive refractory congestive heart failure, and a poor prognosis. Their prevalence in the US population is estimated to be 36.5 per 100 000 persons.² The hypertrophic forms (hypertrophic cardiomyopathy, HCM) are defined by the presence of unexplained left ventricular hypertrophy that is usually predominant in the interventricular septum and may or may not be associated with right ventricular hypertrophy. Cellular disorganization (myocardial disarray) is present in most patients in the interventricular septum as well as in the free wall. The disease is associated with diastolic dysfunction, myocardial ischemia, and life-threatening arrhythmias, and patients are prone to sudden death. The prevalence of HCM is reported to be 17.9 per 100 000 persons.² Restrictive cardiomyopathy is extremely rare in western countries.

Although apparently clear, this clinical classification presents major limitations: specific cardiac diseases such as hypertension or ischemic heart disease, as well as general disorders with cardiac involvement, can mimic the clinical presentation of idiopathic cardiomyopathies. Moreover, an overlap exists between these categories. For instance, in end-stage HCM, a marked dilation of both ventricles, similar to that observed in DCM, can be present. Most important, this classification does not address the underlying molecular disorders responsible for the development of the "clinical" cardiomyopathy.

During the past few years, new and unexpected insights into the pathogenesis and classification of cardiomyopathies have emerged from the localization and the identification of disease genes of several inherited forms. The process of disease gene identification used to be laborious and time consuming. Because of the striking development of the resources provided by the Human Genome project, and more specifically by the generation of highly resolutive genetic maps, this process has been greatly facilitated, and the strategy of positional cloning now allows one to map any mendelian trait and, in particular, monogenic human diseases. Curiously, genetics has been relatively late in being applied to cardiac muscle diseases but has been used extensively in the investigation of atherosclerosis and lipoprotein metabolism diseases for many years. The past 2 to 3 years have marked the dawn of a new era for the genetics of cardiac muscle diseases, and the cardiomyopathies have opened this fascinating route. This review focuses on the relatively few inherited HCMs and DCMs for which an abnormal gene or defective protein has been identified. Particular emphasis is placed on the genetic bases of the diseases and on the correlations between the clinical manifestations (phenotype) and a mutant genotype, and the potential clinical implications are discussed. By definition, diseases in which the myocardial pathology is part of a known systemic disorder have not been included.

	Evidence for the Existence of Familial Forms of Cardiomyopathies

Top Introduction Evidence for the Existence... Disease Genes for FHC... Disease Genes for DCM... Phenotype/Genotype Relation Clinical Implications References

 
The fact that HCM is sometimes familial has been known for a long time. The first genetic study of familial hypertrophic cardiomyopathy (FHC) was performed 30 years ago by Hollman et al,³ who described a pedigree with asymmetrical cardiac hypertrophy transmitted as an autosomal trait. Subsequently, Paré et al⁴ described a large French-Canadian family. Studies carried out before the development of echocardiography underestimated the familial incidence of HCM. Two large family studies using two-dimensional echocardiography showed that HCM is familial in approximately 50% of cases.^{5 6} This number is most probably underestimated since recent genetic data have indicated that some apparently sporadic forms of the disease are in fact related to de novo and transmissible mutations. In most instances, the mode of inheritance is autosomal dominant.^{5 6 7}

Careful screening of families has provided the evidence that, as in HCM, there is a strong genetic component in DCM, although it was generally considered to be a multifactorial disease related to various toxic environmental factors: in a panel of 59 patients, DCM was familial in approximately 20% of the cases.⁸ In the present study, complex segregation analysis of the pedigrees supported the evidence for a single dominant locus with incomplete penetrance. However, in most instances, the size of the family and the number of affected subjects do not allow an accurate analysis of the mode of inheritance. An autosomal dominant transmission was nevertheless most frequently suggested,^{9 10 11} but other modes of inheritance, including autosomal recessive^{9 11} and X-linked,^{9 12} have been found. The apparent heterogeneity in the patterns of inheritance raises the possibility that DCM is a polygenic disease with multiple genetic factors being involved or is even multifactorial with the intervention of polygenic and environmental factors to various degrees from one individual to the other.¹¹ In addition to the small size of most of the families with DCM and the potential genetic heterogeneity, another difficulty in linkage analysis is the presence of middle-aged adults with minor or mild cardiac dilation and/or reduced ejection function, a potentially misleading pattern of ischemic heart disease that makes hazardous an accurate classification of these subjects as unaffected or carriers.

	Disease Genes for FHC

Top Introduction Evidence for the Existence... Disease Genes for FHC... Disease Genes for DCM... Phenotype/Genotype Relation Clinical Implications References

 
It is well known that FHC is phenotypically heterogeneous, but it was a surprise to discover that FHC is also genetically heterogeneous (Figure). The first locus for FHC (CMH1) was identified on chromosome 14.¹³ Since then three other loci have been reported,^{14 15 16} and we have evidence that a fifth locus exists.¹⁷ Three genes have been identified among these loci, and it was again a surprise to find that they encode cardiac sarcomeric proteins, ß–myosin heavy chain (ß-MHC), troponin T, and -tropomyosin. Indeed, none of the previous hypotheses of the pathophysiological mechanisms of the disease would have led us to suspect that one of the molecular bases could be a defect in a contractile protein; nevertheless, certain forms of the disease clearly involve mutations in sarcomeric protein genes.

View larger version (13K): [in this window] [in a new window]   Figure 1. Chromosomal loci for familial hypertrophic cardiomyopathy and corresponding disease genes: CMH1 on chromosome 14q11-q12, CMH2 on chromosome 1q3, CMH3 on chromosome 15q2, and CMH4 on chromosome 11p13-q13. cTNT indicates cardiac troponin T gene; ß-MHC, ß–myosin heavy chain gene; and -TM, -tropomyosin gene.

ß-Myosin Heavy Chain, Cardiac Troponin T, and -Tropomyosin
The genes encoding for the two cardiac myosin heavy chain (MHC) isoforms ( and ß) are located in tandem on chromosome 14q11-q12 and were therefore unexpected candidate genes when this locus was found. Subsequently, with the use of genetic mapping and DNA sequencing, the ß-MHC gene (MYH7) was identified as the morbid gene carrying a point mutation in the original family described by Paré.¹⁸ Following this initial description, several other families have shown evidence for linkage to CMH1.^{19 20 21 22} At the present time, 29 missense mutations have been found in the ß-MHC gene, among which 8 were reported on in abstract form (Table).^{18 21 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44} All are localized either to the head region or to the junction of the head/rod domains. Almost simultaneously, our team and one from South Africa found that codon 403 is a hot spot for mutations, which suggested a major role of this arginine residue in the maintenance of a normal function of the MHC protein.^{31 34} In one family, a deletion involving the carboxyl-terminal region of ß-MHC has also been identified,⁴⁵ but it is not clear in this family whether this is the cause of the disease.

View this table: [in this window] [in a new window]   Table 1. Reported Mutations in FHC Families and Associated Clinical Manifestations

Of course, neither linkage analyses nor identification of the mutations in the ß-MHC gene is sufficient to prove that these mutations are the primary cause of FHC. Some clues have nevertheless been provided over the past 2 years.

First, the substitution of an adenine for a guanine, resulting in the Arg⁴⁰³Gln mutation, was found to be expressed in mRNA of both myocardial and bicep muscle of the same proband.^{46 47} Very recently, the mutant Arg⁷¹⁹Trp ß-MHC protein was found to be present in the myocardium and in the skeletal muscle of two unrelated patients.^{48 49} However, even though in two subjects demonstrating the same missense mutation total myosin and immunoreactive ß-myosin myocardial levels were similar to those found in various disease control subjects,⁵⁰ the respective levels of expression of the normal and mutated genes remain to be determined. It is also not known if the other types of mutant MYH7 alleles are transcribed into the corresponding proteins.

Second, myofibrillar organization appears to be intact in a patient with the Arg⁴⁰³Gln mutation,⁵⁰ and protein stability does not appear to be markedly affected in mammalian nonmuscle cells transfected with expression constructs encoding seven different FHC mutants.⁵¹ However, the ability to form filaments appears to be impaired since as many as one third of the transfected cells fail to form filamentous structures.⁵¹ It should, however, be pointed out that the latter studies have been carried out in nonmuscle cell types and did not include the coexpression of myosin light chains, which are critical for the normal assembly and function of MHC. It is thus not completely clear as to whether the mutant MHC proteins are indeed assembled abnormally in the muscle context, and it is equally unclear whether this would explain myofibrillar disarray in FHC.

Third, crystallographic data suggest that several mutations are in or near functional sites of the myosin molecule.^{52 53} For example, three mutated amino acids are located in the nucleotide-binding pocket; four others, including Arg⁴⁰³, are in the actin-binding site; and Leu⁹⁰⁸ is located in the hinge, where motive force is generated. All of this suggests that the mutations could have a deleterious effect on the various functions of the molecule.

Fourth, in vitro analyses have shown that some of the described mutations induce a decrease in both the actin-activated ATPase activity of myosin fragments⁵⁴ and the actin translocation rate on the mutated myosin bound to a coverslip surface.^{30 54}

Fifth, the last line of evidence comes from patients with sporadic HCM; de novo myosin mutations have been found in individuals with HCM but whose parents are clinically and genetically unaffected, and one of these mutations was transmitted to an affected child.⁵⁵

After analysis of the clinical, echocardiographic, and pathological findings, it became clear that FHC is a heterogeneous disease (see Reference 56 for review). It was shown in 1990 that FHC is also genetically heterogeneous since in two of four families, no linkage to CMH1 was found.⁵⁷ The next major problem in continuing the genetic analysis was to obtain access to large informative pedigrees (more than 50 members). To circumvent this problem and to analyze small families, we have used two highly informative microsatellite markers contained in the ß-MHC gene that we named MYOI and MYOII.^{58 59 60 61} Analysis of these two microsatellites enabled us to exclude linkage to CMH1 in eight unrelated medium-size families.⁶⁰ Almost simultaneously, other families in which the disease was not linked to CMH1 were identified.^{20 22 25 61 62 63} Last year, we and others found in unrelated families three other disease loci: one on chromosome 1q3 (CMH2),¹⁴ one on chromosome 15q2 (CMH3),¹⁶ and one on chromosome 11p13-q13 (CMH4).¹⁵ Moreover, we have evidence that a fifth locus exists.¹⁷ By synteny with the murine genome and by precise genetic analysis, the disease genes contained in CMH2 and CMH3 were identified very recently; they encode for two other sarcomeric proteins: cardiac troponin T on CMH2 and -tropomyosin on CMH3.⁶⁴ Two missense mutations were found in the -tropomyosin gene in exon 5, which encodes part of a putative binding domain for troponin T. As for the cardiac troponin T gene, two missense mutations in the putative exons 8 and 9 and a mutation in the splice donor site of intron 15 were found in three unrelated families (see the Table). The missense mutations affect nucleotides encoding a region involved in calcium-insensitive binding to -tropomyosin, and the mutation in the donor site produces markedly aberrant cardiac troponin T mRNA transcripts that alter the carboxyl terminus of troponin T, a region contributing to calcium-dependent binding to tropomyosin. These observations that -tropomyosin and cardiac troponin T—as ß-MHC–have central roles in the structure and function of the sarcomere in striated muscle confirmed the first hypothesis and suggest that one of the pathophysiological mechanisms of FHC could be an impaired function of the contractile apparatus.

What Are the Other Disease Genes?
These findings suggest that mutations in other contractile protein genes from either the thick or the thin filament, or in any protein implicated in filament assembly, may account for FHC at other loci, including CMH4 on chromosome 11p13-q13. At the present time, only one family shows linkage to CMH4.¹⁵ Enlargement of this family and the analysis of 14 other new, informative microsatellite markers allowed us recently to identify new recombinant individuals and to reduce the candidate interval from 23 centimorgan to 12 centimorgan. From the 60 genes already located in this interval, none encode for another sarcomeric protein. Cardiac troponin C gene, which was not mapped to the genome, was excluded from chromosome 11 by specific analysis of DNA isolated from human x hamster cell lines (data not shown). As for cardiac troponin I gene, it was mapped to chromosome 19p13.2-q13.2⁶⁵ and therefore is a candidate for families in whom the disease is not linked to any known locus. It is clear that much more work is needed to identify the other genes that cause FHC and to be able to propose a general and unifying hypothesis for the pathogenesis of this disease.

Link Between Molecular and Organ Abnormalities
If the hypothesis that FHC is a disease of the sarcomere is valid, one has to explain the paradox of the coexistence of genetic abnormalities that alter sarcomeric function and result in depressed contractility at the molecular level and the reported maintained and even increased systolic function in patients with HCM.⁶⁶ Indeed, pump function indexes such as ejection fraction, cardiac output, or left ventricular systolic pressure are normal or "supernormal" in a majority of patients, and these observations led to the concept of a "hyperdynamic" or a "hypercontractile" state in this disease, particularly in the presence of left ventricular obstruction.^{66 67 68} Because cardiac performance results from preload, afterload, contractility, relaxation, and compliance, normal systolic indexes do not necessarily indicate a normal contractile state.^{69 70 71} Indeed, in a group of patients with HCM, isovolumic phase and ejection phase indexes of contractility (+dp/dt, dp/dt/DP40, ejection fraction) were found to be normal, whereas afterload was significantly decreased.⁷² However, an index of contractility supposed to be independent of loading conditions, ie, the end-systolic stress–to–volume ratio, was reduced in patients to half of the normal value, as was the unit muscle performance (minute work/mass). These results suggest that intrinsic contractility is actually decreased in HCM, and this has been confirmed by other studies when left ventricular hypertrophy was related to HCM.⁷³ These findings at the organ level are therefore in keeping with the in vitro analyses and support the idea that in HCM, hypertrophy would be a compensatory mechanism to maintain normal systolic function. Understanding why this hypertrophy is, in most instances, eccentric and not concentric as it is following a chronic increase in afterload is the next challenge.

	Disease Genes for DCM

Top Introduction Evidence for the Existence... Disease Genes for FHC... Disease Genes for DCM... Phenotype/Genotype Relation Clinical Implications References

 
Much less is known about the disease genes implicated in DCM, but two recent reports of particular interest begin to reveal the genetic origin of this pathology.

In three pedigrees with X-linked DCM, defects in the dystrophin gene and low abundance of cardiac dystrophin but not of skeletal muscle dystrophin were found, and the authors demonstrated that this disease is associated with a deletion of the muscle-promoter region and the first exon of the gene.^{74 75} A reduced abundance of dystrophin was also found in the BIO 14.6 hamster, which is a widely recognized animal model of DCM.⁷⁶ The pathogenetic hypothesis for this type of DCM is a disruption of the membrane cytoskeleton of the myocyte due to the reduced dystrophin content, and this hypothesis has been reinforced by the recent finding of a deficiency of a dystrophin-associated glycoprotein in this same strain of hamster.⁷⁷ Because Duchenne and Becker muscular dystrophies are due to dystrophin gene abnormalities and because there have been some reports of Becker dystrophy with predominant or even exclusive cardiac involvement and no or only minor skeletal muscle involvement,^{78 79} the possibility that some patients with DCM are in fact carriers of a dystrophin gene defect was raised. In a series of patients with familial and nonfamilial DCM, screening of the dystrophin gene defects did not reveal any of the known deletions observed in Duchenne and Becker muscular dystrophy.⁸⁰ However, it should be pointed out that only 14 exons were studied and that the promoter region of the gene was not analyzed. It is possible that the proportion of cases of DCM related to dystrophin gene defects is small and that screening the dystrophin gene in individuals with DCM should be limited to cases of X-linked cardiomyopathy and/or cardiomyopathy with muscle abnormalities.

Most recently, a morbid gene that causes both an atrioventricular conduction defect and DCM in a large kindred with an autosomal dominant inheritance has been mapped to chromosome 1p1-1q1.⁸¹ Based on syntenic mapping studies, the authors speculate that the gap junction protein connexin 40 is a candidate gene for this particular disease.

	Phenotype/Genotype Relation

Top Introduction Evidence for the Existence... Disease Genes for FHC... Disease Genes for DCM... Phenotype/Genotype Relation Clinical Implications References

 
The pattern and extent of left ventricular hypertrophy in patients with HCM vary greatly even in first-degree relatives,⁸² and a high incidence of sudden deaths is reported in selected families. An important issue therefore is to determine whether the genotype heterogeneity observed in FHC accounts for the phenotypic diversity of the disease.

Prognosis
Most known information on differences in the prognosis of HCM according to different mutations comes from the analysis of ß-MHC–related families,^{21 28} and the main clinical consequences of the published mutations of this gene are listed in the Table. Until now, the clinical aspect that has been the most extensively studied is the severity of the disease. For example, several studies report that the Arg⁴⁰³Gln mutation is associated with a high incidence of disease-related deaths, whereas the Leu⁹⁰⁸Arg or the Val⁶⁰⁶Met mutations appear to be more benign.^{21 28} Based on these observations, it has been speculated that mutations that involve a change in the charge of the amino acid residue such as the Arg²⁴⁹Gln, Arg⁴⁰³Gln, or Arg⁴⁵³Cys mutations would be associated with a poor prognosis, whereas neutral mutations such as the Leu⁹⁰⁸Val and the Val⁶⁰⁶Met would be benign.^{21 28} However, a large number of premature sudden cardiac deaths or disease-related deaths were observed in a kindred with the neutral Val⁶⁰⁶Met mutation, whereas in a small Korean kindred with six individuals bearing the Arg⁴⁰³Gln "malignant mutation," no sudden deaths have occurred.⁴⁰ Similarly, in a large kindred, the Gly²⁵⁶Glu mutation was associated with a low incidence of sudden deaths, although this mutation induces a change in the charge of the molecule.⁴⁰ These discrepancies underline the need for large kindreds for the purpose of prognostic analyses and the need for the creation of an international survey on the HCM data base to establish whether a given mutation is benign or malignant. At present, most kindreds are too small to allow any definitive conclusions to be drawn, and most reported data should be considered preliminary.

Penetrance and Left Ventricular Hypertrophy
Correlations between the different mutations observed in the ß-MHC gene and the degree or pattern of ventricular hypertrophy or the penetrance are even more confusing. As observed in the Table, there is no clear relation between the fact that a given mutation is neutral or not and the fact that penetrance is full or partial. Few studies have addressed the relation between missense mutations and the degree or the pattern of hypertrophy. An echocardiographic study of 39 adults carrying six distinct mutations concluded that there were no overt differences in the echocardiographic characteristics, but this study lacked the precision to detect significant differences.⁸³ Furthermore, this kind of analysis is difficult for three main reasons.

First, the number of affected individuals in a given family is in many instances too small to give conclusive evidence that the degree of hypertrophy is influenced by a given mutation. The possibility that distinct ß-MHC mutations are associated with different clinical presentations therefore remains open.

Second, parent mutations occurring within the same codon may result in differences of penetrance and clinical presentation. In one of our families (kindred 720), a GT transversion in codon 403 resulted in the mutation Arg⁴⁰³Leu. This large family is associated with a partial penetrance and a high incidence of end-stage HCM characterized by dilation and pump failure, whereas other families with a GA transition in the same codon, resulting in the mutation of Arg⁴⁰³Gln, have a full penetrance.^{21 28 31} Moreover, in family 720, left ventricular hypertrophy was severe, whereas in another kindred, family 730, another mutation in codon 403 (Arg⁴⁰³Trp) was associated with mild left ventricular hypertrophy.³¹

Third, the degree and pattern of hypertrophy may be different in unrelated families carrying the same mutation or even in relatives of the same family. For example, it was observed that the Val⁶⁰⁶Met mutation is associated with various degrees of hypertrophy in three unrelated families, but this finding did not influence the outcome.²⁸ In three unrelated families carrying the Arg⁴⁰³Gln mutations, variations have been reported with regard to the presence or absence of right ventricular hypertrophy and left ventricular obstruction.^{18 40}

These findings emphasize the role of other factors, including environmental differences, acquired traits (eg, differences in lifestyle, risk factors, and exercise), or modifier genes, that could modulate the phenotypic expression of the disease. Modifier genes are apparent in all genetically mixed populations, and they are commonly referred to as the "genetic background" in which the mutant gene finds itself. Various observations support this idea: (1) first-degree relatives with FHC may exhibit markedly distinct expression of the disease occurring at very different ages⁸⁴ ; (2) monozygotic twins may develop a different expression of the disease, in particular with regard to the extent of hypertrophy and outflow obstruction.⁸⁵ A possible gene modifying the pattern of hypertrophy could be the angiotensin-converting enzyme gene, which contains an insertion/deletion (I/D) polymorphism. This polymorphism is associated with the level of circulating enzyme, the D/D genotype being associated with higher levels of circulating angiotensin-converting enzyme than I/D and I/I genotypes.⁸⁶ The D/D genotype is also associated with an increased risk of left ventricular hypertrophy detected by electrocardiography in middle-aged men recruited in a general population (odds ratio, 2.64).⁸⁷ The frequency of allele D was reported to be higher in FHC families with a high incidence of sudden cardiac deaths than in those with a low incidence.⁸⁸ However, the comparison was made with healthy relatives and not with the general population, and the conclusions of this study, although very interesting, should be considered with caution and deserve further confirmatory results.

Phenotype and genotype analysis of other affected genes, including the -tropomyosin gene on chromosome 15 and the cardiac troponin T gene on chromosome 1, are in an early stage and do not allow any definite conclusions to be made. Preliminary studies suggest differences in phenotypes and prognosis according to the type of mutation.^{14 16 64}

	Clinical Implications

Top Introduction Evidence for the Existence... Disease Genes for FHC... Disease Genes for DCM... Phenotype/Genotype Relation Clinical Implications References

 
The development of molecular biology in the field of cardiomyopathies offers promising perspectives for clinicians.

Revisiting Diagnosis Criteria
Determination of the genotype in FHC provides the opportunity of reassessing major criteria for the diagnosis of HCM by ECG and by Doppler echocardiography. One might expect reexamination of diagnostic criteria in genotyped individuals to be fruitful for clinical cardiology. Assessment of the sensitivity, the specificity, and the predictive values of major abnormalities observed on ECGs and by Doppler echocardiography, including ventricular morphology, systolic anterior motion, and Doppler functional indices such as outflow gradient and diastolic abnormalities, can now be carried out for all of the commonly reported mutations.^{40 83} This analysis may enable one to find new, subtle indexes of the disease and to define more flexible and accurate diagnostic criteria in the highly selected population of families at risk for the disease.

Phenotype/Genotype Relation and Prognosis Stratification
Genetic studies have provided conclusive evidence that the clinical presentation of FHC covers a broad spectrum from apparently normal ventricular function and morphology to severe hypertrophy. The implementation of a large-scale database reporting the different mutations in the different morbid genes associated with the disease in relation to clinical presentations should provide the opportunity to establish a new classification based on the most common genetic defects or on the underlying molecular mechanism. It is therefore likely that the comparison of the clinical data of many unrelated families bearing the same genetic defect will allow the identification of specific clinical subgroups, although this analysis may be obscured by other factors, including ethnic origin or modifier genes.

The analysis of mutation-specific natural history is another major issue. The identification of malignant mutations has important clinical implications with regard to genetic counseling and identification of individuals at high risk of disease-related death, regardless of the mechanism involved (ventricular arrhythmias, atrial arrhythmias, bradyarrhythmias, hypotension, myocardial ischemia, left ventricular outflow obstruction).⁵⁶ Labeling FHC individuals who are prone to sudden death or disease-related death is a difficult clinical issue since clinical and morphological presentations of HCM, including the severity of the hypertrophy, are not accurate prognostic markers,^{89 90 91} and factors recognized as indicating an increased risk of sudden death (ventricular tachycardia on Holter, young age, familial cardiac death, history of cardiac arrest or syncope) are not highly sensitive or specific. Reports of family history and careful follow-up of patients carrying identical mutations will therefore be useful for this purpose, although the question of how to treat these individuals remains open.

Clearly, more studies that would improve our understanding of the relation between phenotype and genotype are warranted, and the ultimate value of genotyping in FHC may be primarily to define an "at-risk" group. This is an area that deserves further careful clinical research.

Identification of Healthy Carriers
Genetic analysis of FHC kindreds has revealed the presence of clinically healthy individuals carrying the mutant allele, which is associated in first-degree relatives with a typical phenotype of the disease.^{21 31} Although it is known that children may develop clinical symptoms during adolescence and that there are reports of selected kindreds with myocardial disarray but no overt hypertrophy,^{56 92} identification of "asymptomatic ill" individuals bearing malignant mutations raises new, important clinical questions, particularly in young adults. Again, exchange of scientific information and careful follow-up of these selected individuals are necessary to assess whether the mutation remains a curiosity without clinical relevance (as in obligate carriers) or whether these individuals will develop the disease later and require early medical management.

Routine Genotyping
Molecular biology applied to routine genotyping offers promising perspectives in genetic counseling, provided that sufficient scientific information is available to establish a genetic-based prognostic database. The main potential application in families with malignant mutations is individual information given to adolescents or young adults for professional purposes (eg, athletes or air crew members). However, evaluation and treatment of each individual should be considered on a case-by-case basis since a widespread difference in phenotype can be seen in patients harboring similar genotypes. Until we define the other contributing modifiers, we will not know what recommendations to make to minimize the risks of the "at-risk" group. Clearly, there is a need to develop animal model systems in which to evaluate these modifier effects on an experimental basis. Moreover, concerns that arose about the psychological, clinical, and discriminative aspects of large-scale genetic risk testing in other diseases such as Huntington's disease also apply to cardiomyopathies, and at present, widespread testing is not indicated in these diseases.

Therapy
Preliminary reports of conventional medical strategies based on specific mutations have been published. In two kindreds with the Arg⁴⁰³Gln mutation, affected individuals have been treated with ß-blockers to prevent excessive tachycardia and with verapamil to prevent myocardial ischemia.⁴⁰ These reports indicate that medical testing (including invasive testing) and medical management of HCM (ß-blockers, verapamil, amiodarone, implantable defibrillator) might be tailored in the future according to the underlying genetic defect. Although research in DCM is preliminary, it is likely that identification of morbid genes in familial forms of the disease will allow early identification and medical management of affected individuals to prevent progressive pump failure, sudden death, or both.

To envisage at this time new gene-based therapeutic strategies to cure or prevent the development of hypertrophic cardiomyopathy is risky, since it is an autosomal dominant disease that involves structural proteins that are expressed at relatively high levels throughout the heart muscle. Once the other determinants (which may very well be acquired) that induce the pathological phenotype in certain patients that harbor the genotype are identified, it should be possible to suggest new preventive or curative strategies. To achieve these important goals, continuous collaboration between geneticists and cardiologists appears to be of high priority for a careful, detailed, large-scale analysis of phenotype/genotype relations of patients that harbor mutations in one of the known loci.

Continued

	Acknowledgments

 
This work was supported by INSERM (Réseau de Recherche Clinique 492010) and by l'Association Française contre les Myopathies.

	References

Top Introduction Evidence for the Existence... Disease Genes for FHC... Disease Genes for DCM... Phenotype/Genotype Relation Clinical Implications References

 
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				S.G. Priori, J. Barhanin, R.N.W. Hauer, W. Haverkamp, H.J. Jongsma, A.G. Kleber, W.J. McKenna, D.M. Roden, Y. Rudy, K. Schwartz, et al. Genetic and molecular basis of cardiac arrhythmias: Impact on clinical management Eur. Heart J., February 1, 1999; 20(3): 174 - 195. [PDF]

				S. D. Nelson, E. A. Sparks, H. L. Graber, H. Boudoulas, A. A. Mehdirad, P. Baker, and C. Wooley Clinical characteristics of sudden death victims in heritable (chromosome 1p1-1q1) conduction and myocardial disease J. Am. Coll. Cardiol., November 15, 1998; 32(6): 1717 - 1723. [Abstract] [Full Text] [PDF]

				B. J. Maron, J. H. Moller, C. E. Seidman, G. M. Vincent, H. C. Dietz, A. J. Moss, J. A. Towbin, H. M. Sondheimer, R. E. Pyeritz, G. McGee, et al. 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 Circulation, October 6, 1998; 98(14): 1460 - 1471. [Full Text] [PDF]

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				F. Fougerousse, A.-L. Delezoide, M. Y. Fiszman, K. Schwartz, J. S. Beckmann, and L. Carrier Cardiac Myosin Binding Protein C Gene Is Specifically Expressed in Heart During Murine and Human Development Circ. Res., January 23, 1998; 82(1): 130 - 133. [Abstract] [Full Text] [PDF]

				P. Spirito, C. E. Seidman, W. J. McKenna, and B. J. Maron The Management of Hypertrophic Cardiomyopathy N. Engl. J. Med., March 13, 1997; 336(11): 775 - 785. [Full Text] [PDF]

				Y. Ohya, I. Abe, K. Fujii, K. Kobayashi, U. Onaka, and M. Fujishima Intima-Media Thickness of the Carotid Artery in Hypertensive Subjects and Hypertrophic Cardiomyopathy Patients Hypertension, January 1, 1997; 29(1): 361 - 365. [Abstract] [Full Text] [PDF]

				J.-F. Forissier, L. Carrier, H. Farza, G. Bonne, J. Bercovici, P. Richard, B. Hainque, P. J. Townsend, M. H. Yacoub, S. Faure, et al. Codon 102 of the Cardiac Troponin T Gene Is a Putative Hot Spot for Mutations in Familial Hypertrophic Cardiomyopathy Circulation, December 15, 1996; 94(12): 3069 - 3073. [Abstract] [Full Text]

				M. L. Schwartz, G. F. Cox, A. E. Lin, M. S. Korson, A. Perez-Atayde, R. V. Lacro, and S. E. Lipshultz Clinical Approach to Genetic Cardiomyopathy in Children Circulation, October 15, 1996; 94(8): 2021 - 2038. [Abstract] [Full Text]

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				K. Schwartz Familial Hypertrophic Cardiomyopathy : Nonsense Versus Missense Mutations Circulation, June 15, 1995; 91(12): 2865 - 2867. [Full Text]

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