STATE-OF-THE-ART PAPER
The Genetic Bases of Cardiomyopathies
Pascale Richard, MD, PhD
,
,
Eric Villard, PhD||,
Philippe Charron, MD, PhD*,
,|| and
Richard Isnard, MD*,,*
* Institut de Cardiologie, Unité Fonctionnelle de Cardiogénétique et Myogénétique, Paris, France
Fédération de Biochimie, Unité Fonctionnelle de Cardiogénétique et Myogénétique, Paris, France
Département de Génétique, Centre Hospitalo-Universitaire Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France
INSERM U 582, Centre Hospitalo-Universitaire Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France
|| INSERM U621, Centre Hospitalo-Universitaire Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France.
Manuscript received August 4, 2006;
revised manuscript received September 15, 2006,
accepted September 15, 2006.
*
Reprint requests and correspondence: Dr. Richard Isnard, Institut de Cardiologie, Centre Hospitalo-Universitaire Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France. (Email: richard.isnard{at}psl.aphp.fr).
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Abstract
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Cardiomyopathies represent an important cause of cardiovascular morbidity and mortality due to heart failure, arrhythmias, and sudden death. A majority of hypertrophic cardiomyopathies (HCM) and at least 30% of dilated cardiomyopathies (DCM) are familial forms, with most often an autosomal dominant mode of inheritance. Over the last 15 years, our knowledge on the genetic bases of these diseases has considerably improved. Cardiomyopathies are characterized by a great genetic heterogeneity at both allelic and non-allelic levels. Hypertrophic cardiomyopathies are mainly linked to mutations on genes encoding sarcomeric proteins, and beta myosin heavy chain and myosin binding protein C gene mutations account for about 80% of genotyped cases. Familial DCM is associated with mutations in genes encoding sarcomeric proteins but also other proteins of the myocyte, such as cytoskeletal or nuclear membrane proteins. Due to the genetic heterogeneity and the variable clinical expressivity of these diseases, the relations between genotype and phenotype remain complex, but the age of onset, the clinical severity, or associated phenotypes may be, at least in part, related to the precise gene mutations. Therefore, besides a better understanding of the molecular basis for cardiac remodeling and heart failure, the genetic analysis of cardiomyopathies is going to play an increasing role in the routine management of these patients in the following years, particularly in HCM.
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Abbreviations and Acronyms
| | ATP = adenosine triphosphate | | DCM = dilated cardiomyopathy | | HCM = hypertrophic cardiomyopathy | | LVH = left ventricular hypertrophy |
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The role of genetic factors in the pathogenesis of cardiomyopathies has received growing attention during the past 15 years and dramatically changed our understanding of these diseases. Cardiomyopathies are defined as diseases of the myocardium with cardiac dysfunction and can be complicated by heart failure, arrhythmias, and sudden death (1). Therefore, they represent an important cause of cardiovascular morbidity and mortality, and a frequent reason for cardiac transplantation. They are classified into 4 main distinct entities according to the type of anatomical and functional impairment: dilated, hypertrophic, restrictive, and arrhythmogenic right ventricular dysplasia, the 2 former being the most frequent forms and focused on in this review. For hypertrophic cardiomyopathy (HCM), increasing recognition that most cases were familial forms has led to attempts for identifying the genetic defect. Since the discovery of the first mutation in the beta-myosin heavy chain gene in a large French-Canadian family in 1990 (2), a large number of mutations on different genes encoding sarcomeric proteins has been found. The identification of morbid genes in dilated cardiomyopathy (DCM) is more recent, but this disease is also characterized by a great genetic heterogeneity, which makes the genetic approach of the cardiomyopathies complex.
Besides the improvement of our knowledge of the molecular mechanisms of these diseases, the genetic diagnosis is beginning to have some important clinical implications in the routine management of the patients.
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HCM
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Hypertrophic cardiomyopathy is a myocardial disease defined by an unexplained left ventricular hypertrophy (LVH), usually asymmetrical and involving the interventricular septum. This definition implies that a detectable cause of hypertrophy such as hypertension or amyloidosis must be excluded. This LVH is generally associated with normal systolic function, abnormal diastolic function, and is responsible for a systolic dynamic obstruction of the left ventricular outflow tract in about 25%. Histopathological features of HCM are myocyte hypertrophy with myocardial disarray and increased interstitial fibrosis (3). Several echocardiographic studies on cohorts of adults from various ages and races have reported an estimated prevalence of unexplained hypertrophied non-dilated left ventricle (wall thickness 
15 mm), compatible with the diagnosis of HCM, of about 1 of 500 (4,5). Hypertrophic cardiomyopathy is a familial disease in at least 50% of cases, with an autosomal dominant mode of inheritance. The penetrance of the disease is nearly complete but dependent on age and gender.
The clinical pattern is highly heterogenous: many patients have no symptoms during their whole life, but, in some cases, HCM may lead to severe symptoms such as syncope or dyspnea, to sudden death, or congestive heart failure, and it remains the most prevalent cause of sudden death in athletes during exercise (3).
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Causal genes and mutations
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Genes.
The genetic aspect of HCM is characterized by a high heterogeneity both at allelic and non-allelic level. The identification of 13 disease genes encoding sarcomeric proteins has led to the definition of primary HCM as a disease of the sarcomere. Four genes code for proteins of the thick filament (MYH7-ß myosin heavy chain, MYH6-
myosin heavy chain, MYL2 regulatory myosin light chain, MYL3 essential myosin light chain); 5 genes code for the thin filament structure (ACTC cardiac actin, TPM1- tropomyosin, TNNT2 cardiac troponin T, TNNI3 cardiac troponin I, TNNC1 cardiac troponin C); 2 genes code for assembly proteins (MYBPC3 cardiac myosin binding protein C and TTN titin); 2 genes code for proteins of the Z band (TCAP telethonin, CRP3 muscle LIM protein) (Table 1). In addition, rare mutations in genes coding for associated proteins such as vinculin and metavinculin have been reported (6).
Distribution of genes.
The distribution of the disease genes by identification of pathogenic mutations was extensively determined in several Caucasian populations. In the experience of the French population, the causal mutation was identified in 61% of HCM patients using single-strand conformation polymorphism as detection method (7), suggesting that a potential higher rate could be found with a more sensitive technology. In all cohorts, MYBPC3 and MYH7 were the most common genes responsible for the disease, each of them being involved in 30% to 40% of genotyped index patients. TNNT2, TNNI3, TPM1, ACTC, MYL2, and MYL3 are involved in 1% to 5% of cases (7–11). The other genes are reported only in few cases not allowing co-segregation analysis (12,13). Nowadays in our experience of a clinical molecular diagnostic laboratory, the mutations detection rate reaches 70% in index patients with HCM. In addition, a recent study showed that the morphology of the septum hypertrophy could predict the yield of mutations found in the sarcomeric genes (14). In the remaining patients, the lack of identified disease-causing mutation may be due to other causes of LVH, lack of sensitivity of screening technologies, mutations in not yet explored intronic or regulation sequences of genes, or still unknown genes.
Mutations.
Extensive analysis of these genes revealed an important non-allelic heterogeneity by the identification of more than 400 mutations. The spectrum of pathogenic mutations is different between the 2 major genes MYH7 and MYBPC3. In MYH7, nearly 200 mutations are described. Among them, 70% are located in the globular head and neck domains of the protein coding regions, and 30% are located in the rod domain. These mutations are almost exclusively missense (96%), but several codon deletions not disrupting the reading frame have also been found, all located in the flexible domain of the protein between the globular head and the rod domain (del Lys847, del Glu883, del Glu927, del Glu930). In MYBPC3, there are about 150 identified mutations, located along the whole gene: 70% of them are non-sense mutations leading to a putative null allele (termination codon, splice site mutations, small deletions, or insertions disrupting the reading frame), whereas 30% of them are missense. In the TNNT2 and MYL2 genes, the identified mutations are located all along the coding sequence, but in TNNI3, all mutations identified so far except 1 are located in exon 7 and 8 encoding for the C-terminal domain of the protein. The only deletion found is at the end of exon 8 encompassing the stop codon (15). Finally, in our experience of a large scale mutation identification study, the rate of unknown mutations found (never identified before but not "de novo" mutations) in 1 of the 2 genes MYH7 and MYBPC3 is between 60% and 80% depending on the population and the number of index patients tested. Thus, most mutations in HCM are private (i.e., only related to a single family and very few mutations are found in more than 1 family). However, in each gene, several residues have been described to be hot spots for mutations as Arg403, Arg453, Arg663, Gly741, Arg719, and Asp778 in the MYH7 gene, and Arg502, and the splice acceptor site variant IVS20-2: a > g in the MYBPC3 gene, codon Arg92 in TNNT2, or codon Arg58 in MYL2. The fact that mutations are private to each family have implications for the molecular diagnosis, in a sense that it is necessary to sequence the entire gene at least for the most commonly involved ones (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, and ACTC).
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Impact of genetics on the understanding of the disease
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Molecular pathogenesis.
The mechanisms by which a sarcomere single mutation leads to HCM is far from being totally understood (16–19). The sarcomere is a complex structure with an exact stoichiometry and multiple sites of interaction between proteins (17,18), and the mechanism of cardiac contraction is also complex. After depolarization, the intracellular calcium binds to the troponin complex; this allows the myosin head to bind to actin and, after adenosine triphosphate (ATP) hydrolysis, to be displaced along the thin filament. Thin and thick filaments slide past one another, driving sarcomere shortening and muscle contraction. The role of cardiac binding myosin protein C remains poorly understood; it may participate in the thick filament assembly by binding to myosin heavy chain and titin, and have some regulatory function (20).
Most of the heterozygous mutations are missense, especially in the MYH7 gene, and lead to a mutant protein with a replacement of an amino acid by another one; this mutant protein has been shown to incorporate into the sarcomere, and is supposed to interfere with the wild-type protein, acting as poison polypeptide with a dominant negative effect (21). The result of this incorporation is an abnormal function and/or assembly of the sarcomere with myofibrillar disarray. This hypothesis is supported by a variety of results obtained by in vitro studies, engineered animal models, and rare in vivo studies from explanted hearts from patients with HCM (16,17).
On the other hand, especially in the MYBPC3 gene but also in other genes, the identification of null mutations (frame-shift and non-sense) have suggested a putative mechanism of haploinsufficiency by the production of an unstable transcript and/or a truncated protein unable to incorporate into the sarcomere. This mechanism was not confirmed in studies related to MYBPC3 and TNNT2 genes (22), in which a dominant negative action was even shown (23). However, it has been recently shown in heterozygous MYBPC3 null mice that this mutant protein was undetectable in the myocardial tissue, and therefore could lead to an altered stoichiometry of sarcomere proteins (24).
The generation of engineered animal models of human mutation has allowed a more accurate evaluation of the processes leading from the gene defect to the HCM phenotype (25–28). However, the experimental studies performed either in vitro or in animal models have shown discrepancies regarding the impact of mutations on the function, not necessarily related to the gene or the mutation. In some models, Ca(+2) sensitivity and actin-activated ATPase activity were reduced, resulting in a decrease of acto-myosin interactions, and finally a decrease in myocyte contractility (29,30). The impaired myocyte contractility is supposed to activate the release of stress-related signaling kinases and trophic factors, which stimulate myocyte hypertrophy. This chronology is supported by the fact that functional impairment (diastolic abnormalities) precedes the development of hypertrophy (31).
However, this concept may be misleading because different results have also been observed in many other models, which are associated with enhanced ATPase activity in myosin and enhanced actomyosin interaction, leading to an increase of the force generation and the cardiomyocyte contractility (21,32–34). The consequence of this gain of function is an increased work and energy consumption. In addition, the co-existence of mutant and wild-type proteins within the sarcomere may result in uncoordinated contraction. Finally, this process may lead to energy depletion, myocyte death, and replacement fibrosis (18). The hypothesis that energy depletion underlies HCM is also supported by the HCM-like phenotype found with mutations in mitochondrial DNA mutations or PRKAG2 gene mutations (35).
Additionally, it has also been suggested that calcium pathways could play a critical role in the myocyte hypertrophy process (36). Other emerging hypothesis have been recently raised: in Drosophila, the overexpression of human mutant cMyBP-C is associated with a down-regulation of several genes encoding sarcomeric proteins and a change in the expression of genes involved in several metabolic pathways, compatible with the energy depletion hypothesis (37). Using an adenovirus-based approach in neonatal rat cardiomyocytes, the expression of human mutant cMyBP-C is decreased, and the truncated proteins are preferentially degraded by the ubiquitin-proteasome system, whose proteolytic capacity for other substrates may be competitively impaired and may result in hypertrophy (38).
Taken together, all these observations and findings in animal models revealed the complexity and the probable involvement of multiple mechanisms implicating multiprotein complexes in the pathophysiology of HCM.
Inheritance and penetrance.
Most of the patients are heterozygous for the mutation, which segregates as an autosomal dominant trait, the mutation being transmitted by one of the parents. However, some de novo mutations have also been reported (39,40). In some cases (3% to 5%), 2 different mutations may be present in a same individual, most often in MYH7 and MYBPC3 leading either to compound heterozygous patients (2 heteroallelic mutations in the same gene), double heterozygous patients (2 heterozygous mutations in 2 different genes), or homozygous patients (same mutation on the 2 alleles of the same gene) (7,41,42). This finding must be taken into account in the context of the genetic counseling.
Molecular studies have shown that 20% to 30% of adult patients were healthy carriers (i.e., carried the mutation but did not express the disease at time of inquest). However, prospective studies are needed in order to confirm whether or not the "healthy carriers" are going to develop the disease later.
Genotype-phenotype relations.
The degree of hypertrophy, the age of onset, and the severity of the symptoms have been shown to be, at least in part, related to the precise gene mutations, but these results remain to be confirmed in large prospective studies. For example, TNNT2 mutations are usually associated with a severe phenotype that is relatively homogenous among mutations and characterized by a high incidence of sudden death, especially in young patients despite a mild degree of hypertrophy (43). However, the Phe110Ile mutation is associated with a favorable outcome (44). In MYH7 mutations, the phenotype varies considerably according to the mutations, some mutations, such as Val606Met being associated with a benign phenotype, when others such as Arg403Gln are associated with reduced survival, complete penetrance in adults, and high degree of hypertrophy (45,46).
The reason for this variability is not clearly understood and does not seem to be related to the affected functional domain. It has been suggested that it could be related to the net electrical charge of the protein. However, many exceptions have been subsequently described. Compared with MYH7 mutations, mutations on MYBPC3 are usually associated with a delayed onset, an incomplete penetrance, a lower degree of hypertrophy, and a better survival (47,48), but another study has reported undistinguishable phenotypes between these 2 genes (8). Finally, patients with double mutations generally exhibit a more severe form of HCM than patients with single gene defects; this is especially true for homozygous patients (7,41,49,50).
There is also a great variability in the expression of the disease even among individuals of the same family who carry the same mutation. It is, therefore, evident that other factors are likely to modulate the phenotype. These factors can be environmental; for example, it has been shown that monogenic twins could have very different degree of hypertrophy (51), and it can be speculated that exercise or blood pressure could play a role in the hypertrophic response to a single major gene mutation. Other factors can be related to the genetic background of the individual (modifier genes); the role of modifier genes has been supported by experimental studies in transgenic mice and also in human beings, in whom several genetic polymorphisms mainly related to the renin-angiotensin-aldosterone system have been shown to play a role. The most commonly implicated is the insertion/deletion polymorphism of the angiotensin-converting enzyme, which has been shown to be associated with the risk of sudden cardiac death and the severity of LVH (52–57), but endothelin (54) and angiotensin II type 2 receptor (58) polymorphisms have also been reported as modifier genes. However, the intrinsic variability related to causal genes makes the search for modifier genes complicated.
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Practical implications for the clinician
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One key issue for the clinician is how to use these new genetic tools for the routine care of patients (59). Until now, these molecular analyses have been confined in few research-oriented laboratories because it is a time-consuming and expensive process, and it is not yet reimbursed by the health care systems. However, there are now several potential clinical applications that deserve the routine sequencing of at least major genes.
Due to the large genetic heterogeneity and the fact that no single mutation predominates within each of the causal genes, the molecular strategy for an index patient in a given family should be based on a direct sequencing of the 2 most frequently involved genes, MYH7 and MYBPC3, which are each responsible for at least 40% of the already known mutations (Fig. 1). If no mutation is found in these 2 genes, this first step should be followed by the sequencing of TNNT2, TNNI3, MYL2, MYL3, TPM1, and ACTC, which allows identification of 10% to 20% more mutations (7,60). The screening of the other genes cannot be recommended in routine care. Although extensive molecular analyses, a mutation is not found with current tools in up to 30% to 50% of families with HCM. Obviously this negative finding does not exclude the diagnosis of HCM but only means that an additional not yet described gene is probably involved in the given family. Another explanation is the possibility of an alternative pathology that may mimic HCM such as metabolic cardiomyopathies; Anderson-Fabry disease due to mutations in the gene of -galactosidase should be considered in all cases of unexplained LVH, as it is a potentially treatable cause (61); unexplained LVH associated with Wolff-Parkinson-White syndrome may reflect mutations in the 
2 regulatory subunit of adenosine monophosphate–activated protein kinase (PRKAG2) (62); finally, X-linked HCM can be related to mutations of lysosome-associated membrane protein (LAMP2) gene (Danon’s disease) (63).
Once a mutation has been identified in an index patient, genetic testing can be proposed to the apparently healthy relatives, in order to know if they carry the mutations and if they have a risk of developing the disease later on (51,64); the identification of a mutation should lead to a more careful clinical follow-up (for example, electrocardiogram and echocardiography every year) and to exclude competitive sports or sportive professional carriers. On the other hand, in the absence of mutation, the relative will be reassured for the risk of developing the disease and of transmitting it to his children, and no more cardiologic follow-up is needed (Fig. 1). However, the potential advantages of the pre-clinical genetic diagnosis may be counterbalanced by the fact that there is no preventive treatment for delaying the onset of the disease; the clinical expression is highly variable and the disclosure of mutation can induce adverse psychological consequences, especially in children. Therefore, this process must be discussed with the individuals using the multidisciplinary approach of a genetic counseling (64). Similarly, the prenatal diagnosis, which is theoretically possible, raises much more complex ethical, psychological, and medical problems, and should be restricted to very few selected cases.
In other situations, molecular analysis can help to distinguish other causes of hypertrophy from HCM; for instance, in athletes with mild cardiac hypertrophy, it is crucial to differentiate a physiological hypertrophy in response to exercise from an early stage of HCM, and in some uncertain forms, the finding of an HCM mutation may have a major implication regarding the continuation of his competitive career. However, on the other hand, the absence of HCM mutation cannot exclude the diagnosis.
Finally, genetic testing may sometimes help the clinician to better stratify the risk of sudden death in patients with HCM. Besides clinical risk factors (familial sudden death, syncope, previous sudden death, severe LVH, and abnormal blood pressure response to exercise), the presence of a malignant mutation (i.e., TNNT2 mutation) can, on a case-by-case basis, influence the decision for the implantation of a cardiac defibrillator. However, this strategy is not validated and applies only to mutations, which have been clearly associated with a high risk of death in several large families.
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DCM
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Dilated cardiomyopathy is the most prevalent cause of congestive heart failure in young patients, with an estimated prevalence of 36 of 100,000 in the U.S., and also an important cause of cardiac transplantation (65). It is characterized by cardiac chamber enlargement, thin wall thickness, and depressed left ventricular systolic function. Histologic findings are non-specific including myocyte loss and interstitial fibrosis (66). Familial cases of DCM were initially considered as quite rare. However, recent studies with a systematic and careful screening of relatives have shown that up to 35% of patients with DCM had a familial disease (30,67–69). In these families, the pattern of inheritance is variable, including autosomal dominant, autosomal recessive, X-linked, or mitochondrial mode of transmission. However, autosomal dominant pattern is the most frequent mode of inheritance. The penetrance of DCM is variable and age-related (70). The phenotype is also highly heterogeneous, in terms of functional severity, degree of cardiac dilatation, and impairment of systolic function, and also because the myocardial disease may be isolated, or associated with cardiac conduction disease or muscular dystrophy (69).
Genes and mutations.
Since the identification of the first mutation responsible for autosomal dominant DCM in the gene encoding the sarcomeric protein alpha-actin in 1998 (71), many studies have been conducted to identify the molecular basis of familial, monogenic forms of DCM. Presently, at least 15 different causal genes have been identified with variable individual prevalence ranging from <1% to 10% (72–74). These genes are related not only to sarcomeric proteins but also to proteins of the nuclear membrane, lamin A and lamin C (lamin A/C) (75), cytoskeletal (desmin, dystrophin, and dystrophin-sarcoglycan complex) (76,77), and phospholamban (78) (Table 2). Moreover, 7 loci genetically linked to DCM have been reported but without gene identification. Interestingly, careful examination of these linkage regions fails to pinpoint strong candidate genes according to standard criteria such as cardiac restricted expression or function related to known heart physiology. Thus, there are some other, yet unknown, genes responsible for familial DCM.
Functional consequences of mutations.
The very large genetic and phenotypic heterogeneity observed in DCM suggests several different mechanisms conducting from mutations to disease. To date, DCM-responsible genes identified are all expressed in the cardiomyocytes. Encoded proteins are involved in many different metabolic or structural functions in the cardiac cell, and numerous pathophysiological hypotheses have been formulated in order to link the mutations to the disease process (19). First, mutations in sarcomeric proteins are believed to be responsible for a deficit in force production. Mutations in contractile apparatus proteins such as beta myosin heavy chain, cardiac alpha-actin, and troponin-tropomyosin complex could lead to DCM. Force production impairment due to reduced actomyosin interaction or impaired ATP utilization, for myosin head mutations, and decreased Ca2+ sensitivity due to mutations in the troponin genes have been postulated and partially confirmed by experimental results (72,79,80). However, given the absence of regional clustering of mutations in specialized domains of encoded proteins, multiple pathways responsible for disease onset can be discussed for mutations taking place in the same gene. For instance, it is unlikely that mutations in the tail domain of beta myosin heavy chain could play a role in force generation but they could more probably be involved in the structural conservation of the thick filament integrity and resistance to stretch. Mutations of sarcomeric structural components, in gene encoding the sarcomeric backbone titin and in components of the Z-line (ZASP/Cypher and alpha-actinin 2) have also been reported (81–83). There is no clear evidence of the disease mechanisms associated with mutations in these genes. An interesting possibility could be an alteration of both stretch sensing and downstream signaling to the nucleus leading to cardiac remodeling and DCM. This has been demonstrated in muscle LIM protein knock-out mice, a model of human DCM, in which stretch sensing is impaired and leads to heart dilation and failure (84). The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human DCM.
Interestingly, even if sarcomere protein gene mutations leading to DCM are distinct from HCM-causing mutations, they may affect very close amino acid residues (73).
Another probable mechanism could be a deficit in force transmission from cell to cell leading to heart dilatation in gene mutations of proteins involving intermediate filament, cytoskeletal architecture, and membrane anchoring of the sarcomere like desmin, dystrophin-sarcoglycan complex, or metavinculin (76,85,86). This functional hypothesis results mainly from the known function of the proteins and a few experimental results. For instance, metavinculin, the cardiac-specific isoforms of vinculin, and desmin are known to participate in sarcomere anchoring to intercalated Z disks, to the plasma membrane, and, for desmin, to the nucleus. Mutated proteins might result in an impairment of the transduction of mechanic forces through the cellular architecture and to adjacent cells. An intriguing question concerns DCM due to LMNA mutations, encoding lamin A/C protein, which is organized as a network, located at the inner nuclear membrane and involved in membrane structure integrity and chromatin interaction. LMNA mutations are associated with a very wide number of phenotypically unrelated syndromes including DCM associated with conduction disorders. There is no definite explanation on underlying mechanisms for cardiac or non-cardiac disorders resulting from LMNA mutations. However, LMNA knock-out in mice suggests that a lack in lamin protein results in a loss of desmin intermediate filament anchoring to the nucleus; this might induce a decrease in cytoskeletal tension and subsequent defect in force transmission (87).
More recently, a role for Ca cycling regulation has been demonstrated in a family presenting with DCM and a mutation in the highly conserved phospholamban protein, the regulator of the sarcoplasmic endoplasmic reticulum calcium ATPase (SERCA)2a calcium pump of the endoplasmic reticulum. The Arg9Cys substitution induced by the heterozygous mutation is, in transgenic mice over-expressing the mutant phospholamban, responsible for chronic inhibition of the SERCA function, depressed contractility and, ultimately, heart dilation (78).
Genotype-phenotype relations.
Some gene mutations are associated with specific phenotype; for example, mutations on genes encoding intermediate filaments or cytoskeletal proteins (dystrophin, dystrophin sarcoglycan complex, desmin) can be responsible for DCM associated with skeletal myopathy or increased plasma creatine kinase (76,77). LMNA mutations can cause DCM with conduction disorders (atrioventricular block of different degree, sinus node dysfunction), atrial fibrillation, and skeletal myopathy (Table 2) (66,67,75,88). Due to the fact that most mutations described so far are private or observed in few families, little information is available on genotype-phenotype relationship for other mutations; however, it has been suggested that MYH7 mutations were associated with later onset, incomplete penetrance, and delayed major cardiac events compared with troponin mutations (73).
Non-monogenic forms of DCM.
Unlike HCM, most DCM forms cannot be assigned to single gene defects. In these forms, environmental, viral, or immunological factors are likely to play a key role in the pathogenesis of the disease. However, even in these multifactorial forms, it can be hypothesized that genetic factors could influence either the development or the evolution of the disease. Some genes, susceptibility genes, have been shown usually through case-control studies to be associated with an increased risk of developing a DCM (Table 3). Other genes such as genes related to the renin-angiotensin system or the adrenoreceptors were reported as modifier genes defined as genetic factors, which may modulate the phenotype of a disease usually in terms of severity and prognosis (Table 4). In addition, very few data are reported about pharmacogenetic interactions. In a retrospective study, interaction between beta-blockers and the insertion/deletion angiotensin-converting enzyme polymorphism on the survival of patients with heart failure was suggested (89). However, all reported studies about multifactorial DCM have methodologic limitations, and results should be considered as preliminary. This is due to the small size of the populations, and to the fact that some of the studies were retrospective, that results were usually not replicated in independent populations, that multiple statistical comparisons may produce false-positive results, and finally that interactions between polymorphisms/genes were not examined. Another important issue is to clearly describe the functional role of the variants identified.
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Practical issues for the clinician
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Because it is now established that familial cases account for at least 30% of all DCM, it should, therefore, be recommended to perform routine echocardiographic evaluation in all first-degree relatives. This evaluation would allow detecting affected relatives, who could benefit from an early follow-up and treatment. It could also identify relatives with minor abnormalities (such as left ventricular enlargement or mild depressed systolic function) who could benefit from a serial echocardiographic follow-up, because these individuals are at risk of developing the disease (90). Although there is no prospective study in this area, early treatment by angiotensin-converting enzyme inhibitors or beta-blockers could limit the progression of the disease in these high-risk patients (91,92). However, unlike HCM, genetic testing cannot be recommended in routine in common forms of familial DCM due to the poor yield and the excessive cost of this strategy. The only exception concerns the MYH7 mutations, which could be involved in up to 10% of these families. We propose an analysis of this gene in some families, when genetic results may have clinical implication in terms of pre-clinical diagnosis. In addition, some associated phenotypes, such as skeletal myopathy, atrial fibrillation, or conduction disorders, must be carefully examined as they could orient toward specific gene mutations, as for example LMNA mutations. In our experience, according to the high rate of de novo mutations found in LMNA, we propose this analysis in all DCM patients (familial and sporadic cases) with conduction disorders (93). This could have therapeutic implication because lamin A/C mutations are associated with a high rate of sudden death (94). Analysis of genetic factors involved in non-monogenic forms of DCM (susceptibility or modifier genes) cannot be recommended in clinical practice at the present time because available results are only preliminary and still required to be confirmed in large independent populations. In the future however, these genetic factors will be probably of great interest. The characterization of modifier genes in a patient with multifactorial DCM will be particularly useful to improve the prognostic stratification and better decide the therapeutic management of the patient.
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Clinical perspectives derived from molecular results
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Today, more than 40% of patients with familial HCM and even more patients with DCM remain with non-identified causing gene defects. In addition, several loci with unknown candidate genes have been identified in patients with DCM. Genetic heterogeneity at both locus and mutation levels leads to time-consuming and expensive genetic analyses that are not taken in charge by health insurances. The development of new sensitive, fast, and cheap technologies for mutation screening could be an important issue in the diagnosis of these diseases. Genetic heterogeneity also represents an important limitation to better understand the complex relations between genotype and phenotype in both HCM and DCM. Therefore, there is a need for large international cohorts of patients and relatives with common phenotypic criteria and follow-up procedures, and for DNA banks. The Eurogene Heart Failure Study, which was launched in 2001 with the support of the Fondation Leducq, is a large European registry of more than 2,500 patients with HCM and DCM and relatives, included from 11 centers in Europe. This registry will provide in the next years important insights regarding the role of genetics in cardiomyopathies. This includes discovery of new causal genes, genes of susceptibility, and modifier genes. It is anticipated that results obtained by this European consortium will translate into a better understanding of the mechanisms of HCM and DCM, and ultimately to better management of these high-risk patients.
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Footnotes
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Supported by the Fondation Leducq.
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Abstract
HCM
