The molecular genetic basis for hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM), a relatively common disease, is diagnosed clinically by unexplained cardiac hypertrophy and pathologically by myocyte hypertrophy, disarray, and interstitial fibrosis. HCM is the most common cause of sudden cardiac death (SCD) in the young and a major cause of morbidity and mortality in elderly. Hypertrophy and fibrosis are the major determinants of morbidity and SCD. More than 100 mutations in nine genes, all encoding sarcomeric proteins have been identified in patients with HCM, which had led to the notion that HCM is a disease of contractile sarcomeric proteins. The beta -myosin heavy chain (MyHC), cardiac troponin T (cTnT) and myosin binding protein-C (MyBP-C) are the most common genes accounting for approximately 2/3 of all HCM cases. Genotype-phenotype correlation studies suggest that mutations in the beta -MyHC gene are associated with more extensive hypertrophy and a higher risk of SCD as compared to mutations in genes coding for other sarcomeric proteins, such as MyBP-C and cTnT. The prognostic significance of mutations is related to their hypertrophic expressivity and penetrance, with the exception of those in the cTnT, which are associated with mild hypertrophic response and a high incidence of SCD. However, there is a significant variability and factors, such as modifier genes and probably the environmental factors affect the phenotypic expression of HCM. The molecular pathogenesis of HCM is not completely understood. In vitro and in vivo studies suggest that mutations impart a diverse array of functional defects including reduced ATPase activity of myosin, acto-myosin interaction, cross-bridging kinetics, myocyte contractility, and altered Ca2+ sensitivity. Hypertrophy and other clinical and pathological phenotypes are considered compensatory phenotypes secondary to functional defects. In summary, the molecular genetic basis of HCM has been identified, which affords the opportunity to delineate its pathogenesis. Understanding the pathogenesis of HCM could provide for genetic based diagnosis, risk stratification, treatment and prevention of cardiac phenotypes.     

Cardiac troponin T Arg92Trp mutation and progression from hypertrophic to dilated cardiomyopathy

BACKGROUND: Mutations in the cardiac troponin T gene causing familial hypertrophic cardiomyopathy (HCM) are associated with a very poor prognosis but only mild hypertrophy. To date, the serial morphologic changes in patients with HCM linked to cardiac troponin T gene mutations have not been reported. HYPOTHESIS: The aim of this study was to determine the long-term course of patients with familial HCM caused by the cardiac troponin T gene mutation, Arg92Trp. METHODS: In all, 140 probands with familial HCM were screened for mutations in the cardiac troponin T gene. RESULTS: The Arg92Trp missense mutation was present in 10 individuals from two unrelated pedigrees. They exhibited different cardiac morphologies: three had dilated cardiomyopathy-like features, five had asymmetric septal hypertrophy with normal left ventricular systolic function, one had electrocardiographic abnormalities without hypertrophy, and one had the disease-causing mutation but did not fulfill the clinical criteria for the disease. The mean maximum wall thickness was 14.1 +/- 6.0 mm. The three patients with dilated cardiomyopathy-like features had progressive left ventricular dilation. Three individuals underwent right ventricular endomyocardial biopsy. There was a modest degree of myocardial hypertrophy (myocyte diameter: 18.9 +/- 5.2 microm), and minimal myocardial disarray and mild fibrosis were noted. CONCLUSION: The Arg92Trp substitution in the cardiac troponin T gene shows a high degree of penetrance, moderate hypertrophy, and early progression to dilated cardiomyopathy in Japanese patients. Early identification of individuals with this mutation may provide the opportunity to evaluate the efficacy of early therapeutic interventions.     

Three-dimensional structure of vertebrate cardiac muscle myosin filaments

Contraction of the heart results from interaction of the myosin and actin filaments. Cardiac myosin filaments consist of the molecular motor myosin II, the sarcomeric template protein, titin, and the cardiac modulatory protein, myosin binding protein C (MyBP-C). Inherited hypertrophic cardiomyopathy (HCM) is a disease caused mainly by mutations in these proteins. The structure of cardiac myosin filaments and the alterations caused by HCM mutations are unknown. We have used electron microscopy and image analysis to determine the three-dimensional structure of myosin filaments from wild-type mouse cardiac muscle and from a MyBP-C knockout model for HCM. Three-dimensional reconstruction of the wild-type filament reveals the conformation of the myosin heads and the organization of titin and MyBP-C at 4 nm resolution. Myosin heads appear to interact with each other intramolecularly, as in off-state smooth muscle myosin [Wendt T, Taylor D, Trybus KM, Taylor K (2001) Proc Natl Acad Sci USA 98:4361-4366], suggesting that all relaxed muscle myosin IIs may adopt this conformation. Titin domains run in an elongated strand along the filament surface, where they appear to interact with part of MyBP-C and with the myosin backbone. In the knockout filament, some of the myosin head interactions are disrupted, suggesting that MyBP-C is important for normal relaxation of the filament. These observations provide key insights into the role of the myosin filament in cardiac contraction, assembly, and disease. The techniques we have developed should be useful in studying the structural basis of other myosin-related HCM diseases.     

Sudden cardiac death in patients with hypertrophic cardiomyopathy: From bench to bedside with an emphasis on genetic markers

Hypertrophic cardiomyopathy (HCM) is the most common cause of death in the young, particularly in young competitive athletes. Death often occurs suddenly in asymptomatic, apparently healthy individuals. Several clinical parameters as well as genetic factors have been characterized that can identify those HCM patients who are at high risk for sudden cardiac death (SCD). The clinical parameters that have some predictive values for SCD in HCM patients are the following: a prior history of SCD, a family history of SCD, history of syncope, symptomatic ventricular tachycardia on Holter monitoring, inducible ventricular tachycardia during electrophysiologic studies, and myocardial ischemia in children with HCM. Recent identification of mutations in the beta myosin heavy chain gene and genotype-phenotype correlation in HCM patients have shown that the beta myosin heavy chain mutations are also prognosticators in HCM families. Several mutations such as Arg⁴⁰³Gln and Arg⁷¹⁹Gln are associated with a high incidence of SCD, while Leu⁹⁰⁸Val mutation is associated with a benign course and a low incidence of SCD in HCM families. Additional genetic factors such as a polymorphism in angiotensin-converting enzyme I gene may also contribute to a high incidence of SCD in HCM families. Identification and characterization of HCM patients at high risk for SCD provide the opportunity to render prophylactic therapeutic interventions, such as implantation of defibrillators, in these individuals.     

Identification of the genotypes causing hypertrophic cardiomyopathy in northern Sweden

Hypertrophic cardiomyopathy (HCM) is a heterogenous disease, with variable genotypic and phenotypic expressions, often caused by mutations in sarcomeric protein genes. The aim of this study was to identify the genotypes and associated phenotypes related to HCM in northern Sweden. In 46 unrelated individuals with familial or sporadic HCM, mutation analysis of eight sarcomeric protein genes was performed; the cardiac beta-myosin heavy chain, cardiac myosin-binding protein C, cardiac troponin T, alpha-tropomyosin, cardiac essential and regulatory myosin light chains, cardiac troponin I and cardiac alpha-actin. A total of 11 mutations, of which six were novel ones, were found in 13 individuals. Seven mutations were located in the myosin-binding protein C gene, two in the beta-myosin heavy chain gene and one in the regulatory myosin light chain and troponin I genes, respectively. This is the first Swedish study, where a population with HCM has been genotyped. Mutations in the cardiac myosin-binding protein C gene were the most common ones found in northern Sweden, whereas mutations in the beta-myosin heavy chain gene were less frequent than previously described. There are differences in the phenotypes mediated by these genes characterised by a more late-onset disease for the myosin-binding protein C gene mutations. This should be taken into consideration, when evaluating clinical findings in the diagnosis of the disease, especially in young adults in families with HCM, where penetrance can be expected to be incomplete in the presence of a myosin-binding protein C gene mutation.     

HCM-linked ∆160E cardiac troponin T mutation causes unique progressive structural and molecular ventricular remodeling in transgenic mice

Hypertrophic cardiomyopathy (HCM) is a primary disease of the cardiac muscle, and one of the most common causes of sudden cardiac death (SCD) in young people. Many mutations in cardiac troponin T (cTnT) lead to a complex form of HCM with varying degrees of ventricular hypertrophy and ~ 65% of all cTnT mutations occur within or flanking the elongated N-terminal TNT1 domain. Biophysical studies have predicted that distal TNT1 mutations, including Δ160E, cause disease by a novel, yet unknown mechanism as compared to N-terminal mutations. To begin to address the specific effects of this commonly observed cTnT mutation we generated two independent transgenic mouse lines carrying variant doses of the mutant transgene. Hearts from the 30% and 70% cTnT Δ160E lines demonstrated a highly unique, dose-dependent disruption in cellular and sarcomeric architecture and a highly progressive pattern of ventricular remodeling. While adult ventricular myocytes isolated from Δ160E transgenic mice exhibited dosage-independent mechanical impairments, decreased sarcoplasmic reticulum calcium load and SERCA2a calcium uptake activity, the observed decreases in calcium transients were dosage-dependent. The latter findings were concordant with measures of calcium regulatory protein abundance and phosphorylation state. Finally, studies of whole heart physiology in the isovolumic mode demonstrated dose-dependent differences in the degree of cardiac dysfunction. We conclude that the observed clinical severity of the cTnT Δ160E mutation is caused by a combination of direct sarcomeric disruption coupled to a profound dysregulation of Ca^2 + homeostasis at the cellular level that results in a unique and highly progressive pattern of ventricular remodeling. This article is part of a Special Issue entitled “Calcium Signaling in Heart”.     

Alcohol septal ablation in elderly patients: Is it as effective as in young patients?

Hypertrophic cardiomyopathy (HCM) is a common genetic abnormality that can occur in as many as 1 in 500persons. 1 Researchers have found multiple mutations in 10different sarcomeric proteins such as myosin heavy chain and tropomyosin can cause this disease. ……     

Phenotypic variation of familial hypertrophic cardiomyopathy caused by the Phe(110)-->Ile mutation in cardiac troponin T

Mutation of the cardiac troponin T (cTnT) gene is a genetic determinant of familial hypertrophic cardiomyopathy (HCM). A Japanese family of 14 individuals, including 6 with HCM, was subjected to genetic and clinical assessment. Five exons of the cTnT gene were sequenced in all family members. A heterozygous or homozygous T(340)-->A (Phe(110)-->Ile) mutation in exon 9 of the cTnT gene was detected in 11 subjects. Morphological and functional evaluation of the left and right ventricles by echocardiography revealed that 4 of 9 individuals heterozygous for the mutant allele exhibited HCM with moderate cardiac hypertrophy. Cardiac hypertrophy and other clinical features in the 2 subjects homozygous for the mutation were more severe than were those in heterozygous individuals with HCM. Thus, the clinical features of HCM due to the Phe(110)-->Ile mutation in the cTnT gene appear to be modified by a gene dosage effect.     

Mechanisms of the pathogenesis of troponin T-based familial hypertrophic cardiomyopathy

Mutations in cardiac troponin T (cTnT) cause hypertrophic cardiomyopathy characterized by comparatively little cardiac hypertrophy, but a high incidence of sudden cardiac death. Transgenic mice modeling this disease have smaller cardiomyocytes, leading to smaller hearts. However, different mutations in cTnT have distinct phenotypes with respect to fibrosis, induction of molecular markers, and systolic function. Such models ideally allow for testing of the role of individual phenotypes in the pathways leading to cardiomyopathy, as well as identification of factors such as exercise that can affect the disease.     

Comparison of two murine models of familial hypertrophic cardiomyopathy

Although sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), individuals bearing a mutant cardiac myosin binding protein C (MyBP-C) gene usually have a better prognosis than individuals bearing beta-cardiac myosin heavy chain (MHC) gene mutations. Heterozygous mice bearing a cardiac MHC missense mutation (alphaMHC(403/+) or a cardiac MyBP-C mutation (MyBP-C(t/+)) were constructed as murine FHC models using homologous recombination in embryonic stem cells. We have compared cardiac structure and function of these mouse strains by several methods to further define mechanisms that determine the severity of FHC. Both strains demonstrated progressive left ventricular (LV) hypertrophy; however, by age 30 weeks, alphaMHC(403/+) mice demonstrated considerably more LV hypertrophy than MyBP-C(t/+) mice. In older heterozygous mice, hypertrophy continued to be more severe in the alphaMHC(403/+) mice than in the MyBP-C(t/+) mice. Consistent with this finding, hearts from 50-week-old alphaMHC(403/+) mice demonstrated increased expression of molecular markers of cardiac hypertrophy, but MyBP-C(t/+) hearts did not demonstrate expression of these molecular markers until the mice were >125 weeks old. Electrophysiological evaluation indicated that MyBP-C(t/+) mice are not as likely to have inducible ventricular tachycardia as alphaMHC(403/+) mice. In addition, cardiac function of alphaMHC(403/+) mice is significantly impaired before the development of LV hypertrophy, whereas cardiac function of MyBP-C(t/+) mice is not impaired even after the development of cardiac hypertrophy. Because these murine FHC models mimic their human counterparts, we propose that similar murine models will be useful for predicting the clinical consequences of other FHC-causing mutations. These data suggest that both electrophysiological and cardiac function studies may enable more definitive risk stratification in FHC patients.     

Mutations at the same amino acid in myosin that cause either skeletal or cardiac myopathy have distinct molecular phenotypes

To date, more than 230 disease-causing mutations have been linked to the slow/cardiac muscle myosin gene, β-MyHC (MYH7). Most of these mutations are located in the globular head region of the protein and result in cardiomyopathies. Recently, however, a number of novel disease-causing mutations have been described in the long, α-helical, coiled coil tail region of the β-MyHC protein. Mutations in this region are of particular interest because they are associated with a multitude of human diseases, including both cardiac and skeletal myopathies. Here, we attempt to dissect the mechanism(s) by which mutations in the rod region of β-MyHC can cause a variety of diseases by analyzing two mutations at a single amino acid (R1500P and R1500W) which cause two distinct diseases (Laing-type early-onset distal myopathy and dilated cardiomyopathy, respectively). For diseases linked to the R1500 residue, we find that each mutation displays distinct structural, thermodynamic, and functional properties. Both R1500P and R1500W cause a decrease in thermodynamic stability, although the R1500W phenotype is more severe. Both mutations also affect filament assembly, with R1500P causing an additional decrease in filament stability. In addition to furthering our understanding of the mechanism of pathogenesis for each of these diseases, these data also suggest how the variance in molecular phenotype may be associated with the variance in clinical phenotype present with mutations in the β-MyHC rod.     

Sarcomeric Proteins and Familial Hypertrophic Cardiomyopathy: Linking Mutations in Structural Proteins to Complex Cardiovascular Phenotypes

Hypertrophic Cardiomyopathy (HCM) is a relatively common primary cardiac disorder defined as the presence of a hypertrophied left ventricle in the absence of any other diagnosed etiology. HCM is the most common cause of sudden cardiac death in young people which often occurs without precedent symptoms. The overall clinical phenotype of patients with HCM is broad, ranging from a complete lack of cardiovascular symptoms to exertional dyspnea, chest pain, and sudden death, often due to arrhythmias. To date, 270 independent mutations in nine sarcomeric protein genes have been linked to Familial Hypertrophic Cardiomyopathy (FHC), thus the clinical variability is matched by significant genetic heterogeneity. While the final clinical phenotype in patients with FHC is a result of multiple factors including modifier genes, environmental influences and genotype, initial screening studies had suggested that individual gene mutations could be linked to specific prognoses. Given that the sarcomeric genes linked to FHC encode proteins with known functions, a vast array of biochemical, biophysical and physiologic experimental approaches have been applied to elucidate the molecular mechanisms that underlie the pathogenesis of this complex cardiovascular disorder. In this review, to illustrate the basic relationship between protein dysfunction and disease pathogenesis we focus on representative gene mutations from each of the major structural components of the cardiac sarcomere: the thick filament (β MyHC), the thin filament (cTnT and Tm) and associated proteins (MyBP-C). The results of these studies will lead to a better understanding of FHC and eventually identify targets for therapeutic intervention.     

Factor V Arg306 → Thr (factor V Cambridge) and factor V Arg306 → Gly mutations in venous thrombotic disease

We investigated the prevalence of two reported mutations of the factor V gene (factor V Arg³⁰⁶ → Thr, or factor V Cambridge, and factor V Arg³⁰⁶ → Gly) in 104 relatively young patients with verified venous thrombosis and in 208 age-, sex- and race-matched controls, in order to establish whether the two mutations are associated with increased predisposition for venous thrombosis. PCR amplification followed by Bst NI and Msp I digestion was employed to determine the genotypes, and each mutation was confirmed by DNA sequencing. Among the controls, one individual was found to be heterozygous for the factor V Arg³⁰⁶ → Thr mutation and one heterozygous for the factor V Arg³⁰⁶ → Gly mutation; none of the patients carried either mutation. Our findings do not support factor V Cambridge and factor V Arg³⁰⁶ → Gly as risk factors for venous thrombosis.     

Absence of mutations at the activated protein C cleavage sites of factor VIII in 125 patients with venous thrombosis

Resistance to activated protein C (APC), caused by a mutation at amino acid position Arg⁵⁰⁶ of the factor V gene, has recently been identified as the most prevalent genetic defect associated with venous thrombosis. Similarly to factor V, mutations at the cleavage sites of factor VIII for APC may occur in patients with venous thrombosis. Here we have analysed 125 consecutive patients with incidental or recurrent venous thromboembolism for the presence of mutations at the cleavage sites for APC at amino acid positions Arg³³⁶ and Arg⁵⁶² of factor VIII. Our findings indicate that mutations at these amino acid positions of factor VIII do not occur in the patient group analysed.     

十个汉族家族性肥厚型心肌病MYH7、MYBPC3和TNNT2基因筛查结果及相应的临床特征

目的研究10个汉族家族性肥厚型心肌病的致病基因及突变特点,分析基因型与临床表型的相互关系。方法对10个无血缘关系的汉族家族性肥厚型心肌病的家系的MYH7基因、MYBPC3基因和TNNT2基因进行扫描,聚合酶链式反应扩增其外显子及剪接部位基因组DNA片段,直接测序分析,并分析各突变患者相应临床表型特点。结果10个汉族家族性肥厚型心肌病的家系中5个家系发现上述基因突变,3个家系MYH7基因发生错义突变,分别为Arg663His、Glu924Lys和Ile736Thr,Glu924Lya在中国患者中首次发现。这3个家系中3例患者猝死;2个家系MYBPC3基因发生错义突变、剪接突变和移码突变,1个家系先证者为复合突变即18外显子错义突变ArgS02Trp及27外显子剪接突变即IVS27＋12C〉T,先证者之母携带错义突变,先证者之父携带剪接突变;在另一家系首次发现Gly347fa移码突变,该家系中1例猝死。10个家系中未发现TNNT2基因的功能区突变,但在内含子3中发现一个STR多态性即CTTCT5个碱基的插入／缺失,7个家系先证者发现D基因型。结论MYH7基因为中国汉族家族性肥厚型心肌病最常见致病基因,临床表现较重,猝死率较高。MYBPC3突变也较常见,症状较轻,发病较晚,但复合突变发病早、症状重。同一突变的临床表型存在异质性提示多因素参与了肥厚型心肌病的发生与发展。     

Prevalence, clinical significance, and genetic basis of hypertrophic cardiomyopathy with restrictive phenotype.

OBJECTIVES: The purpose of this study was to determine the prevalence, clinical significance, and genetic basis of hypertrophic cardiomyopathy (HCM) with "restrictive phenotype" characterized by restrictive filling and minimal or no left ventricular hypertrophy. BACKGROUND: Hypertrophic cardiomyopathy is a heterogeneous myocardial disorder with a broad spectrum of clinical presentation and morphologic features. Recent reports indicated that some patients with restrictive cardiomyopathy, which is an uncommon condition defined by restrictive filling and reduced diastolic volumes with normal or near normal left ventricular wall thickness and contractile function, have features suggestive of HCM with mutations in cardiac troponin I, myocyte disarray at explant/autopsy, and relatives with HCM. Systematic evaluation of the restrictive phenotype in HCM patients has not been performed. METHODS: We evaluated 1,226 patients from 688 consecutive HCM families to identify individuals who fulfilled diagnostic criteria for "restrictive phenotype." RESULTS: Nineteen of 1,226 affected individuals (1.5%) from 16 families (2.3%) had the "restrictive phenotype." During follow up (53.7 +/- 49.2 months), 17 patients (89%) experienced dyspnea (New York Heart Association functional class > or =2). The 5-year survival rate from all-cause mortality, cardiac transplantation, or implantable cardioverter-defibrillator discharge was 56.4%. Mutation analysis for 5 sarcomere genes was feasible in 15 of 16 probands. Mutations were found in 8: 4 in beta-myosin heavy chain, and 4 in cardiac troponin I. CONCLUSIONS: The "restrictive phenotype" in isolation is an uncommon presentation of the clinical spectrum of HCM and is associated with severe limitation and poor prognosis. This phenotype may be associated with beta-myosin heavy chain and cardiac troponin I mutations.     

Cardiac Myosin-binding protein C and hypertrophic cardiomyopathy

The cardiac myosin-binding protein C (MyBP-C) is a sarcomeric protein belonging to the intracellular immunoglobulin superfamily; it has both structural and regulatory roles. The gene-encoding cardiac MyBP-C in humans is located on chromosome 11p11.2, comprises over 21,000 base pairs, and contains 35 exons. Mutations have been identified in this gene in unrelated families with familial hypertrophic cardiomyopathy. Familial hypertrophic cardiomyopathy is an autosomal dominant disease characterized by ventricular hypertrophy associated with a large degree of myocardial and myofibrillar disarray. Most mutations found in the cardiac MyBP-C gene thus far are predicted to lead to an altered mRNA sequence and to produce the C-terminal truncation of the cardiac MyBP-C polypeptides lacking the myosin-binding site and also, in some cases, the titin-binding site. One might reasonably assume that the cardiac MyBP-C mutations exert their effect by altering the multimeric complex assembly of the cardiac sarcomere via the "null allele" mechanism, potentially leading to haploinsufficiency, and/or via a dominant negative effect of a misfolded RNA on the cardiac MyBP-C translation, which could interfere with the proper assembly of sarcomeric structures. These data underline the functional importance of MyBP-C in the regulation of cardiac work and provide the basis for further studies and for the production of transgenic animals for cardiac MyBP-C that will, one hopes, help to resolve the pathogenesis of chromosome-11-associated familial hypertrophic cardiomyopathy.     

Properties of mutant contractile proteins that cause hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is one of the most frequently occurring inherited cardiac disorders, affecting up to 1 in 500 of the population. Molecular genetic analysis has shown that HCM is a disease of the sarcomere, caused by mutations in certain contractile protein genes. To date seven disease-associated genes have been identified, those encoding beta-myosin heavy chain, both regulatory and essential myosin light chains, myosin binding protein-C, cardiac troponin T, cardiac troponin I and alpha-tropomyosin. Here we review the analyses of how these mutations affect the in vitro contractile protein function and the hypotheses derived to explain the development of the disease state.     

beta(2)-Adrenergic receptor and adenylate cyclase gene polymorphisms affect sickle red cell adhesion

Sickle red cell (SS RBC) adhesion is thought to contribute to sickle cell disease (SCD) pathophysiology. SS RBC adhesion to laminin increases in response to adrenaline stimulation of β₂-adrenergic receptors (β₂ARs) and adenylate cyclase (ADCY6), and previous evidence suggests such activation occurs in vivo . We explored whether polymorphisms of the β₂AR and ADCY6 genes ( ADRB2 and ADCY6 , respectively) affect RBC adhesion to laminin. We found that the β₂AR arg¹⁶→gly substitution and two non-coding ADCY6 polymorphisms were associated with elevated adhesion. We postulate that ADRB2 and ADCY6 polymorphisms may influence SCD severity through the mechanism of RBC adhesion.     

A novel missense mutation in the myosin binding protein-C gene is responsible for hypertrophic cardiomyopathy with left ventricular dysfunction and dilation in elderly patients

OBJECTIVES: We studied the clinical features of hypertrophic cardiomyopathy (HCM) caused by a novel mutation in the myosin binding protein-C (MyBP-C) gene in patients and family members of Japanese descent. BACKGROUND: Previous reports have demonstrated that the clinical features of HCM associated with mutations in the MyBP-C gene include late onset and a favorable clinical course. Recently, some mutations in genes encoding sarcomeric proteins have been reported to be a cause of dilated cardiomyopathy (DCM), as well as HCM. However, mutations of the MyBP-C gene have not been reported as a cause of DCM up to now. METHODS: We analyzed MyBP-C gene mutations in 250 unrelated probands with HCM and in 90 with DCM. We used electrocardiography (ECG) and echocardiography to determine clinical phenotypes. RESULTS: We identified 17 individuals in 8 families (7 HCM, 1 DCM) with an Arg820Gln mutation in the MyBP-C gene. Overall, 2 (40%) of 5 carriers age >70 years displayed "burnt-out" phase HCM, and one of them had been diagnosed as having DCM before genetic identification. The disease penetrance in subjects age >50 years was 70% by echocardiography and 100% by ECG, and that in those age <50 years was 40% and 50%, respectively. CONCLUSIONS: Elderly patients with Arg820Gln mutation may show "burnt-out" phase HCM, and patients with this mutation may be included among those diagnosed as having DCM. Screening of patients with DCM, as well as HCM, for this mutation is of significant importance because patients with this mutation may be diagnosed clinically as having DCM.