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William J Mckenna - One of the best experts on this subject based on the ideXlab platform.
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diagnosis of arrhythmogenic right ventricular cardiomyopathy dysplasia proposed modification of the task force criteria
Circulation, 2010Co-Authors: Frank I Marcus, William J Mckenna, Duane L Sherrill, Cristina Basso, Barbara Bauce, David A Bluemke, Hugh Calkins, Domenico Corrado, Moniek G P J Cox, James P DaubertAbstract:Background— In 1994, an International Task Force proposed criteria for the clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) that facilitated recognition and interpretation of the frequently nonspecific clinical features of ARVC/D. This enabled confirmatory clinical diagnosis in index cases through exclusion of phenocopies and provided a standard on which clinical research and genetic studies could be based. Structural, histological, electrocardiographic, arrhythmic, and Familial features of the Disease were incorporated into the criteria, subdivided into major and minor categories according to the specificity of their association with ARVC/D. At that time, clinical experience with ARVC/D was dominated by symptomatic index cases and sudden cardiac death victims—the overt or severe end of the Disease spectrum. Consequently, the 1994 criteria were highly specific but lacked sensitivity for early and Familial Disease. Methods and Results— Revision of the diagnostic crit...
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prevalence of sarcomere protein gene mutations in preadolescent children with hypertrophic cardiomyopathy
Circulation-cardiovascular Genetics, 2009Co-Authors: Juan Pablo Kaski, Petros Syrris, Maria Teresa Tome Esteban, Sharon Jenkins, Antonios Pantazis, John E Deanfield, William J Mckenna, Perry M ElliottAbstract:Background— Hypertrophic cardiomyopathy (HCM) in infants and children is thought to be commonly associated with metabolic disorders and malformation syndromes. Familial Disease caused by mutations in cardiac sarcomere protein genes, which accounts for most cases in adolescents and adults, is believed to be a very rare cause of HCM. Methods and Results— Seventy-nine consecutive patients diagnosed with HCM aged 13 years or younger underwent detailed clinical and genetic evaluation. The protein-coding sequences of 9 sarcomere protein genes ( MYH7 , MYBPC3 , TNNI3 , TNNT2 , TPM1 , MYL2 , MYL3 , ACTC , and TNNC1 ), the genes encoding desmin ( DES ), and the γ-2 subunit of AMP kinase ( PRKAG2 ) were screened for mutations. A family history of HCM was present in 48 patients (60.8%). Forty-seven mutations (15 novel) were identified in 42 (53.2%) patients (5 patients had 2 mutations). The genes most commonly implicated were MYH7 (48.9%) and MYBPC3 (36.2%); mutations in TNNT2 , ACTC , MYL3 , and TNNI3 accounted for <5% of cases each. A total of 16.7% patients with sarcomeric mutations were diagnosed before 1 year of age. There were no differences in clinical and echocardiographic features between those children with sarcomere protein gene mutations and those without or between patients with 2 mutations and those with 1 or no mutations. Conclusions— This study shows that Familial Disease is common among infants and children with HCM and that, in most cases, Disease is caused by mutations in cardiac sarcomere protein genes. The major implication is that all first-degree relatives of any child diagnosed with HCM should be offered screening. Furthermore, the finding that one sixth of patients with sarcomeric Disease were diagnosed in infancy suggests that current views on pathogenesis and natural history of Familial HCM may have to be revised. Received September 11, 2008; accepted May 11, 2009. # CLINICAL PERSPECTIVE {#article-title-2}
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role of genetic analysis in the management of patients with arrhythmogenic right ventricular dysplasia cardiomyopathy
Journal of the American College of Cardiology, 2007Co-Authors: Srijita Senchowdhry, Petros Syrris, William J MckennaAbstract:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a recognized cause of sudden cardiac death, which may be prevented by timely detection and intervention. Clinical diagnosis of ARVC is fraught with difficulties in both index cases and relatives owing to the nonspecific nature of associated features, diverse phenotypic manifestations, and a lack of conspicuous abnormalities in the early, “concealed” phase. During the past 7 years, researchers have isolated causative mutations in several components of the desmosome, shedding light on the molecular mechanisms underlying the Disease and offering the promise of genetic testing as a diagnostic tool. Sequence analysis is likely to be the mainstay of genotyping in ARVC because of marked allelic heterogeneity, frequent “private” mutations, and digenicity in a minority, highlighting the importance of comprehensive genetic screening. The main technical obstacle to implementation of genotyping in clinical practice will be the prohibitive costs of performing sequence analysis of a genomic region exceeding 40 kb. Nevertheless, the success rate of genotyping in ARVC is of the order of 40%, and key clinical applications include confirmatory testing of index cases to facilitate interpretation of borderline investigations and cascade screening of families. The latter is particularly attractive in ARVC, because age-related penetrance otherwise demands lifelong clinical reassessment of extended families. A role for genetic analysis in prognostication is more tenuous at present, but increasing identification of individuals with early and Familial Disease underscores the need for a definitive risk stratification algorithm in this population.
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Desmoglein-2 mutations in arrhythmogenic right ventricular cardiomyopathy: a genotype-phenotype characterization of Familial Disease.
European Heart Journal, 2006Co-Authors: Petros Syrris, Angeliki Asimaki, Alison Evans, Deirdre Ward, Srijita Sen-chowdhry, Sian Hughes, William J MckennaAbstract:Aims Mutations in the desmoglein-2 (DSG2) gene have been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) but clinical information regarding the associated phenotype is at present limited. In this study, we aimed to clinically characterize probands and family members carrying a DSG2 mutation. Methods and results We investigated 86 Caucasian ARVC patients for mutations in DSG2 by direct sequencing and detected eight novel mutations in nine probands. Clinical evaluation of family members with DSG2 mutations demonstrated penetrance of 58% using Task Force criteria, or 75% using proposed modified criteria. Morphological abnormalities of the right ventricle were evident in 66% of gene carriers, left ventricular (LV) involvement in 25%, and classical right precordial T-wave inversion only in 26%. Sustained ventricular arrhythmia was present in 8% and a family history of sudden death/aborted sudden death in 66%. Conclusion Mutations in DSG2 display a high degree of penetrance. Disease expression was of variable severity with LV involvement a prominent feature. The low prevalence of classical ECG changes highlights the need to expand current diagnostic criteria to take account of LV Disease, childhood Disease expression, and incomplete penetrance.
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prospective evaluation of relatives for Familial arrhythmogenic right ventricular cardiomyopathy dysplasia reveals a need to broaden diagnostic criteria
Journal of the American College of Cardiology, 2002Co-Authors: Shoaib M Hamid, Perry M Elliott, Mark Norman, Asifa Quraishi, Sami Firoozi, Rajesh Thaman, Juan R Gimeno, B Sachdev, Edward Rowland, William J MckennaAbstract:Abstract Objectives We sought to ascertain the prevalence and mode of expression of Familial Disease in a consecutive series of patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). Background Autosomal-dominant inheritance is recognized in ARVC. The prevalence and mode of expression of Familial Disease in consecutive, unselected families is uncertain. Methods First- and second-degree relatives of 67 ARVC index patients underwent cardiac evaluation with history and examination, 12-lead and signal-averaged electrocardiogram (ECG), two-dimensional and Doppler echocardiography, metabolic exercise testing and Holter monitoring. Diagnoses were made in accordance with published criteria. Results Of 298 relatives, 29 (10%; mean age 37.4 ± 16.4 years) had ARVC. These were from 19 of the 67 families, representing Familial involvement in 28%. Of these affected relatives, 72% were asymptomatic, 17% had ventricular tachycardia (sustained VT 10%, nonsustained VT 7%) and 21% had left ventricular involvement. A further 32 relatives (11%; 37.7 ± 12.4 years) exhibited nondiagnostic ECG, echocardiographic or Holter abnormalities. Fifteen of these relatives were from families with only the proband affected, and inclusion of this subset of relatives would have resulted in Familial ARVC in 48% of index cases. Four additional relatives (1% to 3%) fulfilled diagnostic criteria for dilated cardiomyopathy without any features of right ventricular Disease. Conclusion By using current diagnostic criteria, Familial Disease was present in 28% of index patients. A further 11% of their relatives had minor cardiac abnormalities, which, in the context of a Disease whose mode of inheritance is autosomal dominant, are likely to represent early or mild Disease expression. We advocate that the current ARVC diagnostic criteria are modified to reflect the broader spectrum of Disease that is observed in family members.
Sabine Klaassen - One of the best experts on this subject based on the ideXlab platform.
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sarcomere gene mutations in isolated left ventricular noncompaction cardiomyopathy do not predict clinical phenotype
Circulation-cardiovascular Genetics, 2011Co-Authors: Susanne Probst, Matthias Greutmann, Erwin Oechslin, Pia K Schuler, Philipp Boye, Walter Knirsch, Felix Berger, Ludwig Thierfelder, Rolf Jenni, Sabine KlaassenAbstract:Background— Left ventricular noncompaction of the myocardium (LVNC) has been recognized as a cardiomyopathy with a genetic etiology. Mutations in genes encoding sarcomere proteins were shown to be associated with LVNC. We evaluated the potential clinical impact of genetic analysis of sarcomere genes in patients with LVNC. Methods and Results— We identified 5 mutations in cardiac myosin-binding protein C ( MYBPC3 ) and 2 mutations in α-tropomyosin ( TPM1 ) in a cohort of unrelated adult probands with isolated LVNC. The mutations in MYBPC3 and TPM1 and in 6 other previously reported sarcomere genes in this cohort resulted in a total of 18 (29%) heterozygous mutations in 63 probands. β-myosin heavy chain ( MYH7 ) was the most prevalent Disease gene and accounts for 13% of cases, followed by MYBPC3 (8%). Comparing sarcomere mutation-positive and mutation-negative LVNC probands showed no significant differences in terms of average age, myocardial function, and presence of heart failure or tachyarrhythmias at initial presentation or at follow-up. Familial Disease was found in 16 probands of whom 8 were sarcomere mutation positive. Nonpenetrance was detected in 2 of 8 mutation-positive families with LVNC. Conclusions— Mutations in sarcomere genes account for a significant (29%) proportion of cases of isolated LVNC in this cohort. The distribution of Disease genes confirms genetic heterogeneity and opens new perspectives in genetic testing in patients with LVNC and their relatives at high risk of inheriting the cardiomyopathy. The presence or absence of a sarcomere gene mutation in LVNC cannot be related to the clinical phenotype.
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mutations in sarcomere protein genes in left ventricular noncompaction
Circulation, 2008Co-Authors: Sabine Klaassen, Matthias Greutmann, Erwin Oechslin, Susanne Probst, Brenda Gerull, Gregor Krings, Pia K Schuler, David Hurlimann, M Yegitbasi, Lucia PonsAbstract:BACKGROUND: Left ventricular noncompaction constitutes a primary cardiomyopathy characterized by a severely thickened, 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses. The genetic basis of this cardiomyopathy is still largely unresolved. We speculated that mutations in sarcomere protein genes known to cause hypertrophic cardiomyopathy and dilated cardiomyopathy may be associated with left ventricular noncompaction. METHODS AND RESULTS: Mutational analysis in a cohort of 63 unrelated adult probands with left ventricular noncompaction and no other congenital heart anomalies was performed by denaturing high-performance liquid chromatography analysis and direct DNA sequencing of 6 genes encoding sarcomere proteins. Heterozygous mutations were identified in 11 of 63 samples in genes encoding beta-myosin heavy chain (MYH7), alpha-cardiac actin (ACTC), and cardiac troponin T (TNNT2). Nine distinct mutations, 7 of them in MYH7, 1 in ACTC, and 1 in TNNT2, were found. Clinical evaluations demonstrated Familial Disease in 6 of 11 probands with sarcomere gene mutations. MYH7 mutations segregated with the Disease in 4 autosomal dominant LVNC kindreds. Six of the MYH7 mutations were novel, and 1 encodes a splice-site mutation, a relatively unique finding for MYH7 mutations. Modified residues in beta-myosin heavy chain were located mainly within the ATP binding site. CONCLUSIONS: We conclude that left ventricular noncompaction is within the diverse spectrum of cardiac morphologies triggered by sarcomere protein gene defects. Our findings support the hypothesis that there is a shared molecular etiology of different cardiomyopathic phenotypes.
Perry M Elliott - One of the best experts on this subject based on the ideXlab platform.
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prevalence of sarcomere protein gene mutations in preadolescent children with hypertrophic cardiomyopathy
Circulation-cardiovascular Genetics, 2009Co-Authors: Juan Pablo Kaski, Petros Syrris, Maria Teresa Tome Esteban, Sharon Jenkins, Antonios Pantazis, John E Deanfield, William J Mckenna, Perry M ElliottAbstract:Background— Hypertrophic cardiomyopathy (HCM) in infants and children is thought to be commonly associated with metabolic disorders and malformation syndromes. Familial Disease caused by mutations in cardiac sarcomere protein genes, which accounts for most cases in adolescents and adults, is believed to be a very rare cause of HCM. Methods and Results— Seventy-nine consecutive patients diagnosed with HCM aged 13 years or younger underwent detailed clinical and genetic evaluation. The protein-coding sequences of 9 sarcomere protein genes ( MYH7 , MYBPC3 , TNNI3 , TNNT2 , TPM1 , MYL2 , MYL3 , ACTC , and TNNC1 ), the genes encoding desmin ( DES ), and the γ-2 subunit of AMP kinase ( PRKAG2 ) were screened for mutations. A family history of HCM was present in 48 patients (60.8%). Forty-seven mutations (15 novel) were identified in 42 (53.2%) patients (5 patients had 2 mutations). The genes most commonly implicated were MYH7 (48.9%) and MYBPC3 (36.2%); mutations in TNNT2 , ACTC , MYL3 , and TNNI3 accounted for <5% of cases each. A total of 16.7% patients with sarcomeric mutations were diagnosed before 1 year of age. There were no differences in clinical and echocardiographic features between those children with sarcomere protein gene mutations and those without or between patients with 2 mutations and those with 1 or no mutations. Conclusions— This study shows that Familial Disease is common among infants and children with HCM and that, in most cases, Disease is caused by mutations in cardiac sarcomere protein genes. The major implication is that all first-degree relatives of any child diagnosed with HCM should be offered screening. Furthermore, the finding that one sixth of patients with sarcomeric Disease were diagnosed in infancy suggests that current views on pathogenesis and natural history of Familial HCM may have to be revised. Received September 11, 2008; accepted May 11, 2009. # CLINICAL PERSPECTIVE {#article-title-2}
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prevalence and clinical significance of cardiovascular abnormalities in patients with the leopard syndrome
American Journal of Cardiology, 2007Co-Authors: Giuseppe Pacileo, Paolo Versacci, Paolo Calabro, Perry M Elliott, Anna Sarkozy, Giuseppe Limongelli, Bruno Marino, Maria Cristina Digilio, Andrea De ZorziAbstract:The aim of this study was to characterize cardiovascular involvement in a large number of patients with LEOPARD syndrome. Twenty-six patients (age range 0 to 63 years, median age at the time of the study evaluation 17 years) underwent clinical and genetic investigations. Familial Disease was ascertained in 9 patients. Nineteen patients (73%) showed electrocardiographic abnormalities. Left ventricular (LV) hypertrophy was present in 19 patients (73%), including 9 with LV outflow tract obstructions; right ventricular hypertrophy was present in 8 patients (30%). Valve (57%) and coronary artery (15%) anomalies were also observed. Single patients showed LV apical aneurysm, LV noncompaction, isolated LV dilation, and atrioventricular canal defect. During follow-up (9.1 ± 4.5 years), 2 patients died suddenly, and 2 patients had cardiac arrest. These patients had LV hypertrophy. Despite the limited number of subjects studied, genotype-phenotype correlations were observed in Familial cases. In conclusion, most patients with LEOPARD syndrome showed LV hypertrophy, often in association with other valvular or congenital defects. A spectrum of underrecognized cardiac anomalies were also observed. Long-term prognosis was benign, but the occurrence of 4 fatal events in patients with LV hypertrophy indicates that such patients require careful risk assessment and, in some cases, consideration for prophylaxis against sudden death.
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prospective evaluation of relatives for Familial arrhythmogenic right ventricular cardiomyopathy dysplasia reveals a need to broaden diagnostic criteria
Journal of the American College of Cardiology, 2002Co-Authors: Shoaib M Hamid, Perry M Elliott, Mark Norman, Asifa Quraishi, Sami Firoozi, Rajesh Thaman, Juan R Gimeno, B Sachdev, Edward Rowland, William J MckennaAbstract:Abstract Objectives We sought to ascertain the prevalence and mode of expression of Familial Disease in a consecutive series of patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). Background Autosomal-dominant inheritance is recognized in ARVC. The prevalence and mode of expression of Familial Disease in consecutive, unselected families is uncertain. Methods First- and second-degree relatives of 67 ARVC index patients underwent cardiac evaluation with history and examination, 12-lead and signal-averaged electrocardiogram (ECG), two-dimensional and Doppler echocardiography, metabolic exercise testing and Holter monitoring. Diagnoses were made in accordance with published criteria. Results Of 298 relatives, 29 (10%; mean age 37.4 ± 16.4 years) had ARVC. These were from 19 of the 67 families, representing Familial involvement in 28%. Of these affected relatives, 72% were asymptomatic, 17% had ventricular tachycardia (sustained VT 10%, nonsustained VT 7%) and 21% had left ventricular involvement. A further 32 relatives (11%; 37.7 ± 12.4 years) exhibited nondiagnostic ECG, echocardiographic or Holter abnormalities. Fifteen of these relatives were from families with only the proband affected, and inclusion of this subset of relatives would have resulted in Familial ARVC in 48% of index cases. Four additional relatives (1% to 3%) fulfilled diagnostic criteria for dilated cardiomyopathy without any features of right ventricular Disease. Conclusion By using current diagnostic criteria, Familial Disease was present in 28% of index patients. A further 11% of their relatives had minor cardiac abnormalities, which, in the context of a Disease whose mode of inheritance is autosomal dominant, are likely to represent early or mild Disease expression. We advocate that the current ARVC diagnostic criteria are modified to reflect the broader spectrum of Disease that is observed in family members.
Susanne Probst - One of the best experts on this subject based on the ideXlab platform.
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sarcomere gene mutations in isolated left ventricular noncompaction cardiomyopathy do not predict clinical phenotype
Circulation-cardiovascular Genetics, 2011Co-Authors: Susanne Probst, Matthias Greutmann, Erwin Oechslin, Pia K Schuler, Philipp Boye, Walter Knirsch, Felix Berger, Ludwig Thierfelder, Rolf Jenni, Sabine KlaassenAbstract:Background— Left ventricular noncompaction of the myocardium (LVNC) has been recognized as a cardiomyopathy with a genetic etiology. Mutations in genes encoding sarcomere proteins were shown to be associated with LVNC. We evaluated the potential clinical impact of genetic analysis of sarcomere genes in patients with LVNC. Methods and Results— We identified 5 mutations in cardiac myosin-binding protein C ( MYBPC3 ) and 2 mutations in α-tropomyosin ( TPM1 ) in a cohort of unrelated adult probands with isolated LVNC. The mutations in MYBPC3 and TPM1 and in 6 other previously reported sarcomere genes in this cohort resulted in a total of 18 (29%) heterozygous mutations in 63 probands. β-myosin heavy chain ( MYH7 ) was the most prevalent Disease gene and accounts for 13% of cases, followed by MYBPC3 (8%). Comparing sarcomere mutation-positive and mutation-negative LVNC probands showed no significant differences in terms of average age, myocardial function, and presence of heart failure or tachyarrhythmias at initial presentation or at follow-up. Familial Disease was found in 16 probands of whom 8 were sarcomere mutation positive. Nonpenetrance was detected in 2 of 8 mutation-positive families with LVNC. Conclusions— Mutations in sarcomere genes account for a significant (29%) proportion of cases of isolated LVNC in this cohort. The distribution of Disease genes confirms genetic heterogeneity and opens new perspectives in genetic testing in patients with LVNC and their relatives at high risk of inheriting the cardiomyopathy. The presence or absence of a sarcomere gene mutation in LVNC cannot be related to the clinical phenotype.
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mutations in sarcomere protein genes in left ventricular noncompaction
Circulation, 2008Co-Authors: Sabine Klaassen, Matthias Greutmann, Erwin Oechslin, Susanne Probst, Brenda Gerull, Gregor Krings, Pia K Schuler, David Hurlimann, M Yegitbasi, Lucia PonsAbstract:BACKGROUND: Left ventricular noncompaction constitutes a primary cardiomyopathy characterized by a severely thickened, 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses. The genetic basis of this cardiomyopathy is still largely unresolved. We speculated that mutations in sarcomere protein genes known to cause hypertrophic cardiomyopathy and dilated cardiomyopathy may be associated with left ventricular noncompaction. METHODS AND RESULTS: Mutational analysis in a cohort of 63 unrelated adult probands with left ventricular noncompaction and no other congenital heart anomalies was performed by denaturing high-performance liquid chromatography analysis and direct DNA sequencing of 6 genes encoding sarcomere proteins. Heterozygous mutations were identified in 11 of 63 samples in genes encoding beta-myosin heavy chain (MYH7), alpha-cardiac actin (ACTC), and cardiac troponin T (TNNT2). Nine distinct mutations, 7 of them in MYH7, 1 in ACTC, and 1 in TNNT2, were found. Clinical evaluations demonstrated Familial Disease in 6 of 11 probands with sarcomere gene mutations. MYH7 mutations segregated with the Disease in 4 autosomal dominant LVNC kindreds. Six of the MYH7 mutations were novel, and 1 encodes a splice-site mutation, a relatively unique finding for MYH7 mutations. Modified residues in beta-myosin heavy chain were located mainly within the ATP binding site. CONCLUSIONS: We conclude that left ventricular noncompaction is within the diverse spectrum of cardiac morphologies triggered by sarcomere protein gene defects. Our findings support the hypothesis that there is a shared molecular etiology of different cardiomyopathic phenotypes.
Lucia Pons - One of the best experts on this subject based on the ideXlab platform.
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mutations in sarcomere protein genes in left ventricular noncompaction
Circulation, 2008Co-Authors: Sabine Klaassen, Matthias Greutmann, Erwin Oechslin, Susanne Probst, Brenda Gerull, Gregor Krings, Pia K Schuler, David Hurlimann, M Yegitbasi, Lucia PonsAbstract:BACKGROUND: Left ventricular noncompaction constitutes a primary cardiomyopathy characterized by a severely thickened, 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses. The genetic basis of this cardiomyopathy is still largely unresolved. We speculated that mutations in sarcomere protein genes known to cause hypertrophic cardiomyopathy and dilated cardiomyopathy may be associated with left ventricular noncompaction. METHODS AND RESULTS: Mutational analysis in a cohort of 63 unrelated adult probands with left ventricular noncompaction and no other congenital heart anomalies was performed by denaturing high-performance liquid chromatography analysis and direct DNA sequencing of 6 genes encoding sarcomere proteins. Heterozygous mutations were identified in 11 of 63 samples in genes encoding beta-myosin heavy chain (MYH7), alpha-cardiac actin (ACTC), and cardiac troponin T (TNNT2). Nine distinct mutations, 7 of them in MYH7, 1 in ACTC, and 1 in TNNT2, were found. Clinical evaluations demonstrated Familial Disease in 6 of 11 probands with sarcomere gene mutations. MYH7 mutations segregated with the Disease in 4 autosomal dominant LVNC kindreds. Six of the MYH7 mutations were novel, and 1 encodes a splice-site mutation, a relatively unique finding for MYH7 mutations. Modified residues in beta-myosin heavy chain were located mainly within the ATP binding site. CONCLUSIONS: We conclude that left ventricular noncompaction is within the diverse spectrum of cardiac morphologies triggered by sarcomere protein gene defects. Our findings support the hypothesis that there is a shared molecular etiology of different cardiomyopathic phenotypes.