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1.
Circ Cardiovasc Genet ; 4(4): 367-74, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21551322

RESUMO

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. ß-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.


Assuntos
Cardiomiopatias/genética , Proteínas de Transporte/genética , Mutação , Sarcômeros/genética , Tropomiosina/genética , Disfunção Ventricular Esquerda , Estudos de Coortes , Análise Mutacional de DNA , Humanos , Linhagem , Penetrância , Fenótipo
2.
Circ Cardiovasc Genet ; 4(1): 43-50, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21127202

RESUMO

BACKGROUND: Ebstein anomaly is a rare congenital heart malformation characterized by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. An association between Ebstein anomaly with left ventricular noncompaction (LVNC) and mutations in MYH7 encoding ß-myosin heavy chain has been shown; in this report, we have screened for MYH7 mutations in a cohort of probands with Ebstein anomaly in a large population-based study. METHODS AND RESULTS: Mutational analysis in a cohort of 141 unrelated probands with Ebstein anomaly was performed by next-generation sequencing and direct DNA sequencing of MYH7. Heterozygous mutations were identified in 8 of 141 samples (6%). Seven distinct mutations were found; 5 were novel and 2 were known to cause hypertrophic cardiomyopathy. All mutations except for 1 3-bp deletion were missense mutations; 1 was a de novo change. Mutation-positive probands and family members showed various congenital heart malformations as well as LVNC. Among 8 mutation-positive probands, 6 had LVNC, whereas among 133 mutation-negative probands, none had LVNC. The frequency of MYH7 mutations was significantly different between probands with and without LVNC accompanying Ebstein anomaly (P<0.0001). LVNC segregated with the MYH7 mutation in the pedigrees of 3 of the probands, 1 of which also included another individual with Ebstein anomaly. CONCLUSIONS: Ebstein anomaly is a congenital heart malformation that is associated with mutations in MYH7. MYH7 mutations are predominantly found in Ebstein anomaly associated with LVNC and may warrant genetic testing and family evaluation in this subset of patients.


Assuntos
Miosinas Cardíacas/genética , Anomalia de Ebstein/genética , Mutação/genética , Cadeias Pesadas de Miosina/genética , Sarcômeros/genética , Adolescente , Adulto , Idoso , Sequência de Aminoácidos , Miosinas Cardíacas/química , Criança , Pré-Escolar , Estudos de Coortes , Anomalia de Ebstein/diagnóstico por imagem , Família , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Cadeias Pesadas de Miosina/química , Linhagem , Ultrassonografia , Adulto Jovem
3.
Circulation ; 117(22): 2893-901, 2008 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-18506004

RESUMO

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.


Assuntos
Actinas/genética , Miosinas Cardíacas/genética , Cardiomiopatias/genética , Ventrículos do Coração/anormalidades , Mutação , Cadeias Pesadas de Miosina/genética , Sarcômeros/genética , Troponina T/genética , Cardiomiopatias/etiologia , Estudos de Coortes , Análise Mutacional de DNA , Coração/crescimento & desenvolvimento , Humanos , Sarcômeros/química
4.
J Am Coll Cardiol ; 48(1): 106-11, 2006 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-16814656

RESUMO

OBJECTIVES: We sought to identify the genetic locus for an inherited form of dilated cardiomyopathy (DCM) that is characterized by diffuse myocardial fibrosis and sudden death. BACKGROUND: Genetic studies have mapped multiple loci for DCM, which is a major cause of nonischemic heart failure; however, the genes responsible for the majority of cases have yet to be identified. METHODS: Sixty-six family members were evaluated by 12-lead electrocardiogram (ECG), echocardiogram, and laboratory studies. Individuals with echocardiographically documented DCM were defined as affected. Subjects were considered unaffected if they were older than 20 years of age, had a normal ECG and echocardiogram, no personal history of heart failure, and had no affected offspring. Genotyping was performed using polymorphic markers. RESULTS: Genome-wide linkage analysis identified a novel locus for this inherited phenotype on chromosome 10q25.3-q26.13. Peak two-point logarithm of the odds scores >3.0 were obtained independently with each family using the markers D10S1773 and D10S1483, respectively. Haplotype analyses defined a critical interval of 14.0 centiMorgans between D10S1237 and D10S1723, corresponding to a physical distance of 9.5 megabases. Multipoint linkage analyses confirmed this interval and generated a peak logarithm of the odds score of 8.2 indicating odds of >100,000,000:1 in favor of this interval as the location of the gene defect responsible for DCM in these families. CONCLUSIONS: We have mapped a novel locus for cardiomyopathy, diffuse myocardial fibrosis, and sudden death to chromosome 10q25-q26. The identification of the causative gene in this interval will be an important step in understanding the fundamental mechanisms of heart failure and sudden death.


Assuntos
Cardiomiopatias/genética , Cardiomiopatia Dilatada/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 10/genética , Morte Súbita Cardíaca , Adolescente , Adulto , Criança , Feminino , Fibrose , Ligação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo
5.
Circulation ; 109(22): 2720-3, 2004 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-15173023

RESUMO

BACKGROUND: Left ventricular noncompaction (LVNC) is a congenital unclassified cardiomyopathy with numerous prominent trabeculations and deep intertrabecular recesses in a hypertrophied and hypokinetic myocardium. It has been reported to occur in isolation or in association with congenital heart disease. Mutations in the X-linked G4.5 gene are responsible for cases of isolated LVNC in male infants, but G4.5 mutations were not found in patients with clinical onset of disease in adulthood. In addition, several families with LVNC and an autosomal dominant pattern of inheritance suggest genetic heterogeneity. METHODS AND RESULTS: We performed a genome-wide linkage analysis in a family with autosomal dominant LVNC and show that a locus containing the LVNC disease gene maps to chromosome 11p15. A peak 2-point logarithm of odds score of 5.06 was obtained with marker D11S902 at theta=0. Haplotype analysis defined a critical interval of 6.4 centimorgan between D11S1794 and D11S928 corresponding to a physical distance of 6.8 megabases. No disease-causing mutation was identified in 2 prime positional candidate genes, muscle LIM protein (MLP) and SOX6. CONCLUSIONS: We have mapped a locus for autosomal dominant LVNC to a 6.8-megabase region on human chromosome 11p15. Identification of the disease gene will allow genetic screening and provide fundamental insight into the understanding of myocardial morphogenesis.


Assuntos
Cardiomiopatias/genética , Cromossomos Humanos Par 11 , Adolescente , Mapeamento Cromossômico , Proteínas de Ligação a DNA/genética , Feminino , Genes Dominantes , Haplótipos , Proteínas de Grupo de Alta Mobilidade/genética , Humanos , Proteínas com Domínio LIM , Escore Lod , Masculino , Proteínas Musculares/genética , Mutação , Linhagem , Fatores de Transcrição SOXD , Fatores de Transcrição/genética
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