Comprehensive Analysis of the Beta-Myosin Heavy Chain Gene in 389 Unrelated Patients With Hypertrophic Cardiomyopathy

Driest, Sara L. Van; Jaeger, Michele A.; Ommen, Steve R.; Will, Melissa L.; Gersh, Bernard J.; Tajik, A. Jamil; Ackerman, Michael J.

doi:10.1016/j.jacc.2004.04.039

Cited by 169 publications

(58 citation statements)

References 32 publications

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“…In the cases of 3 deletion mutations, Glu778Del (exon 21), Glu883Del (exon 22) and Lys847Del (exon 22), the phenotypes presented as HCM; however, the severity of the disorders was not published [5,38]. The deletion of a glycine residue at codon 10, exon 3 resulted in HCM with a ‘relatively good prognosis’ in 4 unrelated patients and no SCDs in any of the families [49].…”

Section: Resultsmentioning

confidence: 99%

“…The symptoms displayed range from asymptomatic carrier status through to dizziness, palpitations, syncope and SCD. The age of onset also varies; some patients are diagnosed close to birth [5,6], while others remain asymptomatic until their third, fourth or even seventh decade [7,8,9]. There are 4 recognised classes of cardiomyopathy: hypertrophic, dilated, restrictive and arrhythmogenic right ventricular [4].…”

Section: Introductionmentioning

confidence: 99%

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Cardiomyopathy: A Systematic Review of Disease-Causing Mutations in Myosin Heavy Chain 7 and Their Phenotypic Manifestations

Walsh¹,

Rutland

Thomas³

et al. 2009

Cardiology

111

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Background:Mutations in myosin heavy chain 7 (MYH7) commonly cause cardiomyopathy. However, the relationship between mutation location, cardiomyopathy type, change in amino acid composition and disease severity is poorly understood. This systematic review aims to provide, on a large scale, important insights into the role mutations in MYH7 play in cardiomyopathy. Methods: The literature was searched from 1966 to March 2009. The mutation location, type of mutation and disease type and severity were documented. When the severity of disease was known, the change in charge and hydropathy of the mutation was determined. Where appropriate, either a χ² test was used or a relative risk ratio was calculated in order to evaluate the data. Results:The data presented in this study demonstrate that there are proportionately more mutations in the head and neck regions of this gene than in the tail. Importantly, mutations in the head of the gene, those that cause large changes in the hydropathy of the amino acid and non-conservative mutations are more likely to lead to a severe phenotype. Conclusions: This study suggests that mutation location in the MYH7 gene and changes in amino acid composition can have a negative impact on the disease outcome in individuals with cardiomyopathy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cardiomyopathy: A Systematic Review of Disease-Causing Mutations in Myosin Heavy Chain 7 and Their Phenotypic Manifestations

Walsh¹,

Rutland

Thomas³

et al. 2009

Cardiology

111

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show abstract

“…6,[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] CMR enables 3-dimensional tomographic assessment of cardiac anatomy and is considered the gold noninvasive standard for the evaluation of LV mass, volumes, and ejection fraction (LVEF). Additionally, LGE has the unique ability to identify areas of fibrosis.…”

Section: Weissler-snir Et Al Phenotypic-genotypic Correlation By Cmr mentioning

confidence: 99%

Lack of Phenotypic Differences by Cardiovascular Magnetic Resonance Imaging in MYH7 (β-Myosin Heavy Chain)- Versus MYBPC3 (Myosin-Binding Protein C)-Related Hypertrophic Cardiomyopathy

Weissler‐Snir

Hindieh

Gruner

et al. 2017

Circ: Cardiovascular Imaging

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H ypertrophic cardiomyopathy (HCM) is the most commonly inherited monogenic cardiac disease with an estimated prevalence of 1:500.1 HCM is inherited as an autosomal dominant trait with a variable expression and age-related penetrance.2,3 In ≈35% to 60% of cases, HCM is caused by mutations in genes encoding sarcomere proteins. 4,5 To date, >1400 mutations in >13 genes have been identified, with the MYH7 (β-myosin heavy chain) and MYBPC3 (myosin-binding protein C) most commonly affected, accounting for >70% of genotyped families. 2,6See Editorial by Tower-Rader and Desai See Clinical PerspectiveAlthough thin-filament disease seems to have distinct phenotypic features in terms of left ventricular (LV) hypertrophy (LVH), cardiac magnetic resonance (CMR) late gadolinium enhancement (LGE) distribution, and diastolic abnormalities, 7 findings on the phenotypic differences between patients with MYH7 and MYBPC3 gene mutations have been inconsistent.Background-The 2 most commonly affected genes in hypertrophic cardiomyopathy (HCM) are MYH7 (β-myosin heavy chain) and MYBPC3 (β-myosin-binding protein C). Phenotypic differences between patients with mutations in these 2 genes have been inconsistent. Scarce data exist on the genotype-phenotype association as assessed by tomographic imaging using cardiac magnetic resonance imaging. Methods and Results-Cardiac magnetic resonance imaging was performed on 358 consecutive genotyped hypertrophic cardiomyopathy probands at 5 tertiary hypertrophic cardiomyopathy centers. Genetic testing revealed a pathogenic mutation in 159 patients (44.4%). The most common genes identified were MYH7 (n=53) and MYBPC3 (n=75); 33.1% and 47% of genopositive patients, respectively. Phenotypic characteristics by cardiac magnetic resonance imaging of these 2 groups were similar, including left ventricular volumes, mass, maximal wall thickness, morphology, left atrial volume, and mitral valve leaflet lengths (all P=non-significant). The presence of late gadolinium enhancement (65% versus 64%; P=0.99) and the proportion of total left ventricular mass (%late gadolinium enhancement; 10.4±13.2% versus 8.5±8.5%; P=0.44) were also similar. Conclusions-This multicenter multinational study shows lack of phenotypic differences between MYH7-and MYBPC3-associated hypertrophic cardiomyopathy when assessed by cardiac magnetic resonance imaging. Postmutational mechanisms appear more relevant to thick-filament disease expression and outcome than the disease-causing variant per se. (Circ Cardiovasc Imaging. 2017;10:e005311.

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“…The MYH7 gene, also known as the β-myosin heavy chain, is the most commonly described defect in HCM and the most frequent cause of familial HCM, accounting for more than 20-30% of cases [16,17]. It is a large gene located in chromosome 14q11.2-q13 in humans, with 40 exons that give rise to a protein comprising 1,935 amino acids.…”

Section: Discussionmentioning

confidence: 99%

“…There are 3 functional domains in the MYH7 gene: the globular head region (S1), the neck region (S2), and the tail (light meromyosin) domain. The head region, which extends from exon 2 into exon 21, contains functional sites necessary for muscle contraction, such as the ATP-binding site, the actin-binding site, and the light chain-binding site, and thus plays a disproportionately large role in the functioning of the molecule [16,17,18,19]. …”

Section: Discussionmentioning

confidence: 99%

The Cumulative Effects of the MYH7-V878A and CACNA1C-A1594V Mutations in a Chinese Family with Hypertrophic Cardiomyopathy

Wang¹,

Guo²,

Wang³

et al. 2017

Cardiology

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Aims: We investigated the pathogenesis of MYH7-V878A and CACNA1C-A1594V mutations in a Chinese family with hypertrophic cardiomyopathy. Methods: Clinical, electrocardiographic (ECG), echocardiographic, and cardiac magnetic resonance (CMR) examinations of members of a Chinese family were followed by exon and boarding intron analyses of 96 genes in the proband using second-generation sequencing. We confirmed the mutations by bidirectional Sanger sequencing in the members and in 300 healthy controls. Results: We detected MYH7-V878A and CACNA1C-A1594V mutations in this family. The members with both mutations showed inverted T-waves and ST-segment depression in ECG recordings, severe left ventricular (LV) hypertrophy in echocardiography, and myocardial fibrosis in CMR; subject II-11 did not show late gadolinium enhancement. Among those with only the MYH7-V878A mutation, subject III-7 showed abnormal ECG recordings, asymmetric septal hypertrophy, and myocardial fibrosis, and subjects II-13 and III-15 showed some abnormal repolarization, borderline LV wall thickness, and normal CMR findings. Those with only the CACNA1C-A1594V mutation showed nearly normal readings in all examinations. The members with both mutations displayed more severe LV hypertrophy and elevated LV filling pressure than those with 1 or no mutation (p < 0.05). Conclusion: Our results suggest that the pathogenesis of MYH7-V878A and CACNA1C-A1594V mutations may have a cumulative effect.

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Comprehensive Analysis of the Beta-Myosin Heavy Chain Gene in 389 Unrelated Patients With Hypertrophic Cardiomyopathy

Cited by 169 publications

References 32 publications

Cardiomyopathy: A Systematic Review of Disease-Causing Mutations in Myosin Heavy Chain 7 and Their Phenotypic Manifestations

Cardiomyopathy: A Systematic Review of Disease-Causing Mutations in Myosin Heavy Chain 7 and Their Phenotypic Manifestations

Lack of Phenotypic Differences by Cardiovascular Magnetic Resonance Imaging in MYH7 (β-Myosin Heavy Chain)- Versus MYBPC3 (Myosin-Binding Protein C)-Related Hypertrophic Cardiomyopathy

The Cumulative Effects of the <b><i>MYH7</i></b>-V878A and <b><i>CACNA1C</i></b>-A1594V Mutations in a Chinese Family with Hypertrophic Cardiomyopathy

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