A founder<i>MYBPC3</i>mutation results in HCM with a high risk of sudden death after the fourth decade of life

Calore, Chiara; Bortoli, Marzia De; Romualdi, Chiara; Lorenzon, Alessandra; Angelini, Annalisa; Basso, Cristina; Thiene, Gaetano; Iliceto, Sabino; Melacini, Paola

doi:10.1136/jmedgenet-2014-102923

Cited by 42 publications

(33 citation statements)

References 30 publications

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“…26,[28][29][30][31] Extreme hypertrophy was absent in FG+ relatives, and there was less adverse remodeling. Identification of HCM leads to lifestyle modifications, periodic SCD risk stratification, and close clinical follow-up, with the opportunity to implant an ICD for primary prevention and timely referral for septal reduction therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have previously demonstrated an increased risk of cardiac death in G+ versus G− HCM, [22][23][24] including studies of MYBPC3 founder mutations. 25,26 G− probands in this study were older and more symptomatic most likely related to LVOT obstruction and diastolic dysfunction. Possibly, G− HCM represents a separate disease with a different pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

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Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation

Velzen

Schinkel

Oldenburg

et al. 2017

Circ Cardiovasc Genet

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Background— MYBPC3 (Myosin-binding protein C) founder mutations account for 35% of hypertrophic cardiomyopathy (HCM) cases in the Netherlands. We compared clinical characteristics and outcome of MYBPC3 founder mutation (FG+) HCM with nonfounder genotype-positive (G+) and genotype-negative (G−) HCM. Methods and Results— The study included 680 subjects: 271 FG+ carriers, 132 G+ probands with HCM, and 277 G− probands with HCM. FG+ carriers included 134 FG+ probands with HCM, 54 FG+ relatives diagnosed with HCM after family screening, 74 FG+/phenotype-negative relatives, and 9 with noncompaction or dilated cardiomyopathy. The clinical phenotype of FG+ and G+ probands with HCM was similar. FG+ and G+ probands were younger with less left ventricular outflow tract obstruction than G− probands, however, had more hypertrophy, and nonsustained ventricular tachycardia. FG+ relatives with HCM had less hypertrophy, smaller left atria, and less systolic and diastolic dysfunction than FG+ probands with HCM. After 8±6 years, cardiovascular mortality in FG+ probands with HCM was similar to G+ HCM (22% versus 14%; log-rank P =0.14), but higher than G− HCM (22% versus 6%; log-rank P <0.001) and FG+ relatives with HCM (22% versus 4%; P =0.009). Cardiac events were absent in FG+/phenotype-negative relatives; subtle HCM developed in 11% during 6 years of follow-up. Conclusions— Clinical phenotype and outcome of FG+ HCM was similar to G+ HCM but worse than G− HCM and FG+ HCM diagnosed in the context of family screening. These findings indicate the need for more intensive follow-up of FG+ and G+ HCM versus G− HCM and FG+ HCM in relatives.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation

Velzen

Schinkel

Oldenburg

et al. 2017

Circ Cardiovasc Genet

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“…Co-segregation analysis of the variant and the disorder within families was possible only for MYBPC3 -c.506-2A>C and SCN5A -c.393-5C>A, but the number of informative meioses within the pedigrees was not sufficient to establish pathogenicity [28]. However, these two variants co-occurred with the disorder (HCM and BrS, respectively) in previous reports [15,30]. …”

Section: Discussionmentioning

confidence: 99%

Functional Studies and In Silico Analyses to Evaluate Non-Coding Variants in Inherited Cardiomyopathies

Frisso

Detta

Coppola

et al. 2016

IJMS

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Point mutations are the most common cause of inherited diseases. Bioinformatics tools can help to predict the pathogenicity of mutations found during genetic screening, but they may work less well in determining the effect of point mutations in non-coding regions. In silico analysis of intronic variants can reveal their impact on the splicing process, but the consequence of a given substitution is generally not predictable. The aim of this study was to functionally test five intronic variants (MYBPC3-c.506-2A>C, MYBPC3-c.906-7G>T, MYBPC3-c.2308+3G>C, SCN5A-c.393-5C>A, and ACTC1-c.617-7T>C) found in five patients affected by inherited cardiomyopathies in the attempt to verify their pathogenic role. Analysis of the MYBPC3-c.506-2A>C mutation in mRNA from the peripheral blood of one of the patients affected by hypertrophic cardiac myopathy revealed the loss of the canonical splice site and the use of an alternative splicing site, which caused the loss of the first seven nucleotides of exon 5 (MYBPC3-G169AfsX14). In the other four patients, we generated minigene constructs and transfected them in HEK-293 cells. This minigene approach showed that MYBPC3-c.2308+3G>C and SCN5A-c.393-5C>A altered pre-mRNA processing, thus resulting in the skipping of one exon. No alterations were found in either MYBPC3-c.906-7G>T or ACTC1-c.617-7T>C. In conclusion, functional in vitro analysis of the effects of potential splicing mutations can confirm or otherwise the putative pathogenicity of non-coding mutations, and thus help to guide the patient's clinical management and improve genetic counseling in affected families.

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“…Notably, 2 of these developed LV dilatation with LV wall thinning. 38 Whether these differences in LV systolic function between patients with MYBPC3 and MYH7 gene mutations after the age of 40 years are indeed of significance will need further study.…”

Section: Discussionmentioning

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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A founderMYBPC3mutation results in HCM with a high risk of sudden death after the fourth decade of life

Cited by 42 publications

References 30 publications

Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation

Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation

Functional Studies and In Silico Analyses to Evaluate Non-Coding Variants in Inherited Cardiomyopathies

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

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