Screening Mutations of MYBPC3 in 114 Unrelated Patients with Hypertrophic Cardiomyopathy by Targeted Capture and Next-generation Sequencing

Liu, Xuxia; Jiang, Taiyi; Piao, Chunmei; Li, Xiaoyan; Guo, Jun; Zheng, Shuai; Zhang, Xiaoping; Cai, Tao; Du, Jie

doi:10.1038/srep11411

Cited by 34 publications

(37 citation statements)

References 29 publications

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“…This is in contrast to previous ndings, which suggest earlier onset and diagnosis of the disease for MYH7 mutation [16,18]. Patients in our study were predominantly male, which is consistent with gender distribution across literature, where about two-thirds of HCM patients are male [13,19,20].…”

Section: Discussionsupporting

confidence: 87%

Genetic Determinants Of Clinical Phenotype In Hypertrophic Cardiomyopathy 

Velicki

Jakovljevic

Preveden

et al. 2020

Preprint

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Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease that affects approximately one in 500 people. HCM is a recognized genetic disorder most often caused by mutations involving myosin-binding protein C (MYBPC3) and β-myosin heavy chain (MYH7) which are responsible for approximately three-quarters of the identified mutations.Methods: As a part of the international multidisciplinary SILICOFCM project (www.silicofcm.eu) the present study evaluated the association between underlying genetic mutations and clinical phenotype in patients with HCM. Only patients with confirmed single pathogenic mutations in either MYBPC3 or MYH7 genes were included in the study and divided into two groups accordingly. The MYBPC3 group was comprised of 48 patients (76%), while the MYH7 group included 15 patients (24%). Each patient underwent clinical examination and echocardiography.Results: The most prevalent symptom in patients with MYBPC3 was dyspnea (44%), whereas in patients with MYH7 it was palpitations (33%). The MYBPC3 group had a significantly higher number of patients with a positive family history of HCM (46% vs. 7%; p=0.014). There was a numerically higher prevalence of atrial fibrillation in the MYH7 group (60% vs. 35%, p=0.085). Laboratory analyses revealed normal levels of creatinine (85.5±18.3 vs. 81.3±16.4 µmol/l; p=0.487) and blood urea nitrogen (10.2±15.6 vs. 6.9±3.9 mmol/l; p=0.472) which were similar in both groups. The systolic anterior motion presence was significantly more frequent in patients caring MYH7 mutation (33% vs. 10%; p=0.025), as well as mitral leaflet abnormalities (40% vs. 19%; p=0.039). Calcifications of mitral annulus were registered only in MYH7 patients (20% vs. 0%; p=0.001). The difference in diastolic function, i.e. E/e’ ratio between the two groups was also noted (MYBPC3 8.8±3.3, MYH7 13.9±6.9, p=0.079).Conclusions: Major findings of the present study corroborate the notion that MYH7 gene mutation patients are presented with more pronounced disease severity than those with MYBPC3.

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Section: Discussionsupporting

confidence: 87%

Genetic Determinants Of Clinical Phenotype In Hypertrophic Cardiomyopathy 

Velicki

Jakovljevic

Preveden

et al. 2020

Preprint

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“…further confirm the relation between zebrafish and human cardiac biology, where HCM patients have a smaller end-diastolic diameter and increased wall thickness in presence of significant hypertrophy(Liu et al, 2015;Olivotto et al, 2008).…”

supporting

confidence: 68%

Functional characterization of human myosin‐binding protein C3 variants associated with hypertrophic cardiomyopathy reveals exon‐specific cardiac phenotypes in zebrafish model

Da’as

Yalcin

Nasrallah

et al. 2020

Journal Cellular Physiology

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Myosin‐binding protein C 3 (MYBPC3) variants are the most common cause of hypertrophic cardiomyopathy (HCM). HCM is a complex cardiac disorder due to its significant genetic and clinical heterogeneity. MYBPC3 variants genotype–phenotype associations remain poorly understood. We investigated the impact of two novel human MYBPC3 splice‐site variants: V1: c.654+2_654+4dupTGG targeting exon 5 using morpholino MOe5i5; and V2: c.772+1G>A targeting exon 6 using MOe6i6; located within C1 domain of cMyBP‐C protein, known to be critical in regulating sarcomere structure and contractility. Zebrafish MOe5i5 and MOe6i6 morphants recapitulated typical characteristics of human HCM with cardiac phenotypes of varying severity, including reduced cardiomyocyte count, thickened ventricular myocardial wall, a drastic reduction in heart rate, stroke volume, and cardiac output. Analysis of all cardiac morphological and functional parameters demonstrated that V2 cardiac phenotype was more severe than V1. Coinjection with synthetic human MYBPC3 messenger RNA (mRNA) partially rescued disparate cardiac phenotypes in each zebrafish morphant. While human MYBPC3 mRNA partially restored the decreased heart rate in V1 morphants and displayed increased percentages of ejection fraction, fractional shortening, and area change, it failed to revert the V1 ventricular myocardial thickness. These results suggest a possible V1 impact on cardiac contractility. In contrast, attempts to rescue V2 morphants only restored the ventricular myocardial wall hypertrophy phenotype but had no significant effect on impaired heart rate, suggesting a potential V2 impact on the cardiac structure. Our study provides evidence of an association between MYBPC3 exon‐specific cardiac phenotypes in the zebrafish model providing important insights into how these genetic variants contribute to HCM disease.

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“…HCM is a common cause of sudden cardiac arrest in young people, including young athletes (5,6). Accordingly, early diagnosis is essential for the prevention of such catastrophic events (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

RNA-seq profiling of mRNA associated with hypertrophic cardiomyopathy

Ren

Liu

et al. 2016

Molecular Medicine Reports

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The mechanisms of hypertrophic cardiomyopathy (HCM) pathogenesis can be investigated by determining the differences between healthy and disease states at the molecular level. In the present study, large‑scale transcriptome sequencing was performed to compare mRNA expression in patients with HCM and control groups using an Illumina sequencing platform. Compared with the genome background, 257 differentially expressed genes (DEGs) were identified in which 62 genes were downregulated and 195 genes were upregulated. Reverse transcription‑quantitative polymerase chain reaction was performed to validate the expression pattern of certain mRNAs. Gene ontology enrichment and KEGG analysis of mRNAs was conducted to identify the biological modules and pathological pathways associated with the DEGs. To the best of our knowledge, this is the first time study to investigate the differences in mRNA between patients with HCM and normal controls at the transcriptome level. The results of the study will contributed to the understanding of the important molecular mechanisms involved in HCM and aid the selection of key genes to investigate in the future.

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Screening Mutations of MYBPC3 in 114 Unrelated Patients with Hypertrophic Cardiomyopathy by Targeted Capture and Next-generation Sequencing

Cited by 34 publications

References 29 publications

Genetic Determinants Of Clinical Phenotype In Hypertrophic Cardiomyopathy

Genetic Determinants Of Clinical Phenotype In Hypertrophic Cardiomyopathy

Functional characterization of human myosin‐binding protein C3 variants associated with hypertrophic cardiomyopathy reveals exon‐specific cardiac phenotypes in zebrafish model

RNA-seq profiling of mRNA associated with hypertrophic cardiomyopathy

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Screening Mutations of MYBPC3 in 114 Unrelated Patients with Hypertrophic Cardiomyopathy by Targeted Capture and Next-generation Sequencing

Cited by 34 publications

References 29 publications

Genetic Determinants Of Clinical Phenotype In Hypertrophic Cardiomyopathy&nbsp;

Genetic Determinants Of Clinical Phenotype In Hypertrophic Cardiomyopathy&nbsp;

Functional characterization of human myosin‐binding protein C3 variants associated with hypertrophic cardiomyopathy reveals exon‐specific cardiac phenotypes in zebrafish model

RNA-seq profiling of mRNA associated with hypertrophic cardiomyopathy

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Genetic Determinants Of Clinical Phenotype In Hypertrophic Cardiomyopathy

Genetic Determinants Of Clinical Phenotype In Hypertrophic Cardiomyopathy