Abstract
Background: Hypertrophic cardiomyopathy (HCM) is an inherited disorder of the myocardium, and pathogenic mutations in the sarcomere genes MYH7 and MYBPC3 explain 60-70% of observed clinical cases. The heterogeneity of phenotypes observed in HCM patients, however, suggests that novel causative genes or genetic modifiers likely exist and that further elucidation of these genes is needed. Methods: In order to identify genes and potential networks that affect the HCM phenotype, we systemically evaluated RNA-seq data from 28 HCM patients and 9 healthy controls with pathogenic variant identification, differential expression analysis, and gene co-expression and protein-protein interaction network analyses. Findings: We identified 43 potential pathogenic variants in 19 genes in 24 HCM patients. Genes with more than one variant included the following: MYBPC3, TTN, MYH7, PSEN2, and LDB3. A total of 2538 protein-coding genes, 6 microRNAs (miRNAs), and 1617 long noncoding RNAs (lncRNAs) were identified differentially expressed between the groups, including several well-characterized cardiomyopathy-related genes (ANKRD1, FHL2, MYH6, TGFB3, miR-30d, and miR-154). Gene enrichment analysis revealed that those genes are significantly involved in heart development and physiology. Furthermore, by integrating gene co-expression and protein-protein interaction network analyses, we highlighted four subnetworks: Mitochondrial DNA (mtDNA)-subnetwork, Desmoplakin (DSP) -subnetwork, myosin heavy chain 7 (MYH7) -subnetwork, and cardiac myosin-binding protein C (MYBPC3)-subnetwork, which could play significant roles in the progression of HCM. Interpretation: Our findings further illustrate that HCM is a complex disease, which results from mutations in multiple protein-coding genes, modulation by non-coding RNAs and perturbations in gene networks. Funding Statement: The authors received no specific funding for this work. Declaration of Interests: All other authors declare no competing interests. Ethics Approval Statement: Not required.
Highlights
Hypertrophic cardiomyopathy (HCM) is a global, inherited cardiovascular disease that can lead to arrhythmia, heart failure and even sudden cardiac death [1,2]
The results demonstrated that a high-quality dataset was obtained and hundreds of differentially expressed genes (DEGs) were identified between
For HCM samples, MYBPC3 mutations were previously identified in 10 samples and myosin heavy chain 7 (MYH7) mutations in eight (Table 1)
Summary
Hypertrophic cardiomyopathy (HCM) is a global, inherited cardiovascular disease that can lead to arrhythmia, heart failure and even sudden cardiac death [1,2]. It is characterized by ventricular hypertrophy (usually the left ventricle), small ventricular cavity, and decreased ventricular diastolic compliance. Though, has revealed that some mutation carriers do not exhibit obvious clinical symptoms of HCM. It is still possible for a carrier to later demonstrate HCM symptoms and to pass these potentially pathogenic mutations on to offspring [5]. With the use of these more sophisticated technologies, the prevalence of HCM should be modified to 0.5% or even greater [2]
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