Genetic Dissection of Hypertrophic Cardiomyopathy with Myocardial RNA-Seq

Int J Mol Sci. 2020 Apr 25;21(9):3040. doi: 10.3390/ijms21093040.


Hypertrophic cardiomyopathy (HCM) is an inherited disorder of the myocardium, and pathogenic mutations in the sarcomere genes myosin heavy chain 7 (MYH7) and myosin-binding protein C (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. Here, we systemically evaluated RNA-seq data from 28 HCM patients and nine healthy controls with pathogenic variant identification, differential expression analysis, and gene co-expression and protein-protein interaction network analyses. 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, six microRNAs (miRNAs), and 1617 long noncoding RNAs (lncRNAs) were identified differentially expressed between the groups, including several well-characterized cardiomyopathy-related genes (ANKRD1, FHL2, TGFB3, miR-30d, and miR-154). Gene enrichment analysis revealed that those genes are significantly involved in heart development and physiology. Furthermore, we highlighted four subnetworks: mtDNA-subnetwork, DSP-subnetwork, MYH7-subnetwork, and MYBPC3-subnetwork, which could play significant roles in the progression of HCM. 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.

Keywords: RNA-seq; differential gene expression; gene network; hypertrophic cardiomyopathy; pathogenic variants.

MeSH terms

  • Adult
  • Cardiac Myosins / deficiency
  • Cardiac Myosins / genetics
  • Cardiomyopathy, Hypertrophic / genetics
  • Carrier Proteins / genetics
  • Exons / genetics
  • Female
  • Gene Expression Profiling
  • Gene Ontology
  • Gene Regulatory Networks* / genetics
  • Genetic Association Studies*
  • Genetic Heterogeneity*
  • Humans
  • INDEL Mutation
  • Male
  • Middle Aged
  • Mutation
  • Myocardium / chemistry*
  • Myosin Heavy Chains / deficiency
  • Myosin Heavy Chains / genetics
  • Polymorphism, Single Nucleotide
  • RNA, Untranslated / genetics
  • Sequence Analysis, RNA*
  • Smoking
  • Young Adult


  • Carrier Proteins
  • MYH7 protein, human
  • RNA, Untranslated
  • myosin-binding protein C
  • Cardiac Myosins
  • Myosin Heavy Chains