A Novel Recessive Mutation in SPEG Causes Early Onset Dilated Cardiomyopathy

PLoS Genet. 2020 Sep 14;16(9):e1009000. doi: 10.1371/journal.pgen.1009000. eCollection 2020 Sep.


Dilated cardiomyopathy (DCM) is a common cause of heart failure and sudden cardiac death. It has been estimated that up to half of DCM cases are hereditary. Mutations in more than 50 genes, primarily autosomal dominant, have been reported. Although rare, recessive mutations are thought to contribute considerably to DCM, especially in young children. Here we identified a novel recessive mutation in the striated muscle enriched protein kinase (SPEG, p. E1680K) gene in a family with nonsyndromic, early onset DCM. To ascertain the pathogenicity of this mutation, we generated SPEG E1680K homozygous mutant human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) using CRISPR/Cas9-mediated genome editing. Functional studies in mutant iPSC-CMs showed aberrant calcium homeostasis, impaired contractility, and sarcomeric disorganization, recapitulating the hallmarks of DCM. By combining genetic analysis with human iPSCs, genome editing, and functional assays, we identified SPEG E1680K as a novel mutation associated with early onset DCM and provide evidence for its pathogenicity in vitro. Our study provides a conceptual paradigm for establishing genotype-phenotype associations in DCM with autosomal recessive inheritance.

MeSH terms

  • Adolescent
  • Age of Onset
  • Calcium / metabolism
  • Cardiomyopathy, Dilated / etiology
  • Cardiomyopathy, Dilated / genetics*
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Exome Sequencing
  • Female
  • Gene Editing
  • Genes, Recessive
  • Heat-Shock Proteins
  • Homozygote
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / drug effects
  • Infant
  • Male
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism
  • Mutation
  • Myocardial Contraction
  • Myocytes, Cardiac / pathology
  • Pedigree
  • Peptide Fragments
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism


  • Heat-Shock Proteins
  • Muscle Proteins
  • Peptide Fragments
  • SNP nonapeptide
  • Protein Serine-Threonine Kinases
  • SPEG protein, human
  • Calcium