Oligogenic inheritance of a human heart disease involving a genetic modifier

Science. 2019 May 31;364(6443):865-870. doi: 10.1126/science.aat5056. Epub 2019 May 30.


Complex genetic mechanisms are thought to underlie many human diseases, yet experimental proof of this model has been elusive. Here, we show that a human cardiac anomaly can be caused by a combination of rare, inherited heterozygous mutations. Whole-exome sequencing of a nuclear family revealed that three offspring with childhood-onset cardiomyopathy had inherited three missense single-nucleotide variants in the MKL2, MYH7, and NKX2-5 genes. The MYH7 and MKL2 variants were inherited from the affected, asymptomatic father and the rare NKX2-5 variant (minor allele frequency, 0.0012) from the unaffected mother. We used CRISPR-Cas9 to generate mice encoding the orthologous variants and found that compound heterozygosity for all three variants recapitulated the human disease phenotype. Analysis of murine hearts and human induced pluripotent stem cell-derived cardiomyocytes provided histologic and molecular evidence for the NKX2-5 variant's contribution as a genetic modifier.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Associated Protein 9
  • Cardiac Myosins / genetics
  • Cardiomyopathies / genetics*
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Exome
  • Gene Frequency
  • Heterozygote*
  • Homeobox Protein Nkx-2.5 / genetics*
  • Humans
  • Induced Pluripotent Stem Cells
  • Mice
  • Mice, Mutant Strains
  • Multifactorial Inheritance*
  • Mutation, Missense
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Myosin Heavy Chains / genetics
  • Paternal Inheritance / genetics
  • Thyroid Nuclear Factor 1 / genetics*
  • Transcription Factors / genetics


  • Homeobox Protein Nkx-2.5
  • MRTFB protein, human
  • MYH7 protein, human
  • NKX2-5 protein, human
  • Nkx2-1 protein, mouse
  • Thyroid Nuclear Factor 1
  • Transcription Factors
  • CRISPR-Associated Protein 9
  • Cardiac Myosins
  • Myosin Heavy Chains