The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing

Genet Med. 2014 Aug;16(8):601-8. doi: 10.1038/gim.2013.204. Epub 2014 Feb 6.


Purpose: Dilated cardiomyopathy is characterized by substantial locus, allelic, and clinical heterogeneity that necessitates testing of many genes across clinically overlapping diseases. Few studies have sequenced sufficient individuals; thus, the contributions of individual genes and the pathogenic variant spectrum are still poorly defined. We analyzed 766 dilated cardiomyopathy patients tested over 5 years in our molecular diagnostics laboratory.

Methods: Patients were tested using gene panels of increasing size from 5 to 46 genes, including 121 cases tested with a multiple-cardiomyopathy next-generation panel covering 46 genes. All variants were reassessed using our current clinical-grade scoring system to eliminate false-positive disease associations that afflict many older analyses.

Results: Up to 37% of dilated cardiomyopathy cases carry a clinically relevant variant in one of 20 genes, titin (TTN) being the largest contributor (up to 14%). Desmoplakin (DSP), an arrhythmogenic right ventricular cardiomyopathy gene, contributed 2.4%, illustrating the utility of multidisease testing. The clinical sensitivity increased from 10 to 37% as gene panel sizes increased. However, the number of inconclusive cases also increased from 4.6 to 51%.

Conclusion: Our data illustrate the utility of broad gene panels for genetically and clinically heterogeneous diseases but also highlight challenges as molecular diagnostics moves toward genome-wide testing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cardiomyopathy, Dilated / genetics*
  • Carrier Proteins / genetics
  • Connectin / genetics*
  • Desmoplakins / genetics
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Humans
  • Male
  • Sequence Analysis, DNA / methods*
  • Vinculin / genetics


  • Carrier Proteins
  • Connectin
  • DSP protein, human
  • Desmoplakins
  • TTN protein, human
  • VCL protein, human
  • myosin-binding protein C
  • Vinculin