title: The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing.
abstract: OBJECTIVE
  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%.
  
  
  CONCLUSIONS
  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.
authors: 1] Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Molecular Medicine, Cambridge, Massachusetts, USA [2] Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA [3] Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors: Trevor J
authors: TJ
authors: Pugh
authors: Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Molecular Medicine, Cambridge, Massachusetts, USA.
authors: Melissa A
authors: MA
authors: Kelly
authors: Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Molecular Medicine, Cambridge, Massachusetts, USA.
authors: Sivakumar
authors: S
authors: Gowrisankar
authors: Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Molecular Medicine, Cambridge, Massachusetts, USA.
authors: Elizabeth
authors: E
authors: Hynes
authors: 1] Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Molecular Medicine, Cambridge, Massachusetts, USA [2] Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors: Michael A
authors: MA
authors: Seidman
authors: Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Molecular Medicine, Cambridge, Massachusetts, USA.
authors: Samantha M
authors: SM
authors: Baxter
authors: Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Molecular Medicine, Cambridge, Massachusetts, USA.
authors: Mark
authors: M
authors: Bowser
authors: Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Molecular Medicine, Cambridge, Massachusetts, USA.
authors: Bryan
authors: B
authors: Harrison
authors: Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Molecular Medicine, Cambridge, Massachusetts, USA.
authors: Daniel
authors: D
authors: Aaron
authors: Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Molecular Medicine, Cambridge, Massachusetts, USA.
authors: Lisa M
authors: LM
authors: Mahanta
authors: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors: Neal K
authors: NK
authors: Lakdawala
authors: Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Molecular Medicine, Cambridge, Massachusetts, USA.
authors: Gregory
authors: G
authors: McDermott
authors: Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Molecular Medicine, Cambridge, Massachusetts, USA.
authors: Emily T
authors: ET
authors: White
authors: 1] Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Molecular Medicine, Cambridge, Massachusetts, USA [2] Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors: Heidi L
authors: HL
authors: Rehm
authors: 1] Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Molecular Medicine, Cambridge, Massachusetts, USA [2] Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors: Matthew
authors: M
authors: Lebo
authors: 1] Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Molecular Medicine, Cambridge, Massachusetts, USA [2] Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors: Birgit H
authors: BH
authors: Funke
mesh_terms: D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D064211:Connectin / Q000235:genetics*; D051180:Desmoplakins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D017422:Sequence Analysis, DNA / Q000379:methods*; D016596:Vinculin / Q000235:genetics; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D064211:Connectin; D051180:Desmoplakins; D016596:Vinculin; D000099163:Myosin Binding Protein C; C495294:DSP protein, human; C577285:TTN protein, human; C488955:VCL protein, human