title: Interpreting secondary cardiac disease variants in an exome cohort.
abstract: BACKGROUND
  Massively parallel sequencing to identify rare variants is widely practiced in medical research and in the clinic. Genome and exome sequencing can identify the genetic cause of a disease (primary results), but it can also identify pathogenic variants underlying diseases that are not being sought (secondary or incidental results). A major controversy has developed surrounding the return of secondary results to research participants. We have piloted a method to analyze exomes to identify participants at risk for cardiac arrhythmias, cardiomyopathies, or sudden death.
  
  
  RESULTS
  Exome sequencing was performed on 870 participants not selected for arrhythmia, cardiomyopathy, or a family history of sudden death. Exome data from 22 cardiac arrhythmia- and 41 cardiomyopathy-associated genes were analyzed using an algorithm that filtered results on genotype quality, frequency, and database information. We identified 1367 variants in the cardiomyopathy genes and 360 variants in the arrhythmia genes. Six participants had pathogenic variants associated with dilated cardiomyopathy (n=1), hypertrophic cardiomyopathy (n=2), left ventricular noncompaction (n=1), or long-QT syndrome (n=2). Two of these participants had evidence of cardiomyopathy and 1 had left ventricular noncompaction on echocardiogram. Three participants with likely pathogenic variants had prolonged QTc. Family history included unexplained sudden death among relatives.
  
  
  CONCLUSIONS
  Approximately 0.5% of participants in this study had pathogenic variants in known cardiomyopathy or arrhythmia genes. This high frequency may be due to self-selection, false positives, or underestimation of the prevalence of these conditions. We conclude that clinically important cardiomyopathy and dysrhythmia secondary variants can be identified in unselected exomes.
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ng
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Johnston
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Teer
authors.forename: Larry N
authors.initials: LN
authors.lastname: Singh
authors.forename: Lindsey C
authors.initials: LC
authors.lastname: Peller
authors.forename: Jamila S
authors.initials: JS
authors.lastname: Wynter
authors.forename: Katie L
authors.initials: KL
authors.lastname: Lewis
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.forename: Peter D
authors.initials: PD
authors.lastname: Stenson
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
mesh_terms: D000368:Aged; D001145:Arrhythmias, Cardiac / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics; D024722:Cardiac Myosins / Q000235:genetics; D009202:Cardiomyopathies / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D015331:Cohort Studies; D030541:Databases, Genetic; D016757:Death, Sudden, Cardiac; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D059472:Exome; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006331:Heart Diseases / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018995:Myosin Heavy Chains / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D017422:Sequence Analysis, DNA; D000099211:Phospholamban; D000099163:Myosin Binding Protein C
chemical_list: D002135:Calcium-Binding Proteins; D024722:Cardiac Myosins; D002352:Carrier Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D018995:Myosin Heavy Chains; D024642:Potassium Channels, Voltage-Gated; D000099211:Phospholamban; D000099163:Myosin Binding Protein C; C489622:KCNE1 protein, human; C501641:MYH7 protein, human
keywords: arrhythmias, cardiac; cardiomyopathies; genetic susceptibility; genetic variation; genetics; genomics; long QT syndrome