title: Analyses of more than 60,000 exomes questions the role of numerous genes previously associated with dilated cardiomyopathy.
abstract: BACKGROUND
  Hundreds of genetic variants have been described as disease causing in dilated cardiomyopathy (DCM). Some of these associations are now being questioned. We aimed to identify the prevalence of previously DCM associated variants in the Exome Aggregation Consortium (ExAC), in order to identify potentially false-positive DCM variants.
  
  
  METHODS
  Variants listed as DCM disease-causing variants in the Human Gene Mutation Database were extracted from ExAC. Pathogenicity predictions for these variants were mined from dbNSFP v 2.9 database.
  
  
  RESULTS
  Of the 473 DCM variants listed in HGMD, 148 (31%) were found in ExAC. The expected number of individuals with DCM in ExAC is 25 based on the prevalence in the general population. Yet, 35 variants were found in more than 25 individuals. In 13 genes, we identified all variants previously associated with DCM; four genes contained variants above our estimated cut-off. Prediction tools found ExAC variants to be significantly more tolerated when compared to variants not found in ExAC (P= 0.004).
  
  
  CONCLUSIONS
  In ExAC, we identified a higher genotype prevalence of variants considered disease-causing than expected. More importantly, we found 13 genes in which all variants previously associated with DCM were identified in ExAC, questioning the association of these genes with the monogenic form of DCM.
authors.affiliation: Laboratory of Molecular Cardiology Department of Cardiology The Heart Centre University Hospital of Copenhagen Rigshospitalet Copenhagen Denmark.
authors.forename: Nina
authors.initials: N
authors.lastname: Nouhravesh
authors.affiliation: Laboratory of Molecular Cardiology Department of Cardiology The Heart Centre University Hospital of Copenhagen Rigshospitalet Copenhagen Denmark.
authors.forename: Gustav
authors.initials: G
authors.lastname: Ahlberg
authors.affiliation: Laboratory of Molecular Cardiology Department of Cardiology The Heart Centre University Hospital of Copenhagen Rigshospitalet Copenhagen Denmark.
authors.forename: Jonas
authors.initials: J
authors.lastname: Ghouse
authors.affiliation: Laboratory of Molecular Cardiology Department of Cardiology The Heart Centre University Hospital of Copenhagen Rigshospitalet Copenhagen Denmark.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Andreasen
authors.affiliation: Laboratory of Molecular CardiologyDepartment of CardiologyThe Heart CentreUniversity Hospital of CopenhagenRigshospitaletCopenhagenDenmark; Department of Clinical MedicineFaculty of Medicine and Health SciencesUniversity of CopenhagenCopenhagenDenmark.
authors.forename: Jesper H
authors.initials: JH
authors.lastname: Svendsen
authors.affiliation: Laboratory of Molecular Cardiology Department of Cardiology The Heart Centre University Hospital of Copenhagen Rigshospitalet Copenhagen Denmark.
authors.forename: Stig
authors.initials: S
authors.lastname: Haunsø
authors.affiliation: Unit for Inherited Cardiac Diseases The Heart Center National University Hospitals Rigshospitalet Copenhagen Denmark.
authors.forename: Henning
authors.initials: H
authors.lastname: Bundgaard
authors.affiliation: Laboratory of Molecular Cardiology Department of Cardiology The Heart Centre University Hospital of Copenhagen Rigshospitalet Copenhagen Denmark.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Weeke
authors.affiliation: Laboratory of Molecular Cardiology Department of Cardiology The Heart Centre University Hospital of Copenhagen Rigshospitalet Copenhagen Denmark.
authors.forename: Morten S
authors.initials: MS
authors.lastname: Olesen
keywords: Exome; NGS; false‐positive variants; familial dilated cardiomyopathy; next‐generation sequencing