title: Mutation of a common amino acid in NKX2.5 results in dilated cardiomyopathy in two large families.
abstract: BACKGROUND
  The genetic basis for dilated cardiomyopathy (DCM) can be difficult to determine, particularly in familial cases with complex phenotypes. Next generation sequencing may be useful in the management of such cases.
  
  
  METHODS
  We report two large families with pleiotropic inherited cardiomyopathy. In addition to DCM, the phenotypes included atrial and ventricular septal defects, cardiac arrhythmia and sudden death. Probands underwent whole exome sequencing to identify potentially causative variants.
  
  
  RESULTS
  Each whole exome sequence yielded over 18,000 variants. We identified distinct mutations affecting a common amino acid in NKX2.5. Segregation analysis of the families support the pathogenic role of these variants.
  
  
  CONCLUSIONS
  Our study emphasizes the utility of next generation sequencing in identifying causative mutations in complex inherited cardiac disease. We also report a novel pathogenic NKX2.5 mutation.
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.|Program in Medical and Populations Genetics, Broad Institute, Cambridge, MA, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Hanley
authors.affiliation: Cork University Hospital, Cork, Wilton, Ireland.
authors.forename: Katie A
authors.initials: KA
authors.lastname: Walsh
authors.affiliation: Cork University Hospital, Cork, Wilton, Ireland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Joyce
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McLellan
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Clauss
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Amaya
authors.initials: A
authors.lastname: Hagen
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Marisa A
authors.initials: MA
authors.lastname: Shea
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.|Program in Medical and Populations Genetics, Broad Institute, Cambridge, MA, USA.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Tucker
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Honghuang
authors.initials: H
authors.lastname: Lin
authors.affiliation: Cork University Hospital, Cork, Wilton, Ireland.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Fahy
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. ellinor@mgh.harvard.edu.|Program in Medical and Populations Genetics, Broad Institute, Cambridge, MA, USA. ellinor@mgh.harvard.edu.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Ellinor
mesh_terms: D000596:Amino Acids / Q000235:genetics* / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000209:etiology; D004562:Electrocardiography; D005260:Female; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D000072576:Homeobox Protein Nkx-2.5 / Q000235:genetics*; D006801:Humans; D008297:Male; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D000596:Amino Acids; D000072576:Homeobox Protein Nkx-2.5; C095552:NKX2-5 protein, human; D004247:DNA
keywords: Arrhythmia; Cardiomyopathy; Next generation sequencing; Sudden cardiac death