title: Familial Atrial Septal Defect and Sudden Cardiac Death: Identification of a Novel NKX2-5 Mutation and a Review of the Literature.
abstract: OBJECTIVE
  Atrial septal defect (ASD) is the second most common congenital heart defect (CHD) and is observed in families as an autosomal dominant trait as well as in nonfamilial CHD. Mutations in the NKX2-5 gene, located on chromosome 5, are associated with ASD, often combined with conduction disturbances, cardiomyopathies, complex CHD, and sudden cardiac death as well. Here, we show that NKX2-5 mutations primarily occur in ASD patients with conduction disturbances and heritable ASD. Furthermore, these families are at increased risk of sudden cardiac death.
  
  
  RESULTS
  We screened 39 probands with familial CHD for mutations in NKX2-5 and discovered a novel mutation in one family (2.5%) with ASD and atrioventricular block. A review of the literature revealed 59 different NKX2-5 mutations in 202 patients. Mutations were significantly more common in familial cases compared to nonfamilial cases (P = 7.1 × 10(-9) ). The majority of patients (74%) had ASD with conduction disturbance. Nineteen patients (15%) of 120 with familial ASD and conduction disturbance died from sudden cardiac death of which nine (8%) were confirmed mutation carriers, and 10 were possible carriers.
  
  
  CONCLUSIONS
  NKX2-5 mutations mainly occur in familial CHD, the signature phenotype is ASD with conduction disturbances and mutation carriers are at increased risk of sudden cardiac death. We suggest that familial ASD patients should be screened for NKX2-5 mutations and, if they are mutation carriers, implantation of an implantable cardioverter-defibrillator should be considered in these patients.
authors.affiliation: Department of Disease Systems Biology, NNF Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Sabrina Gade
authors.initials: SG
authors.lastname: Ellesøe
authors.affiliation: Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Morten Munk
authors.initials: MM
authors.lastname: Johansen
authors.affiliation: Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jesper Vandborg
authors.initials: JV
authors.lastname: Bjerre
authors.affiliation: Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Vibeke Elisabeth
authors.initials: VE
authors.lastname: Hjortdal
authors.affiliation: Department of Disease Systems Biology, NNF Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Brunak
authors.affiliation: Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lars Allan
authors.initials: LA
authors.lastname: Larsen
mesh_terms: D000328:Adult; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006344:Heart Septal Defects, Atrial / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D040941:Heredity; D006579:Heterozygote; D000072576:Homeobox Protein Nkx-2.5 / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011379:Prognosis; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D055815:Young Adult
chemical_list: D000072576:Homeobox Protein Nkx-2.5; C095552:NKX2-5 protein, human
keywords: Congenital Atrioventricular Block; Congenital Heart Disease; Familial ASD; NKX2-5; Sudden Cardiac Death