title: Association of common variants in ERBB4 with congenital left ventricular outflow tract obstruction defects.
abstract: BACKGROUND
  The left ventricular outflow tract (LVOT) defects aortic valve stenosis (AVS), coarctation of the aorta (COA), and hypoplastic left heart syndrome (HLHS) represent an embryologically related group of congenital cardiovascular malformations. They are common and cause substantial morbidity and mortality. Prior evidence suggests a strong genetic component in their causation.
  
  
  METHODS
  We selected NRG1, ERBB3, and ERBB4 of the epidermal growth factor receptor (EGFR) signaling pathway as candidate genes for investigation of association with LVOT defects based on the importance of this pathway in cardiac development and the phenotypes in knockout mouse models. Single nucleotide polymorphism (SNP) genotyping was performed on 343 affected case-parent trios of European ancestry.
  
  
  RESULTS
  We identified a specific haplotype in intron 3 of ERBB4 that was positively associated with the combined LVOT defects phenotype (p=0.0005) and in each anatomic defect AVS, COA, and HLHS separately. Mutation screening of individuals with an LVOT defect failed to identify a coding sequence or splice site change in ERBB4. RT-PCR on lymphoblastoid cells from LVOT subjects did not show altered splice variant ratios among those homozygous for the associated haplotype.
  
  
  CONCLUSIONS
  These results suggest ERBB4 is associated with LVOT defects. Further replication will be required in separate cohorts to confirm the consistency of the observed association.
authors.affiliation: Center for Molecular and Human Genetics, Nationwide Children's Hospital, Department of Pediatrics, Ohio State University, Columbus, Ohio 43205, USA. Kim.McBride@NationwideChildrens.org
authors.forename: Kim L
authors.initials: KL
authors.lastname: McBride
authors.forename: Gloria A
authors.initials: GA
authors.lastname: Zender
authors.forename: Sara M
authors.initials: SM
authors.lastname: Fitzgerald-Butt
authors.forename: Nikki J
authors.initials: NJ
authors.lastname: Seagraves
authors.forename: Susan D
authors.initials: SD
authors.lastname: Fernbach
authors.forename: Gladys
authors.initials: G
authors.lastname: Zapata
authors.forename: Mark
authors.initials: M
authors.lastname: Lewin
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.forename: John W
authors.initials: JW
authors.lastname: Belmont
mesh_terms: D002648:Child; D015331:Cohort Studies; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D018815:Genes, erbB / Q000235:genetics; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics; D006801:Humans; D008297:Male; D020890:Neuregulin-1 / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics; D066247:Receptor, ErbB-4; D014694:Ventricular Outflow Obstruction / Q000151:congenital* / Q000235:genetics*
chemical_list: D020890:Neuregulin-1; D020033:Protein Isoforms; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4