title: Rare GATA5 sequence variants identified in individuals with bicuspid aortic valve.
abstract: BACKGROUND
  Bicuspid aortic valve (BAV) is the most common type of congenital heart disease (CHD) and has a proposed genetic etiology. BAV is categorized by cusp fusion, with right-left (R-L) cusp fusion being associated with additional CHD, and right-noncoronary cusp (R-NC) fusion being associated with aortic valve dysfunction. Loss of murine Gata5, which encodes a cardiac transcription factor, results in a partially penetrant R-NC BAV, and we hypothesize that mutations in GATA5 are associated with R-NC BAV in humans.
  
  
  METHODS
  A cohort of 78 BAV patients (50 with isolated BAV and 28 with associated aortic coarctation) was analyzed using Sanger sequencing to identify GATA5 sequence variants. Biochemical assays were performed to identify functional deficits of identified sequence variants.
  
  
  RESULTS
  We identified two rare heterozygous nonsynonymous variants, p.Gln3Arg and p.Leu233Pro, for a frequency of 2.6% (2/78). Both individuals with nonsynonymous variants had BAV and aortic coarctation, one R-L and one R-NC subtype. Of the nonsynonymous variants, only p.Gln3Arg demonstrated decreased transcriptional activity in vitro.
  
  
  CONCLUSIONS
  Rare sequence variants in GATA5 are associated with human BAV. Our findings suggest a genotype-phenotype correlation in regards to associated CHD but not cusp fusion.
authors.affiliation: Department of Pediatrics, The Ohio State University, Columbus, Ohio.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Bonachea
authors.affiliation: 1] Center for Cardiovascular and Pulmonary Research, Nationwide Children's Hospital, Columbus, Ohio [2] The Heart Center, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Sheng-Wei
authors.initials: SW
authors.lastname: Chang
authors.affiliation: 1] Center for Cardiovascular and Pulmonary Research, Nationwide Children's Hospital, Columbus, Ohio [2] The Heart Center, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Gloria
authors.initials: G
authors.lastname: Zender
authors.affiliation: 1] Center for Cardiovascular and Pulmonary Research, Nationwide Children's Hospital, Columbus, Ohio [2] The Heart Center, Nationwide Children's Hospital, Columbus, Ohio [3] Department of Molecular Genetics, The Ohio State University, Columbus, Ohio.
authors.forename: Stephanie
authors.initials: S
authors.lastname: LaHaye
authors.affiliation: 1] Department of Pediatrics, The Ohio State University, Columbus, Ohio [2] Center for Cardiovascular and Pulmonary Research, Nationwide Children's Hospital, Columbus, Ohio [3] The Heart Center, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Sara
authors.initials: S
authors.lastname: Fitzgerald-Butt
authors.affiliation: 1] Department of Pediatrics, The Ohio State University, Columbus, Ohio [2] Center for Cardiovascular and Pulmonary Research, Nationwide Children's Hospital, Columbus, Ohio [3] The Heart Center, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Kim L
authors.initials: KL
authors.lastname: McBride
authors.affiliation: 1] Department of Pediatrics, The Ohio State University, Columbus, Ohio [2] Center for Cardiovascular and Pulmonary Research, Nationwide Children's Hospital, Columbus, Ohio [3] The Heart Center, Nationwide Children's Hospital, Columbus, Ohio [4] Department of Molecular Genetics, The Ohio State University, Columbus, Ohio.
authors.forename: Vidu
authors.initials: V
authors.lastname: Garg
mesh_terms: D001021:Aortic Valve / Q000002:abnormalities* / Q000473:pathology; D001483:Base Sequence; D000082882:Bicuspid Aortic Valve Disease; D015331:Cohort Studies; D017931:DNA Primers / Q000235:genetics; D005260:Female; D050992:GATA5 Transcription Factor / Q000235:genetics*; D014644:Genetic Variation; D006349:Heart Valve Diseases / Q000235:genetics* / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D009820:Ohio; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: D017931:DNA Primers; D050992:GATA5 Transcription Factor; C494755:GATA5 protein, human