title: Whole exome sequencing identifies de novo mutations in GATA6 associated with congenital diaphragmatic hernia.
abstract: BACKGROUND
  Congenital diaphragmatic hernia (CDH) is a common birth defect affecting 1 in 3000 births. It is characterised by herniation of abdominal viscera through an incompletely formed diaphragm. Although chromosomal anomalies and mutations in several genes have been implicated, the cause for most patients is unknown.
  
  
  METHODS
  We used whole exome sequencing in two families with CDH and congenital heart disease, and identified mutations in GATA6 in both.
  
  
  RESULTS
  In the first family, we identified a de novo missense mutation (c.1366C>T, p.R456C) in a sporadic CDH patient with tetralogy of Fallot. In the second, a nonsense mutation (c.712G>T, p.G238*) was identified in two siblings with CDH and a large ventricular septal defect. The G238* mutation was inherited from their mother, who was clinically affected with congenital absence of the pericardium, patent ductus arteriosus and intestinal malrotation. Deep sequencing of blood and saliva-derived DNA from the mother suggested somatic mosaicism as an explanation for her milder phenotype, with only approximately 15% mutant alleles. To determine the frequency of GATA6 mutations in CDH, we sequenced the gene in 378 patients with CDH. We identified one additional de novo mutation (c.1071delG, p.V358Cfs34*).
  
  
  CONCLUSIONS
  Mutations in GATA6 have been previously associated with pancreatic agenesis and congenital heart disease. We conclude that, in addition to the heart and the pancreas, GATA6 is involved in development of two additional organs, the diaphragm and the pericardium. In addition, we have shown that de novo mutations can contribute to the development of CDH, a common birth defect.
authors.affiliation: Division of Molecular Genetics, Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Yu
authors.forename: James T
authors.initials: JT
authors.lastname: Bennett
authors.forename: Julia
authors.initials: J
authors.lastname: Wynn
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Carvill
authors.forename: Yee Him
authors.initials: YH
authors.lastname: Cheung
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Shen
authors.forename: George B
authors.initials: GB
authors.lastname: Mychaliska
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Azarow
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Crombleholme
authors.forename: Dai H
authors.initials: DH
authors.lastname: Chung
authors.forename: Douglas
authors.initials: D
authors.lastname: Potoka
authors.forename: Brad W
authors.initials: BW
authors.lastname: Warner
authors.forename: Brian
authors.initials: B
authors.lastname: Bucher
authors.forename: Foong-Yen
authors.initials: FY
authors.lastname: Lim
authors.forename: John
authors.initials: J
authors.lastname: Pietsch
authors.forename: Charles
authors.initials: C
authors.lastname: Stolar
authors.forename: Gudrun
authors.initials: G
authors.lastname: Aspelund
authors.forename: Marc S
authors.initials: MS
authors.lastname: Arkovitz
authors.forename: Heather
authors.initials: H
authors.lastname: Mefford
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
mesh_terms: D000595:Amino Acid Sequence; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005260:Female; D050993:GATA6 Transcription Factor / Q000235:genetics*; D006548:Hernia, Diaphragmatic / Q000235:genetics; D065630:Hernias, Diaphragmatic, Congenital / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
chemical_list: D050993:GATA6 Transcription Factor
keywords: Clinical Genetics; Congenital Heart Disease; Developmental; Diagnosis; Genome-wide