Whole exome sequencing identifies de novo mutations in GATA6 associated with congenital diaphragmatic hernia

Lan Yu, James T. Bennett, Julia Wynn, Gemma L. Carvill, Yee Him Cheung, Yufeng Shen, George B. Mychaliska, Kenneth S. Azarow, Timothy M. Crombleholme, Dai H. Chung, Douglas Potoka, Brad W. Warner, Brian Bucher, Foong Yen Lim, John Pietsch, Charles Stolar, Gudrun Aspelund, Marc S. Arkovitz, Heather Mefford, Wendy K. Chung*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)197-202
Number of pages6
JournalJournal of medical genetics
Issue number3
StatePublished - 2014

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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