TY - JOUR T1 - Whole exome sequencing identifies de novo mutations in <em>GATA6</em> associated with congenital diaphragmatic hernia JF - Journal of Medical Genetics JO - J Med Genet SP - 197 LP - 202 DO - 10.1136/jmedgenet-2013-101989 VL - 51 IS - 3 AU - Lan Yu AU - James T Bennett AU - Julia Wynn AU - Gemma L Carvill AU - Yee Him Cheung AU - Yufeng Shen AU - George B Mychaliska AU - Kenneth S Azarow AU - Timothy M Crombleholme AU - Dai H Chung AU - Douglas Potoka AU - Brad W Warner AU - Brian Bucher AU - Foong-Yen Lim AU - John Pietsch AU - Charles Stolar AU - Gudrun Aspelund AU - Marc S Arkovitz AU - University of Washington Center for Mendelian Genomics AU - Heather Mefford AU - Wendy K Chung Y1 - 2014/03/01 UR - http://jmg.bmj.com/content/51/3/197.abstract N2 - 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&gt;T, p.R456C) in a sporadic CDH patient with tetralogy of Fallot. In the second, a nonsense mutation (c.712G&gt;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. ER -