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Whole exome sequencing identifies de novo mutations in GATA6 associated with congenital diaphragmatic hernia
  1. Lan Yu1,
  2. James T Bennett2,
  3. Julia Wynn1,
  4. Gemma L Carvill2,
  5. Yee Him Cheung1,
  6. Yufeng Shen3,
  7. George B Mychaliska4,
  8. Kenneth S Azarow5,
  9. Timothy M Crombleholme6,
  10. Dai H Chung7,
  11. Douglas Potoka8,
  12. Brad W Warner9,
  13. Brian Bucher9,
  14. Foong-Yen Lim10,
  15. John Pietsch11,
  16. Charles Stolar12,
  17. Gudrun Aspelund12,
  18. Marc S Arkovitz13,
  19. University of Washington Center for Mendelian Genomics,
  20. Heather Mefford2,14,
  21. Wendy K Chung1
  1. 1Division of Molecular Genetics, Department of Pediatrics, Columbia University Medical Center, New York, New York, USA
  2. 2Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA
  3. 3Department of Biomedical Informatics, Columbia University Medical Center, New York, New York, USA
  4. 4Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA
  5. 5Department of Surgery, University of Nebraska College of Medicine, Omaha, USA
  6. 6Division of Pediatric General, Thoracic, and Fetal Surgery, Colorado Fetal Care Center, Children's Hospital Colorado and the University of Colorado School of Medicine, Aurora, Colorado, USA
  7. 7Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
  8. 8Department of Pediatric Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
  9. 9Division of Pediatric Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
  10. 10Division of Pediatric General, Thoracic, and Fetal Surgery, Center for Molecular Fetal Therapy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  11. 11Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
  12. 12Division of Pediatric Surgery, Department of Surgery, Columbia University Medical Center, New York, New York, USA
  13. 13Division of Pediatric Surgery, Tel Hashomer Medical Center, Tel Hashomer, Israel
  14. 14Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA USA
  1. Correspondence to Dr Wendy K Chung, Division of Molecular Genetics, Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, Room 620, New York, NY 10032, USA; wkc15{at}columbia.edu Heather C Mefford, MD, PhD, Division of Genetic Medicine, Department of Pediatrics, University of Washington, 1959 NE Pacific St. Box 356320, Seattle, WA 98115, USA; hmefford{at}uw.edu

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.

  • Clinical Genetics
  • Congenital Heart Disease
  • Developmental
  • Diagnosis
  • Genome-wide

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