Human Genetics

, Volume 132, Issue 3, pp 285–292

Variants in GATA4 are a rare cause of familial and sporadic congenital diaphragmatic hernia

  • Lan Yu
  • Julia Wynn
  • Yee Him Cheung
  • Yufeng Shen
  • George B. Mychaliska
  • Timothy M. Crombleholme
  • Kenneth S. Azarow
  • Foong Yen Lim
  • Dai H. Chung
  • Douglas Potoka
  • Brad W. Warner
  • Brian Bucher
  • Charles Stolar
  • Gudrun Aspelund
  • Marc S. Arkovitz
  • Wendy K. Chung
Original Investigation

DOI: 10.1007/s00439-012-1249-0

Cite this article as:
Yu, L., Wynn, J., Cheung, Y.H. et al. Hum Genet (2013) 132: 285. doi:10.1007/s00439-012-1249-0

Abstract

Congenital diaphragmatic hernia (CDH) is characterized by incomplete formation of the diaphragm occurring as either an isolated defect or in association with other anomalies. Genetic factors including aneuploidies and copy number variants are important in the pathogenesis of many cases of CDH, but few single genes have been definitively implicated in human CDH. In this study, we used whole exome sequencing (WES) to identify a paternally inherited novel missense GATA4 variant (c.754C>T; p.R252W) in a familial case of CDH with incomplete penetrance. Phenotypic characterization of the family included magnetic resonance imaging of the chest and abdomen demonstrating asymptomatic defects in the diaphragm in the two “unaffected” missense variant carriers. Screening 96 additional CDH patients identified a de novo heterozygous GATA4 variant (c.848G>A; p.R283H) in a non-isolated CDH patient. In summary, GATA4 is implicated in both familial and sporadic CDH, and our data suggests that WES may be a powerful tool to discover rare variants for CDH.

Supplementary material

439_2012_1249_MOESM1_ESM.pdf (224 kb)
Supplementary material 1 (PDF 224 kb)
439_2012_1249_MOESM2_ESM.pdf (282 kb)
Supplementary material 2 (PDF 282 kb)
439_2012_1249_MOESM3_ESM.pdf (133 kb)
Supplementary material 2 (PDF 134 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Lan Yu
    • 1
  • Julia Wynn
    • 1
  • Yee Him Cheung
    • 1
  • Yufeng Shen
    • 2
  • George B. Mychaliska
    • 3
  • Timothy M. Crombleholme
    • 4
  • Kenneth S. Azarow
    • 5
  • Foong Yen Lim
    • 6
  • Dai H. Chung
    • 7
  • Douglas Potoka
    • 8
  • Brad W. Warner
    • 9
  • Brian Bucher
    • 9
  • Charles Stolar
    • 10
  • Gudrun Aspelund
    • 10
  • Marc S. Arkovitz
    • 11
  • Wendy K. Chung
    • 1
  1. 1.Division of Molecular Genetics, Department of PediatricsColumbia University Medical CenterNew YorkUSA
  2. 2.Department of Biomedical InformaticsColumbia University Medical CenterNew YorkUSA
  3. 3.Department of SurgeryUniversity of Michigan Health SystemAnn ArborUSA
  4. 4.Colorado Fetal Care Center, Division of Pediatric General, Thoracic, and Fetal SurgeryChildren’s Hospital Colorado and The University of Colorado School of MedicineAuroraUSA
  5. 5.Department of Pediatric SurgeryUniversity of Nebraska College of MedicineOmahaUSA
  6. 6.Division of Pediatric General, Thoracic, and Fetal Surgery, Center for Molecular Fetal TherapyCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  7. 7.Department of Pediatric SurgeryVanderbilt University Medical Center, Vanderbilt Children’s HospitalNashvilleUSA
  8. 8.Department of Pediatric SurgeryUniversity of Pittsburgh School of MedicinePittsburghUSA
  9. 9.Division of Pediatric SurgeryWashington University School of MedicineMOUSA
  10. 10.Division of Pediatric Surgery, Department of SurgeryColumbia University Medical CenterNew YorkUSA
  11. 11.Division of Pediatric SurgeryTel Hashomer Medical CenterTel HashomerIsrael