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

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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.

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Acknowledgments

We greatly appreciate the families who participated in this study and all the clinical care teams who assisted with study coordination. We are grateful for the technical assistance provided by Patricia Lanzano, Jiancheng Guo, Liyong Deng and Josue Martinez from Columbia University. We thank Dr. Orpheus Kolokythas for assistance with obtaining and reading the abdominal and thoracic MRIs. We also thank Jeannie Kreutzman, and Robert Drongowski from University of Michigan; Trish Burns from Cincinnati Children’s Hospital Medical Center; Sheila Horak from University of Nebraska; Mary Dabrowiak from Monroe Carell Jr Children’s Hospital at Vanderbilt; Laurie Luther from University of Pittsburgh. Study data were collected and managed using Research Electronic Data Capture (REDCap) electronic data capture tools hosted at Columbia University. REDCap is a secure, web-based application designed to support data capture for research studies. This work was supported by NIH Grant HD057036 and was supported in part by Columbia University’s CTSA Grant UL1 RR024156 from NCATS-NCRR/NIH.

Ethical standards

The authors declare that the experiments in this study comply with the current laws of the country in which they were performed.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Molecular Genetics, Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, Room 620, New York, NY, 10032, USA

    Lan Yu, Julia Wynn, Yee Him Cheung & Wendy K. Chung

  2. Department of Biomedical Informatics, Columbia University Medical Center, New York, NY, USA

    Yufeng Shen

  3. Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA

    George B. Mychaliska

  4. Colorado Fetal Care Center, Division of Pediatric General, Thoracic, and Fetal Surgery, Children’s Hospital Colorado and The University of Colorado School of Medicine, Aurora, CO, USA

    Timothy M. Crombleholme

  5. Department of Pediatric Surgery, University of Nebraska College of Medicine, Omaha, NE, USA

    Kenneth S. Azarow

  6. Division of Pediatric General, Thoracic, and Fetal Surgery, Center for Molecular Fetal Therapy, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Foong Yen Lim

  7. Department of Pediatric Surgery, Vanderbilt University Medical Center, Vanderbilt Children’s Hospital, Nashville, TN, USA

    Dai H. Chung

  8. Department of Pediatric Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Douglas Potoka

  9. Division of Pediatric Surgery, Washington University School of Medicine, St. Louis, MO, USA

    Brad W. Warner & Brian Bucher

  10. Division of Pediatric Surgery, Department of Surgery, Columbia University Medical Center, New York, USA

    Charles Stolar & Gudrun Aspelund

  11. Division of Pediatric Surgery, Tel Hashomer Medical Center, Tel Hashomer, Israel

    Marc S. Arkovitz

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  1. Lan Yu
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  2. Julia Wynn
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  3. Yee Him Cheung
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  9. Dai H. Chung
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  11. Brad W. Warner
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  12. Brian Bucher
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  13. Charles Stolar
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  14. Gudrun Aspelund
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  16. Wendy K. Chung
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Correspondence to Wendy K. Chung.

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Yu, L., Wynn, J., Cheung, Y.H. et al. Variants in GATA4 are a rare cause of familial and sporadic congenital diaphragmatic hernia. Hum Genet 132, 285–292 (2013). https://doi.org/10.1007/s00439-012-1249-0

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  • DOI: https://doi.org/10.1007/s00439-012-1249-0

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