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De novo copy number variants are associated with congenital diaphragmatic hernia
  1. Lan Yu1,
  2. Julia Wynn1,
  3. Lijiang Ma1,
  4. Saurav Guha1,
  5. George B Mychaliska2,
  6. Timothy M Crombleholme3,
  7. Kenneth S Azarow4,
  8. Foong Yen Lim5,
  9. Dai H Chung6,
  10. Douglas Potoka7,
  11. Brad W Warner8,
  12. Brian Bucher8,
  13. Charles A LeDuc1,
  14. Katherine Costa9,
  15. Charles Stolar10,
  16. Gudrun Aspelund10,
  17. Marc S Arkovitz11,
  18. Wendy K Chung1
  1. 1Department of Pediatrics, Columbia University Medical Center, New York, New York, USA
  2. 2Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA
  3. 3Colorado Fetal Care Center, Division of Pediatric General, Thoracic, and Fetal Surgery, Children's Hospital Colorado and the University of Colorado School of Medicine, Aurora, Colorado, USA
  4. 4Department of Pediatric Surgery, University of Nebraska College of Medicine, Omaha, Nebraska, USA
  5. 5Division of Pediatric General, Thoracic, and Fetal Surgery, Center for Molecular Fetal Therapy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  6. 6Department of Pediatric Surgery, Vanderbilt University Medical Center, Vanderbilt Children's Hospital, Nashville, Tennessee, USA
  7. 7Department of Pediatric Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
  8. 8Division of Pediatric Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
  9. 9College of Physicians and Surgeons, Columbia University, New York, New York, USA
  10. 10Division of Pediatric Surgery, Department of Surgery, Columbia University Medical Center, New York, New York, USA
  11. 11Division of Pediatric Surgery, Tel Hashomer Medical Center, Tel Hashomer, Israel
  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}


Background Congenital diaphragmatic hernia (CDH) is a common birth defect with significant morbidity and mortality. Although the aetiology of CDH remains poorly understood, studies from animal models and patients with CDH suggest that genetic factors play an important role in the development of CDH. Chromosomal anomalies have been reported in CDH.

Methods In this study, the authors investigated the frequency of chromosomal anomalies and copy number variants (CNVs) in 256 parent–child trios of CDH using clinical conventional cytogenetic and microarray analysis. The authors also selected a set of CDH related training genes to prioritise the genes in those segmental aneuploidies and identified the genes and gene sets that may contribute to the aetiology of CDH.

Results The authors identified chromosomal anomalies in 16 patients (6.3%) of the series including three aneuploidies, two unbalanced translocation, and 11 patients with de novo CNVs ranging in size from 95 kb to 104.6 Mb. The authors prioritised the genes in the CNV segments and identified KCNA2, LMNA, CACNA1S, MYOG, HLX, LBR, AGT, GATA4, SOX7, HYLS1, FOXC1, FOXF2, PDGFA, FGF6, COL4A1, COL4A2, HOMER2, BNC1, BID, and TBX1 as genes that may be involved in diaphragm development. Gene enrichment analysis identified the most relevant gene ontology categories as those involved in tissue development (p=4.4×10−11) or regulation of multicellular organismal processes (p=2.8×10−10) and ‘receptor binding’ (p=8.7×10−14) and ‘DNA binding transcription factor activity’ (p=4.4×10−10).

Conclusions The present findings support the role of chromosomal anomalies in CDH and provide a set of candidate genes including FOXC1, FOXF2, PDGFA, FGF6, COL4A1, COL4A2, SOX7, BNC1, BID, and TBX1 for further analysis in CDH.

  • Copy-number
  • Chromosomal
  • Cytogenetics
  • Genome-wide
  • Microarray

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