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Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):12450-5. doi: 10.1073/pnas.1412509111. Epub 2014 Aug 8.

Molecular pathogenesis of congenital diaphragmatic hernia revealed by exome sequencing, developmental data, and bioinformatics.

Author information

1
The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114; Department of Surgery, Harvard Medical School, Boston, MA 02115;
2
The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114; Division of Genetics and.
3
The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114; Broad Institute, Cambridge, MA 02141;
4
The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114;
5
The Jackson Laboratory, Bar Harbor, ME 04609;
6
Departments of Pediatrics and Biomedical Genetics, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642;
7
Department of Surgery, Boston Children's Hospital, Boston, MA 02115;
8
The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032; and.
9
The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114; Department of Surgery, Harvard Medical School, Boston, MA 02115; Broad Institute, Cambridge, MA 02141;
10
The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114; Department of Surgery, Boston Children's Hospital, Boston, MA 02115; Frank H. Netter School of Medicine, Quinnipiac University, North Haven, CT 06473.
11
The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114; Department of Surgery, Harvard Medical School, Boston, MA 02115; Broad Institute, Cambridge, MA 02141; pdonahoe@partners.org.

Abstract

Congenital diaphragmatic hernia (CDH) is a common and severe birth defect. Despite its clinical significance, the genetic and developmental pathways underlying this disorder are incompletely understood. In this study, we report a catalog of variants detected by a whole exome sequencing study on 275 individuals with CDH. Predicted pathogenic variants in genes previously identified in either humans or mice with diaphragm defects are enriched in our CDH cohort compared with 120 size-matched random gene sets. This enrichment was absent in control populations. Variants in these critical genes can be found in up to 30.9% of individuals with CDH. In addition, we filtered variants by using genes derived from regions of recurrent copy number variations in CDH, expression profiles of the developing diaphragm, protein interaction networks expanded from the known CDH-causing genes, and prioritized genes with ultrarare and highly disruptive variants, in 11.3% of CDH patients. These strategies have identified several high priority genes and developmental pathways that likely contribute to the CDH phenotype. These data are valuable for comparison of candidate genes generated from whole exome sequencing of other CDH cohorts or multiplex kindreds and provide ideal candidates for further functional studies. Furthermore, we propose that these genes and pathways will enhance our understanding of the heterogeneous molecular etiology of CDH.

KEYWORDS:

CDH genetics; diaphragm development; network analysis

PMID:
25107291
PMCID:
PMC4151769
DOI:
10.1073/pnas.1412509111
[Indexed for MEDLINE]
Free PMC Article

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