title: Molecular pathogenesis of congenital diaphragmatic hernia revealed by exome sequencing, developmental data, and bioinformatics.
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.
authors.affiliation: The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114; Department of Surgery, Harvard Medical School, Boston, MA 02115;
authors.forename: Mauro
authors.initials: M
authors.lastname: Longoni
authors.affiliation: The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114; Division of Genetics and.
authors.forename: Frances A
authors.initials: FA
authors.lastname: High
authors.affiliation: The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114; Department of Surgery, Harvard Medical School, Boston, MA 02115;
authors.forename: Meaghan K
authors.initials: MK
authors.lastname: Russell
authors.affiliation: The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114; Broad Institute, Cambridge, MA 02141;
authors.forename: Alireza
authors.initials: A
authors.lastname: Kashani
authors.affiliation: The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Adam A
authors.initials: AA
authors.lastname: Tracy
authors.affiliation: The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Coletti
authors.affiliation: The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Regis
authors.initials: R
authors.lastname: Hila
authors.affiliation: The Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Ahmed
authors.initials: A
authors.lastname: Shamia
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609;
authors.forename: Julie
authors.initials: J
authors.lastname: Wells
authors.affiliation: Departments of Pediatrics and Biomedical Genetics, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642;
authors.forename: Kate G
authors.initials: KG
authors.lastname: Ackerman
authors.affiliation: Department of Surgery, Boston Children's Hospital, Boston, MA 02115;
authors.forename: Jay M
authors.initials: JM
authors.lastname: Wilson
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609;
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Bult
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032; and.
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.affiliation: 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;
authors.forename: Kasper
authors.initials: K
authors.lastname: Lage
authors.affiliation: 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.
authors.forename: Barbara R
authors.initials: BR
authors.lastname: Pober
authors.affiliation: 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.
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Donahoe
mesh_terms: D000818:Animals; D015331:Cohort Studies; D019295:Computational Biology; D056915:DNA Copy Number Variations; D003964:Diaphragm / Q000196:embryology; D059472:Exome; D014644:Genetic Variation; D065630:Hernias, Diaphragmatic, Congenital / Q000196:embryology / Q000209:etiology* / Q000235:genetics*; D006801:Humans; D051379:Mice; D060066:Protein Interaction Maps
keywords: CDH genetics; diaphragm development; network analysis
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