You are here

Proc Natl Acad Sci U S A DOI:10.1073/pnas.1412509111

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

Publication TypeJournal Article
Year of Publication2014
AuthorsLongoni, M, High, FA, Russell, MK, Kashani, A, Tracy, AA, Coletti, CM, Hila, R, Shamia, A, Wells, J, Ackerman, KG, Wilson, JM, Bult, CJ, Lee, C, Lage, K, Pober, BR, Donahoe, PK
JournalProc Natl Acad Sci U S A
Date Published2014 Aug 26
KeywordsAnimals, Cohort Studies, Computational Biology, Diaphragm, DNA Copy Number Variations, Exome, Genetic Variation, Hernias, Diaphragmatic, Congenital, Humans, Mice, Protein Interaction Maps

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.


Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID25107291
PubMed Central IDPMC4151769
Grant ListHHSN268201100037C / HL / NHLBI NIH HHS / United States
2T32GM007748-35 / GM / NIGMS NIH HHS / United States
P01 HD068250-03 / HD / NICHD NIH HHS / United States
HHSN268201100037C / / PHS HHS / United States
P01 HD068250 / HD / NICHD NIH HHS / United States
T32 GM007748 / GM / NIGMS NIH HHS / United States