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

Proc Natl Acad Sci U S A
Authors
Keywords
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.

Year of Publication
2014
Journal
Proc Natl Acad Sci U S A
Volume
111
Issue
34
Pages
12450-5
Date Published
2014 Aug 26
ISSN
1091-6490
URL
DOI
10.1073/pnas.1412509111
PubMed ID
25107291
PubMed Central ID
PMC4151769
Links
Grant list
HHSN268201100037C / 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