Congenital diaphragmatic hernia (CDH) is a common and severe birth defect characterized by structural defects of the diaphragm and by pulmonary hypoplasia. Congenital diaphragmatic hernia patient may present either as an isolated phenotype or together with other congenital anomalies in a complex phenotype. Despite the clinical significance of CDH, the underlying genetic and developmental pathways are incompletely understood. In order to establish a catalog of human genetic variation for this condition, we performed whole exome sequencing (WES) on 275 carefully phenotyped individuals with CDH in the Pediatric Surgical Research Laboratories at the Massachusetts General Hospital (Boston, MA, USA) and Boston Children's Hospital (Boston, MA, USA). The exome data generated are valuable for comparison of candidate genes derived from WES of other CDH cohorts or affected kindreds, and to provide ideal candidates for further functional studies with the ultimate goal of enhancing our understanding of the heterogeneous and, possibly, oligogenic molecular etiology of CDH. While familial clustering has been reported in rare kindreds, the majority of probands with CDH have no family history of CDH leading to the hypothesis that de novo variants are an important and relatively frequent etiological mechanism. In the second version of the study, we performed WES analysis on 87 trios, to assess the contribution of de novo mutations in the etiology of diaphragmatic and pulmonary defects and to identify previously unknown candidate genes. This dbGaP submission includes WES data on: (a) 20 new probands, (b) 9 probands also reported in the previous version (dbGaP accession no. <a href="https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000783.v1.p1">phs000783.v1.p1</a>), (c) 174 unaffected parents, including the parents of 67 previously reported probands. Combined analysis with other available cohorts of congenital diaphragmatic hernia revealed a genome-wide enrichment of likely gene-disrupting de novo variants (i.e., nonsense, frameshift or splice site), and missense de novo variants predicted in silico to be damaging.

Gene Mutation and Rescue in Human Congenital Diaphragmatic Hernia (CDH)

Genome-wide enrichment of damaging de novo variants in patients with isolated and complex congenital diaphragmatic hernia

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

Prevalence and penetrance of ZFPM2 mutations and deletions causing congenital diaphragmatic hernia

De novo frameshift mutation in COUP‐TFII (NR2F2) in human congenital diaphragmatic hernia