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Study Description

Congenital diaphragmatic hernia (CDH) is a common and severe birth defect. 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, a large whole exome sequencing study was performed on 275 carefully phenotyped individuals with CDH in the Pediatric Surgical Research Laboratories at the Massachusetts General Hospital (Boston, MA, USA). Using this dataset, we determined that variants in genes previously identified in either humans or mice with diaphragm defects are present in a large fraction of CDH patients. Rare pathogenic variants within these critical genes are specifically enriched in our CDH cohort compared to random size-matched gene sets. Further, gene lists derived from expression profiles of the developing diaphragm, from protein protein interaction networks expanded from the known CDH-causing genes, and from regions of recurrent copy number variations in CDH were used as filters in a gene discovery approach, allowing the identification of high priority genes and developmental pathways that likely contribute to the CDH phenotype. The exome data generated by this project are valuable for comparison of candidate genes derived from whole exome sequencing of other CDH cohorts or affected kindreds, and 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.

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Publicly Available Data (Public ftp)

Connect to the public download site. The site contains release notes and manifests. The site also contains data dictionaries, variable summaries, documents, and truncated analyses, whenever available.

Study Inclusion/Exclusion Criteria

Inclusion: Individuals who have been diagnosed with Congenital Diaphragmatic Hernia, and their family members. We plan to ask over 500 individuals with Congenital Diaphragmatic Hernia and their families to be a part of this study.

Exclusion: N/A (Individuals must sign the consent form before being allowed to participate in this study).

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Exome Sequencing Illumina HiSeq 2000 N/A N/A Human reference genome (build hg19) using Burrows-Wheeler Aligner (BWA 0.7.5a)
Exome Capture Roche NimbleGen SeqCap EZ Human Exome Library v2.0 N/A N/A
Study History

The purpose of the study is to learn more about the genetics, or how traits are passed on through generations, of individuals with Congenital Diaphragmatic Hernia (CDH) or a CDH associated condition and abnormal lung development. This study is being done so that in the future new CDH treatments can be developed. We are hopeful that these treatments will allow us to improve lung growth in CDH patients before birth, and thus provide them with a better quality of life.

Dr. Patricia K. Donahoe is the leading investigator of the study in collaboration with doctors, scientists, and study staff at MassGeneral Hospital for Children and Children's Hospital Boston.
Longoni M, High FA, Russell MK, Kashani, Tracy AA, Coletti CM, Hila R, Shamia A, Wells J, Ackerman KG, Wilson JM, Bult C, Lee C, Lage K, Pober BR, and Donahoe PK. Congenital diaphragmatic hernia, exome variants prioritized by developmental and bioinformatics algorithms. (Exome landscape of congenital diaphragmatic hernia. 2014, PNAS. PMID: 25107291.

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