PROJECT I: GENOMIC AND GENE EXPRESSION ANALYSES TO DISCOVER GENES AND PATHWAYS IN HUMAN CONGENITAL DIAPHRAGMATIC HERNIA ABSTRACT: This project focuses on the characterization of genomic variation in human patients with congenital diaphragmatic hernia (CDH) to identify novel genes and pathways causing CDH. We will use whole genome sequencing (WGS) and whole exome sequencing (WES) to identify rare and predicted pathogenic de novo and inherited sequence, copy number, and structural variants in sporadic CDH cases, and inherited variants in families containing more than one affected individual. A challenge in studying CDH, like most birth defects, has been its genetic heterogeneity. To overcome this obstacle, we have maximized our sample size by combining two well-established CDH research studies, generating one of the largest and most well-characterized cohorts of patients with CDH in the world. We have recruited 1500 patients to date, with WES or WGS data completed or in the pipeline for approximately 800 proband-parent trios. We show that this will provide sufficient power to identify multiple CDH genes with statistical significance. These data will be analyzed using novel and well- established bioinformatics tools to prioritize variants and identify molecular pathways that are likely to be disease-associated. In addition, the DHREAMS consortium has collected diaphragm specimens from a large number of patients, allowing for the study of somatic mutations and tissue-specific gene expression changes that may be associated with genetic subtypes of CDH. Together, the data derived from these large-scale genomic experiments have already identified key candidate genes that are being pursued in functional experiments in Projects II and III, and will continue to provide novel candidates that will allow identification of genotype-phenotype associations, help inform and refine prognosis for patients with CDH, and will elucidate molecular pathways that could be targets for future therapeutic strategies.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZHD1)
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Massachusetts General Hospital
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Longoni, Mauro; High, Frances A; Qi, Hongjian et al. (2017) Genome-wide enrichment of damaging de novo variants in patients with isolated and complex congenital diaphragmatic hernia. Hum Genet 136:679-691
High, Frances A; Bhayani, Pooja; Wilson, Jay M et al. (2016) De novo frameshift mutation in COUP-TFII (NR2F2) in human congenital diaphragmatic hernia. Am J Med Genet A 170:2457-61
Loscertales, Maria; Nicolaou, Fotini; Jeanne, Marion et al. (2016) Type IV collagen drives alveolar epithelial-endothelial association and the morphogenetic movements of septation. BMC Biol 14:59
Donahoe, Patricia K; Longoni, Mauro; High, Frances A (2016) Polygenic Causes of Congenital Diaphragmatic Hernia Produce Common Lung Pathologies. Am J Pathol 186:2532-43
Sanford, Ethan L; Choy, Kwong W; Donahoe, Patricia K et al. (2016) MiR-449a Affects Epithelial Proliferation during the Pseudoglandular and Canalicular Phases of Avian and Mammal Lung Development. PLoS One 11:e0149425
Longoni, M; Russell, M K; High, F A et al. (2015) Prevalence and penetrance of ZFPM2 mutations and deletions causing congenital diaphragmatic hernia. Clin Genet 87:362-7
Lundby, Alicia; Rossin, Elizabeth J; Steffensen, Annette B et al. (2014) Annotation of loci from genome-wide association studies using tissue-specific quantitative interaction proteomics. Nat Methods 11:868-74
Longoni, Mauro; High, Frances A; Russell, Meaghan K et al. (2014) Molecular pathogenesis of congenital diaphragmatic hernia revealed by exome sequencing, developmental data, and bioinformatics. Proc Natl Acad Sci U S A 111:12450-5
Lage, Kasper (2014) Protein-protein interactions and genetic diseases: The interactome. Biochim Biophys Acta 1842:1971-1980
Russell, Meaghan K; Longoni, Mauro; Wells, Julie et al. (2012) Congenital diaphragmatic hernia candidate genes derived from embryonic transcriptomes. Proc Natl Acad Sci U S A 109:2978-83

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