Program Project: GENE MUTATION AND RESCUE IN HUMAN DIAPHRAGMATIC HERNIA
Principal Investigator: Patricia K Donahoe
Abstract: DESCRIPTION (provided by applicant): In the quest to unravel the etiology of Congenital Diaphragmatic Hernia (CDH), a prevalent (1:2500 live births) high impact (50% mortality with high morbidity) birth defect with phenotypic and genetic complexity, we are combining novel and traditional investigative strategies to one of the largest cohort of human patients with CDH. Collectively, we are employing molecular genetic, molecular cytogenetic, genomic, developmental, bioinformatic, and stem cell strategies along with the use of multiple model organisms. The strategies that we employ can serve as a template for identifying genes in pathways responsible not only for CDH, but for additional congenital anomalies, as well. The foundation of our work is the Infrastructure developed for ascertaining and recruiting almost all patients with CDH from two academic tertiary pediatric surgical centers, Massachusetts General Hospital (MGH) and Children's Hospital Boston (CHB), each offering state of the art medical, surgical, and genetic diagnosis, and management. Patients and families with CDH are interviewed comprehensively by study staff and carefully phenotyped by a senior geneticist;biological samples are obtained using sensitive protocols adapted for infants and children from each proband and from as many family members as possible, and are banked for proposed iterative genetic studies. Gene candidates are selected for sequencing when there is convergence from multiple lines of inquiry [i.e., copy number variations (CNVs) detected on array Comparative Genomic Hybridization (aCGH) or Single Nucleotide Polymorphism (SNP) arrays, genes in shared intervals detected on linkage analysis in affected belonging to multiplex CDH families, expressed genes in the developing primordial diaphragm, and bioinformatic algorithms that prioritize multiple candidate variants detected by the aforementioned platforms and from annotation of animal models with diaphragm defects]. The functional significance of the most promising candidates is subsequently assessed in multiple animal models. The evolution of available sequencing capabilities to lower costs opens the door to examine the multiple genes or polygeneity that we now know will contribute to a birth defect phenotype such as CDH. Given the national and International outreach and reputation of our genetic partnerships and the strength of the voluntary support network provided by the exceptional parents of patients with CDH, the study has extended beyond our two institutions to ascertain a number of seminal multiplex kindreds, including both consanguineous and non-consanguineous families, from the U.S. and internationally. RELEVANCE: The overarching goal of this study is to converge the multiple genes detected by these complementary approaches into cogent molecular pathways that will reveal polygeneic defects in the pathways and point toward potential treatment paradigms to prevent or alleviate this mortal or morbid congenital anomaly. Further, the methods devised for this study of CDH may have broader implications across other congenital anomalies.
Funding Period: 2011-07-01 - 2016-06-30
more information: NIH RePORT
- Congenital diaphragmatic defects: proposal for a new classification based on observations in 234 patientsKate G Ackerman
Center for Pediatric Biomedical Research, University of Rochester, Rochester, NY, USA
Pediatr Dev Pathol 15:265-74. 2012....
- Genetic and environmental risk factors in congenital heart disease functionally converge in protein networks driving heart developmentKasper Lage
Pediatric Surgical Research Laboratories, Department of Molecular Biology, and Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA
Proc Natl Acad Sci U S A 109:14035-40. 2012..This integrative analysis of CHD risk factors and responses suggests a complex pattern of functional interactions between genomic variation and environmental exposures that modulate critical biological systems during heart development...
- Congenital diaphragmatic hernia interval on chromosome 8p23.1 characterized by genetics and protein interaction networksMauro Longoni
Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
Am J Med Genet A 158:3148-58. 2012..This combination of bioinformatics and expression studies can be applied to other chromosomal hotspots, as well as private microdeletions or microduplications, to identify causative genes and their interaction networks...
- Annotation of loci from genome-wide association studies using tissue-specific quantitative interaction proteomicsAlicia Lundby
1 Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark 2 The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark 3 The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA 4
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