OVERALL PROGRAM ABSTRACT Our research strategy for the Program project ?Gene Mutation and Rescue in Human Diaphragmatic Hernia? is to 1) identify gene variants in patients with Congenital Diaphragmatic Hernia from genomic analyses, 2) test high priority candidates for validation and function in vitro and ex vivo, and in animal models, 3) determine molecular pathways defined by integrating already known and new candidate genes, and 4) select molecular targets from which to conceive postnatal treatment strategies for CDH. CDH is a birth defect which occurs in 1/3000 live births, and has a high mortality and morbidity, with survivors requiring high technology-driven interventional perinatal care in tertiary or quarternary neonatal intensive care units. 40% of CDH patients have multiple anomalies in addition to CDH, but as many as 60% are isolated with the potential for increased survival if we can improve the associated lung hypoplasia responsible for its high morbidity. The societal and individual burden of CDH can hopefully be lessened by reducing the patient and family stresses caused by the considerable morbidity and mortality, as well as the cost of care, coincident with this birth defect. If substantial pulmonary differentiation can be induced to occur in the lung postnatally, the use of Extra Corporeal Membrane Oxygenation (ECMO) and aggressive ventilatory management may be reduced, thus protecting fragile lungs from secondary barotrauma and bronchopulmonary dysplasia. To affect a salutary change, we plan to continue to employ genomic methods such as Whole Exome Sequencing (WES), array Comparative Genomic Hybridization (aCGH), and Whole Genomic Sequencing (WGS), and to integrate variant findings with data from expression analyses of developing diaphragm and lung tissues in mouse models, and with diaphragm biopsies from human CDH patients. WES, WGS, and aCGH data will be continually ascertained and analyzed on a clinically well characterized cohort of singletons and parent/child trios, as well as rare extended families. It is the goal of this P01 to use this growing cohort and our analytic approach to generate candidate genes that will yield important clues as to the molecular pathogenesis of CDH, particularly after integrating the highest priority candidates into molecular pathways. PROJECT I: Genomic and gene expression analyses to discover human CHD genes and pathways. PROJECT II: Mouse models will elucidate genetics of CDH and associated pulmonary defects and identify clinically relevant targets. PROJECT III: Functional evaluation of CDH patient gene variants in vitro and in select animal models.

Public Health Relevance

OVERALL PROGRAM NARRATIVE: Congenital Diaphragmatic Hernia (CDH) is a prevalent (1:3000 live births) high impact (50% mortality with high morbidity) birth defect with phenotypic and genetic complexity and heterogeneity. The aim of this Program Project 'Gene Mutation and Rescue in Human Congenital Diaphragmatic Hernia' is to 1) identify gene variants in patients with Congenital Diaphragmatic Hernia from genomic sequencing and structural variant analyses, 2) test high priority candidates for validation and function in vitro and ex vivo, and in animal models, 3) determine molecular pathways defined by integrating already known and new candidate genes, and 4) select molecular targets from which to conceive postnatal treatment strategies for CDH. 40% of CDH patients have multiple anomalies in addition to CDH, but as many as 60% are isolated with the potential for increased survival if we can improve the associated lung hypoplasia responsible for its high morbidity. The societal and individual burden of CDH can hopefully be lessened by reducing the patient and family stresses caused by the considerable morbidity and mortality, as well as the cost of care, coincident with this birth defect. Steps that we employ herein can serve ultimately as a template to address other polygenic congenital anomalies and treatment strategies conceived for CDH can have broader applications in the care of children with the bronchopulmonary dysplasia of prematurity.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD068250-07
Application #
9551655
Study Section
Special Emphasis Panel (ZHD1)
Program Officer
Henken, Deborah B
Project Start
2011-08-29
Project End
2022-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
Anglani, F; Terrin, L; Brugnara, M et al. (2018) Hypercalciuria and nephrolithiasis: Expanding the renal phenotype of Donnai-Barrow syndrome. Clin Genet 94:187-188
Qi, Hongjian; Yu, Lan; Zhou, Xueya et al. (2018) De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders. PLoS Genet 14:e1007822
Zhu, Qihui; High, Frances A; Zhang, Chengsheng et al. (2018) Systematic analysis of copy number variation associated with congenital diaphragmatic hernia. Proc Natl Acad Sci U S A 115:5247-5252
Kardon, Gabrielle; Ackerman, Kate G; McCulley, David J et al. (2017) Congenital diaphragmatic hernias: from genes to mechanisms to therapies. Dis Model Mech 10:955-970
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
Li, Taibo; Wernersson, Rasmus; Hansen, Rasmus B et al. (2017) A scored human protein-protein interaction network to catalyze genomic interpretation. Nat Methods 14:61-64
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

Showing the most recent 10 out of 20 publications