Congenital Diaphragmatic Hernia (CDH) is a frequent and often fatal developmental condition of diaphragm defects associated with lung hypoplasia caused by diverse factors that we hypothesize are predominantly genetic, but heterogeneous. Project IV will use a combination of clinical, molecular, developmental, genomic and cytogenetic strategies to identify mutations causing CDH, with the hope of elucidating perturbed biochemical pathways that can then serve as functional targets for pharmacological intervention or treatment.
Aim I : We will recruit a cohort of carefully phenotyped isolated and complex CDH patients from two major clinical sites, MGH and Children's Hospital Boston, establish cell lines on each patient, and parents,and siblings, and enter deceased populations of patients, families with multiple affected members, consanguineous families, and monozygotic twins. DNA will be extracted from various sources for mutational analysis of candidate genes, arrayed based Comparative Genomic Hybridization (aCGH), loss of heterozygosity studies (LOH), and metaphase preparations for subtelomeric FISH.
Aim II : High resolution cytogenetic tools such as 1 Mb array CDH, subtelomeric FISH, and multiplex ligand-directed probe amplification (MLPA) will be used to identify microdeletions, microduplications, and balanced and unbalanced translocations followed by breakpoint analyses to identify genes in these regions that have mutations causative for CDH.
Aim III : nonsynonomous SNPs identified will be studied as plausible causative mutations. Genome wide SNP analysis will be used to reveal regions of LOH in consanguineous Donnai Barrow kindreds and in discordant monozygotic twins.
Aim I V: Candidate genes from animal models or from LOH regions with CDH in human will be studied for abnormal expression in human CDH lungs or diaphragms and tested in Drosophila or mouse cell-based or organ culture assays to determine functional significance. CDH gene defects uncovered by these studies will serve as targets for pharmacological or other therapeutic interventions to ameliorate or prevent this severe birth malformation.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
3R01HD055150-04S2
Application #
7933157
Study Section
Special Emphasis Panel (ZHD1-MRG-C (PD))
Program Officer
Javois, Lorette Claire
Project Start
2009-09-30
Project End
2011-01-31
Budget Start
2009-09-30
Budget End
2011-01-31
Support Year
4
Fiscal Year
2009
Total Cost
$124,146
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Pinto, Dalila; Darvishi, Katayoon; Shi, Xinghua et al. (2011) Comprehensive assessment of array-based platforms and calling algorithms for detection of copy number variants. Nat Biotechnol 29:512-20
Rossin, Elizabeth J; Lage, Kasper; Raychaudhuri, Soumya et al. (2011) Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology. PLoS Genet 7:e1001273
Lage, Kasper; Møllgård, Kjeld; Greenway, Steven et al. (2010) Dissecting spatio-temporal protein networks driving human heart development and related disorders. Mol Syst Biol 6:381
Kantarci, Sibel; Ackerman, Kate G; Russell, Meaghan K et al. (2010) Characterization of the chromosome 1q41q42.12 region, and the candidate gene DISP1, in patients with CDH. Am J Med Genet A 152A:2493-504
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Donahoe, Patricia K; Noonan, Kristin M; Lage, Kasper (2009) Genetic tools and algorithms for gene discovery in major congenital anomalies. Birth Defects Res A Clin Mol Teratol 85:6-12
Donahoe, Patricia K (2009) A pediatric surgeon retools in genetics and genomics to study congenital diaphragmatic hernia. J Pediatr Surg 44:307-11
Pober, Barbara R; Longoni, Mauro; Noonan, Kristin M (2009) A review of Donnai-Barrow and facio-oculo-acoustico-renal (DB/FOAR) syndrome: clinical features and differential diagnosis. Birth Defects Res A Clin Mol Teratol 85:76-81

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