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Back to Annual Meeting Program Genomic Variants from High Density Array Platforms can be Integrated with Developmental Expression to Yield Causative Genes in Congenital Diaphragmatic Hernia *Adam A. Tracy1, *Klaus E. Schmitz2, *Mauro Longoni1, *Meaghan K. Russell1, *Caroline Coletti1, *Kasper Lage1, *Barbara R. Pober1, Patricia K. Donahoe1 1Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA;2Department of Pediatrics, Children's Hospital Boston, Boston, MA Objective: Congenital diaphragmatic hernia (CDH) is a common and often lethal anomaly with a birth prevalence of 1/3000. Despite improvements in medical and surgical care, many infants with CDH die from associated complications, most often pulmonary hypoplasia and pulmonary hypertension. Evidence from familial clustering and animal models indicates a genetic component to CDH. To discover candidate genes for CDH, we screened a patient cohort for microdeletions or microduplications using microarrays. Design: Study of causation (cohort and animal models). Setting: Academic Medical Center/Developmental Biology and Genetics Laboratory. Patients: 141 individuals with CDH recruited from Boston Hospitals and international referrals. Main Outcome Measures: Identify loci involved in diaphragm development in a human cohort through a combination of genetics and bioinformatics. Results: We have established a strategy to discover genes associated with CDH. We identified 324 copy number variable regions using Agilent 244K and Affy 6.0 arrays, occurring with a frequency of less than 1% in a HapMap control group. Ninety-nine [99] unique protein coding genes mapping to these regions were prioritized by their interaction with proteins encoded by genes previously known to cause CDH in mouse knockout models or in humans. Twenty-two [22] were differentially expressed between early [E11.5/E12.5] and late [E16.5] mouse diaphragm development. The earlier time point is when diaphragm defects are thought to occur. These genes are now being further validated as candidates associated with CDH. Conclusions: Converging multiple genes detected by genomic platforms used to analyze data from patients and from model organisms with CDH can reveal molecular defects which can contribute causally to CDH and may provide insights for new treatment paradigms. Back to Annual Meeting Program
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