Genomic alterations that contribute to the development of isolated and non-isolated congenital diaphragmatic hernia. Issue 5 (27th April 2011)

• Record Type: Journal Article
• Authors: Wat, Margaret J; Veenma, Danielle; Hogue, Jacob; Holder, Ashley M; Yu, Zhiyin; Wat, Jeanette J; Hanchard, Neil; Shchelochkov, Oleg A; Fernandes, Caraciolo J; Johnson, Anthony; Lally, Kevin P; Slavotinek, Anne; Danhaive, Olivier; Schaible, Thomas; Cheung, Sau Wai; Rauen, Katherine A; Tonk, Vijay S; Tibboel, Dick; de Klein, Annelies; Scott, Daryl A
• Is Part Of: Journal of medical genetics. Volume 48:Issue 5(2011)
• Page Start: 299
• Page End: 307
• Publication Date: 2011-04-27
• Subjects: Diaphragmatic hernia -- ZFPM2 -- microdeletion 1q41q42 -- microdeletion 16p11.2 -- FZD2 -- clinical genetics -- cytogenetics -- molecular genetics; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmg.2011.089680
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: Congenital diaphragmatic hernia (CDH) is a life threatening birth defect. Most of the genetic factors that contribute to the development of CDH remain unidentified. Objective: To identify genomic alterations that contribute to the development of diaphragmatic defects. Methods: A cohort of 45 unrelated patients with CDH or diaphragmatic eventrations was screened for genomic alterations by array comparative genomic hybridisation or single nucleotide polymorphism based copy number analysis. Results: Genomic alterations that were likely to have contributed to the development of CDH were identified in 8 patients. Inherited deletions of ZFPM2 were identified in 2 patients with isolated diaphragmatic defects and a large de novo 8q deletion overlapping the same gene was found in a patient with non-isolated CDH. A de novo microdeletion of chromosome 1q41q42 and two de novo microdeletions on chromosome 16p11.2 were identified in patients with non-isolated CDH. Duplications of distal 11q and proximal 13q were found in a patient with non-isolated CDH and a de novo single gene deletion of FZD2 was identified in a patient with a partial pentalogy of Cantrell phenotype. Conclusions: Haploinsufficiency of ZFPM2 can cause dominantly inherited isolated diaphragmatic defects with incomplete penetrance. These data define a new minimal deleted region for CDH on 1q41q42, provide evidence for the existence of CDH related genes on chromosomes 16p11.2, 11q23-24 and 13q12, and suggest a possible role for FZD2 and Wnt signalling in pentalogy of Cantrell phenotypes. These results demonstrate the clinical utility of screening for genomic alterations in individuals with both isolated and non-isolated diaphragmatic defects.