1. ¹Department of Pediatrics, Division of Genetics, University of California, San Francisco, Room U585P, 533 Parnassus St, San Francisco, CA 94143-0748, USA
2. ²Comprehensive Cancer Center, University of California, San Francisco, 2340 Sutter St, San Francisco, CA 94143-0808, USA
3. ³Fetal Diagnostic Center, Evanston Northwestern Hospital, 303 E Superior St, Chicago, IL 60611, USA
4. ⁴University of Nebraska Medical Center, Omaha, NE
5. ⁵UCSF Lung Biology Center, San Francisco, CA 94143-2911, USA
6. ⁶California Birth Defects Monitoring Program, 1917 Fifth Street, Berkeley, CA, 94710, USA
7. ⁷US Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA
8. ⁸Box 2922, 1550 4th St., bldg, University of California, San Francisco, CA, 94143-2922, USA
9. ⁹Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA

Correspondence: Dr AM Slavotinek, Department of Pediatrics, Division of Genetics, University of California, San Francisco, Room U585P, 533 Parnassus St, San Francisco, CA 94143-0748, USA. Tel: +1 415 514 1783; Fax: +1 415 476 9976; E-mail: slavotia@peds.ucsf.edu

Received 19 January 2006; Revised 10 April 2006; Accepted 11 April 2006; Published online 31 May 2006.

Abstract

Congenital diaphragmatic hernia (CDH) is a common birth defect with a high mortality and morbidity. There have been few studies that have assessed copy number changes in CDH. We present array comparative genomic hybridization data for 29 CDH patients to identify and map chromosome aberrations in this disease. Three patients with 15q26.1–15q26.2 deletions had heterogeneous breakpoints that overlapped with the critical 4 Mb region previously delineated for CDH, confirming 15q26.1–15q26.2 as a critical region for CDH. The three other most compelling CDH-critical regions for genomic deletions based on these data and a literature review are located at chromosomes 8p23.1, 4p16.3–4pter, and 1q41–1q42.1. Based on these recurrent deletions at 15q26.1–15q26.2, we hypothesized that loss-of-function mutations in a gene or genes from this region could cause CDH and sequenced six candidate genes from this region in more than 100 patients with CDH. For three of these genes (CHD2, ARRDC4, and RGMA), we identified missense changes and that were not identified in normal controls; however, none of these alterations appeared unambiguously causal with CDH. These data suggest that CDH caused by chromosome deletions at 15q26.2 may arise because of a contiguous gene deletion syndrome or may have a multifactorial etiology. In addition, there is evidence for substantial genetic heterogeneity in CDH and diaphragmatic hernias can be non-penetrant in patients who have deletions involving CDH-critical regions.