Human Molecular Genetics Advance Access originally published online on January 8, 2007
Human Molecular Genetics 2007 16(4):424-430; doi:10.1093/hmg/ddl475
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Genome-wide oligonucleotide-based array comparative genome hybridization analysis of non-isolated congenital diaphragmatic hernia
1 Department of Molecular and Human Genetics, 2 Department of Pediatrics, 3 Howard Hughes Medical Institute, Baylor College of Medicine, 635E, One Baylor Plaza, Houston, TX 77030, USA, 4 Department of Clinical Genetics and 5 Department of Paediatric Surgery, Erasmus Medical Center, Rotterdam, 3015 GE, The Netherlands and 6 Department of Pediatric Surgery, University of Texas Medical School, Houston, TX 77030, USA
* To whom correspondence should be addressed. Tel: +1 7137988835; Fax: +1 7137985168; Email: blee{at}bcm.tmc.edu
Received September 26, 2006; Revised November 28, 2006; Accepted December 23, 2006
Non-isolated congenital diaphragmatic hernia (CDH+) is a severe birth defect that is often caused by de novo chromosomal anomalies. In this report, we use genome-wide oligonucleotide-based array comparative genome hybridization (aCGH) followed by rapid real-time quantitative PCR analysis to identify, confirm and map chromosomal anomalies in a cohort of 26 CDH+ patients. One hundred and five putative copy number changes were identified by aCGH in our cohort of CDH+ patients. Sixty-one of these changes (58%) had been previously described in normal controls. Twenty of the remaining 44 changes (45%) were confirmed by quantitative real-time PCR or standard cytogenetic techniques. These changes included de novo chromosomal abnormalities in five of the 26 patients (19%), two of whom had previously normal G-banded chromosome analyses. Data from these patients provide evidence for the existence of CDH-related genes on chromosomes 2q37, 6p22–25 and 14q, and refine the CDH minimal deleted region on 15q26 to an interval that contains COUP-TFII and only eight other known genes. Although COUP-TFII is likely to play a role in the development of CDH in patients with 15q26 deletions, we did not find COUP-TFII mutations in 73 CDH samples. We conclude that the combination of oligonucleotide-based aCGH and quantitative real-time PCR is an effective method of identifying, confirming and mapping clinically relevant copy number changes in patients with CDH+. This method is more sensitive than G-banded chromosome analysis and may find wide application in screening patients with congenital anomalies.
The authors should be identified as having contributed equally.
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