HUMAN MUTATION 27(5), 467^473, 2006 RESEARCH ARTICLE Rapid Detection of Submicroscopic Chromosomal Rearrangements in Children With Multiple Congenital Anomalies Using High Density Oligonucleotide Arrays Jeffrey E. Ming, 1,3 Elizabeth Geiger, 1 Alison C. James, 1 Karen L. Ciprero, 1 Manjunath Nimmakayalu, 1 Yi Zhang, 1 Andrew Huang, 1 Madhavi Vaddi, 1 Eric Rappaport, 2 Elaine H. Zackai, 1,3 and Tamim H. Shaikh 1,3,4Ã 1 Division of Human Genetics, Stokes Research Institute, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; 2 Nucleic Acid and Protein Core Facility, Stokes Research Institute, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; 3 Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; 4 Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Communicated by Richard G.H. Cotton Chromosomal rearrangements such as microdeletions and interstitial duplications are the underlying cause of many human genetic disorders. These disorders can manifest in the form of multiple congenital anomalies (MCA), which are a significant cause of morbidity and mortality in children. The major limitations of cytogenetic tests currently used for the detection of such chromosomal rearrangements are low resolution and limited coverage of the genome. Thus, it is likely that children with MCA may have submicroscopic chromosomal rearrangements that are not detectable by current techniques. We report the use of a commercially available, oligonucleotide-based microarray for genome-wide analysis of copy number alterations. First, we validated the microarray in patients with known chromosomal rearrangements. Next, we identified previously undetected, de novo chromosomal deletions in patients with MCA who have had a normal high- resolution karyotype and subtelomeric fluorescence in situ hybridization (FISH) analysis. These findings indicate that high-density, oligonucleotide-based microarrays can be successfully used as tools for the detection of chromosomal rearrangement in clinical samples. Their higher resolution and commercial availability make this type of microarray highly desirable for application in the diagnosis of patients with multiple congenital defects. Hum Mutat 27(5), 467–473, 2006. Published 2006 Wiley-Liss, Inc. y KEY WORDS: microarray; SNP; oligonucleotide; copy number alteration; chromosomal rearrangement; multiple congenital anomalies; MCA INTRODUCTION Recent evidence suggests that a significant proportion of human diseases are chromosomal rearrangement-based disorders, arising from microdeletions and microduplications [Shaw and Lupski, 2004]. Diseases arising from such structural rearrangements have been designated ‘‘genomic disorders’’ [Lupski, 1998] and are estimated to occur at a frequency of 0.7–1 out of 1000 live births [Ji et al., 2000]. A few of the better characterized genomic disorders include Prader-Willi (PWS; MIM] 176270) and Angelman syndromes (AS; MIM] 105830) on 15q11–q13 [Amos- Landgraf et al., 1999; Christian et al., 1999] Williams-Beuren syndrome (WBS; MIM] 194050) on 7q11.23 [Peoples et al., 2000], Smith-Magenis syndrome (SMS; MIM] 182290)/ duplication 17p11.2 on 17p11.2 [Chen et al., 1997], and several rearrangements associated with 22q11 including DiGeorge and velocardiofacial syndromes (DGS/VCFS; MIM] 188400) [Edelmann et al., 1999; Shaikh et al., 2000] and cat eye syndrome (CES; MIM] 115470) [McTaggart et al. 1998]. Although a number of patients with multiple congenital anomalies (MCA) can be diagnosed with a well-defined genetic Published online 17 April 2006 in Wiley InterScience (www. interscience.wiley.com). y This article is a US Government work and, as such, is in the public domain in the United States of America. DOI 10.1002/humu.20322 The Supplementary Material referred to in this article can be accessed at http://www.interscience.wiley.com/jpages/1059-7794/ suppmat. Received 18 September 2005; accepted revised manuscript 19 January 2006. Grant sponsor: Ethel Brown Foerderer Fund; Grant sponsor: National Institutes of Health (NIH); Grant numbers: GM64725, HD26979, and DE015874. Ã Correspondence to: Tamim H. Shaikh, Ph.D., The Children’s Hospital of Philadelphia, 1002 Abramson Research Center, 3615 Civic Center Blvd., Philadelphia, PA19104. E-mail: shaikh@email.chop.edu PUBLISHED 2006 WILEY-LISS, INC.