Copyright © 2005 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 77, Issue 5, 709-726, 1 November 2005
doi:10.1086/497343
High-Resolution Identification of Chromosomal Abnormalities Using Oligonucleotide Arrays Containing 116,204 SNPs
Howard R. Slater1, 2, *, 
, 
, Dione K. Bailey5, *, Hua Ren3, Manqiu Cao6, Katrina Bell3, Steven Nasioulas1, Robert Henke4, K.H. Andy Choo2, 3 and Giulia C. Kennedy5
1 Genetic Health Cytogenetics Laboratory, Melbourne
2 University of Melbourne Department of Paediatrics, Melbourne
3 Murdoch Children's Research Institute and Royal Children's Hospital, Melbourne
4 Millennium Biosciences, Box Hill, Australia
5 Affymetrix, Santa Clara, CA
Address for correspondence and reprints: Dr. Howard R. Slater, Genetic Health Services Victoria Cytogenetics Laboratory, 10th Floor, Royal Children's Hospital, Parkville, Victoria 3052, Australia* These two authors contributed equally to this work.
Abstract
Mutation of the human genome ranges from single base-pair changes to whole-chromosome aneuploidy. Karyotyping, fluorescence in situ hybridization, and comparative genome hybridization are currently used to detect chromosome abnormalities of clinical significance. These methods, although powerful, suffer from limitations in speed, ease of use, and resolution, and they do not detect copy-neutral chromosomal aberrations—for example, uniparental disomy (UPD). We have developed a high-throughput approach for assessment of DNA copy-number changes, through use of high-density synthetic oligonucleotide arrays containing 116,204 single-nucleotide polymorphisms, spaced at an average distance of 23.6 kb across the genome. Using this approach, we analyzed samples that failed conventional karyotypic analysis, and we detected amplifications and deletions across a wide range of sizes (1.3–145.9 Mb), identified chromosomes containing anonymous chromatin, and used genotype data to determine the molecular origin of two cases of UPD. Furthermore, our data provided independent confirmation for a case that had been misinterpreted by karyotype analysis. The high resolution of our approach provides more-precise breakpoint mapping, which allows subtle phenotypic heterogeneity to be distinguished at a molecular level. The accurate genotype information provided on these arrays enables the identification of copy-neutral loss-of-heterozygosity events, and the minimal requirement of DNA (250 ng per array) allows rapid analysis of samples without the need for cell culture. This technology overcomes many limitations currently encountered in routine clinical diagnostic laboratories tasked with accurate and rapid diagnosis of chromosomal abnormalities.
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