Published online before print March 26, 2009

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Copyright © 2009 American Society for Investigative Pathology
Journal of Molecular Diagnostics, doi:10.2353/jmoldx.2009.080064

Accepted for publication January 6, 2009.

Article

Microarray-Based Comparative Genomic Hybridization Using Sex-Matched Reference DNA Provides Greater Sensitivity for Detection of Sex Chromosome Imbalances than Array-Comparative Genomic Hybridization with Sex-Mismatched Reference DNA

Svetlana A. Yatsenko^*, Chad A. Shaw^*, Zhishuo Ou^*, Amber N. Pursley^*, Ankita Patel^*, Weimin Bi^*, Sau Wai Cheung^*, James R. Lupski^*@, A. Craig Chinault^*, and Arthur L. Beaudet^*

From the Departments of Molecular and Human Genetics,* and Pediatrics, Baylor College of Medicine, Houston; and the Texas Children's Hospital, Houston, Texas

^@ To whom correspondence should be addressed. E-mail: jlupski{at}bcm.tmc.edu.

	Abstract

In array-comparative genomic hybridization (array-CGH) experiments, the measurement of DNA copy number of sex chromosomal regions depends on the sex of the patient and the reference DNAs used. We evaluated the ability of bacterial artificial chromosomes/P1-derived artificial and oligonucleotide array-CGH analyses to detect constitutional sex chromosome imbalances using sex-mismatched reference DNAs. Twenty-two samples with imbalances involving either the X or Y chromosome, including deletions, duplications, triplications, derivative or isodicentric chromosomes, and aneuploidy, were analyzed. Although concordant results were obtained for approximately one-half of the samples when using sex-mismatched and sex-matched reference DNAs, array-CGH analyses with sex-mismatched reference DNAs did not detect genomic imbalances that were detected using sex-matched reference DNAs in 6 of 22 patients. Small duplications and deletions of the X chromosome were most difficult to detect in female and male patients, respectively, when sex-mismatched reference DNAs were used. Sex-matched reference DNAs in array-CGH analyses provides optimal sensitivity and enables an automated statistical evaluation for the detection of sex chromosome imbalances when compared with an experimental design using sex-mismatched reference DNAs. Using sex-mismatched reference DNAs in array-CGH analyses may generate false-negative, false-positive, and ambiguous results for sex chromosome-specific probes, thus masking potential pathogenic genomic imbalances. Therefore, to optimize both detection of clinically relevant sex chromosome imbalances and ensure proper experimental performance, we suggest that alternative internal controls be developed and used instead of using sex-mismatched reference DNAs.