Enhanced detection of clinically relevant genomic imbalances using a targeted plus whole genome oligonucleotide microarray.
OBJECTIVE
Array comparative genomic hybridization is rapidly becoming an integral part of cytogenetic diagnostics. We report the design, validation, and clinical utility of an oligonucleotide array which combines genome-wide coverage with targeted enhancement at known clinically relevant regions.


METHODS
Probes were placed every 75 kb across the entire euchromatic genome to establish a chromosomal "backbone" with a resolution of approximately 500 kb, which is increased to approximately 50 kb in targeted regions.


RESULTS
For validation, 30 samples showed 100% concordance with previous G-banding and/or fluorescence in situ hybridization results. Prospective array analysis of 211 clinical samples identified 33 (15.6%) cases with clinically significant abnormalities. Of these, 23 (10.9%) were detected by the "targeted" coverage and 10 (4.7%) by the genome-wide coverage (average size of 3.7 Mb). All abnormalities were verified by fluorescence in situ hybridization, using commercially available or homebrew probes using the 32K bacterial artificial chromosome set. Four (1.9%) cases had previously reported imbalances of uncertain clinical significance. Five (2.4%) cases required parental studies for interpretation and all were benign familial variants.


CONCLUSIONS
Our results highlight the enhanced diagnostic utility of a genome-wide plus targeted array design, as the use of only a targeted array would have failed to detect 4.7% of the clinically relevant imbalances.
Baldwin
Erin L
EL
Department of Human Genetics, Emory University, Atlanta, Georgia 30322, USA.
Lee
Ji-Yun
JY
Blake
Douglas M
DM
Bunke
Brian P
BP
Alexander
Chad R
CR
Kogan
Amy L
AL
Ledbetter
David H
DH
Martin
Christa L
CL
D000328:Adult; D002871:Chromosome Banding; D002874:Chromosome Mapping; D003582:Cytogenetics / Q000379:methods*; D005260:Female; D015894:Genome, Human; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008297:Male; D008957:Models, Genetic; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D015345:Oligonucleotide Probes / Q000737:chemistry; D016615:Telomere / Q000648:ultrastructure
D015345:Oligonucleotide Probes