Detection of clinically relevant exonic copy-number changes by array CGH

• Published in: Human mutation Vol. 31; no. 12; pp. 1326 - 1342
• Main Authors: Boone, Philip M., Bacino, Carlos A., Shaw, Chad A., Eng, Patricia A., Hixson, Patricia M., Pursley, Amber N., Kang, Sung-Hae L., Yang, Yaping, Wiszniewska, Joanna, Nowakowska, Beata A., del Gaudio, Daniela, Xia, Zhilian, Simpson-Patel, Gayle, Immken, LaDonna L., Gibson, James B., Tsai, Anne C.-H., Bowers, Jennifer A., Reimschisel, Tyler E., Schaaf, Christian P., Potocki, Lorraine, Scaglia, Fernando, Gambin, Tomasz, Sykulski, Maciej, Bartnik, Magdalena, Derwinska, Katarzyna, Wisniowiecka-Kowalnik, Barbara, Lalani, Seema R., Probst, Frank J., Bi, Weimin, Beaudet, Arthur L., Patel, Ankita, Lupski, James R., Cheung, Sau Wai, Stankiewicz, Pawel
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-12-2010; Hindawi Limited
• Subjects: Adolescent; Base Sequence; CGH; Child; Child, Preschool; Chromosome Breakpoints; CNV; comparative genomic hybridization; Comparative Genomic Hybridization - methods; copy-number variation; DNA Copy Number Variations - genetics; exon mutations; Exons - genetics; Female; Genetic Association Studies; Humans; Infant; Infant, Newborn; intragenic rearrangements; Male; Molecular Sequence Data; Sequence Analysis, DNA; Sequence Deletion - genetics; Young Adult
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.21360

Array comparative genomic hybridization (aCGH) is a powerful tool for the molecular elucidation and diagnosis of disorders resulting from genomic copy‐number variation (CNV). However, intragenic deletions or duplications—those including genomic intervals of a size smaller than a gene—have remained beyond the detection limit of most clinical aCGH analyses. Increasing array probe number improves genomic resolution, although higher cost may limit implementation, and enhanced detection of benign CNV can confound clinical interpretation. We designed an array with exonic coverage of selected disease and candidate genes and used it clinically to identify losses or gains throughout the genome involving at least one exon and as small as several hundred base pairs in size. In some patients, the detected copy‐number change occurs within a gene known to be causative of the observed clinical phenotype, demonstrating the ability of this array to detect clinically relevant CNVs with subkilobase resolution. In summary, we demonstrate the utility of a custom‐designed, exon‐targeted oligonucleotide array to detect intragenic copy‐number changes in patients with various clinical phenotypes. Hum Mutat 31:1–17, 2010. © 2010 Wiley‐Liss, Inc.