Assessing copy number from exome sequencing and exome array CGH based on CNV spectrum in a large clinical cohort

• Published in: Genetics in medicine Vol. 17; no. 8; pp. 623 - 629
• Main Authors: Retterer, Kyle, Scuffins, Julie, Schmidt, Daniel, Lewis, Rachel, Pineda-Alvarez, Daniel, Stafford, Amanda, Schmidt, Lindsay, Warren, Stephanie, Gibellini, Federica, Kondakova, Anastasia, Blair, Amanda, Bale, Sherri, Matyakhina, Ludmila, Meck, Jeanne, Aradhya, Swaroop, Haverfield, Eden
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2015; Elsevier Limited
• Subjects: 631/114; 631/208/2489/1512; 631/208/726/649/2157; Algorithms; Biomedicine; Cohort Studies; Comparative Genomic Hybridization - methods; Computational Biology - methods; DNA - analysis; DNA - blood; DNA - genetics; DNA Copy Number Variations; Exome; Genetic Variation; High-Throughput Nucleotide Sequencing - methods; Human Genetics; Humans; Laboratory Medicine; original-research-article; exome; array CGH; deletion; next-generation sequencing; duplication
• ISSN: 1098-3600; 1530-0366; 1530-0366
• DOI: 10.1038/gim.2014.160

Purpose: Detection of copy-number variation (CNV) is important for investigating many genetic disorders. Testing a large clinical cohort by array comparative genomic hybridization provides a deep perspective on the spectrum of pathogenic CNV. In this context, we describe a bioinformatics approach to extract CNV information from whole-exome sequencing and demonstrate its utility in clinical testing. Methods: Exon-focused arrays and whole-genome chromosomal microarray analysis were used to test 14,228 and 14,000 individuals, respectively. Based on these results, we developed an algorithm to detect deletions/duplications in whole-exome sequencing data and a novel whole-exome array. Results: In the exon array cohort, we observed a positive detection rate of 2.4% (25 duplications, 318 deletions), of which 39% involved one or two exons. Chromosomal microarray analysis identified 3,345 CNVs affecting single genes (18%). We demonstrate that our whole-exome sequencing algorithm resolves CNVs of three or more exons. Conclusion: These results demonstrate the clinical utility of single-exon resolution in CNV assays. Our whole-exome sequencing algorithm approaches this resolution but is complemented by a whole-exome array to unambiguously identify intragenic CNVs and single-exon changes. These data illustrate the next advancements in CNV analysis through whole-exome sequencing and whole-exome array. Genet Med 17 8, 623–629.