Abstract
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. 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. 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. 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.
Highlights
Significant advances in copy-number detection have broadened the mutation spectrum for many clinical genetic disorders.[1,2] Intragenic deletion mutations are of considerable frequency in many disease genes, such as PAX6, CDKL5, and STXPB1
With the increasing uptake of exome sequencing into the clinical diagnostic approach, the need for testing previously uncharacterized genes for pathogenic copynumber variation (CNV) is a significant consideration, to detect aberrations in genes that may cause disease when haplo-insufficient and in genes associated with recessive disorders for which the mutation has been identified in only one of the alleles by exome sequencing.[4]
Whereas exome sequencing is still gaining popularity as a powerful clinical tool, whole-genome chromosomal microarray analysis (CMA) has become an indispensable screening method that is routinely used as a first-tier test for children with intellectual disability, developmental delay, or congenital anomalies.[5]
Summary
Significant advances in copy-number detection have broadened the mutation spectrum for many clinical genetic disorders.[1,2] Intragenic deletion mutations are of considerable frequency in many disease genes, such as PAX6, CDKL5, and STXPB1. With the increasing uptake of exome sequencing into the clinical diagnostic approach, the need for testing previously uncharacterized genes for pathogenic copynumber variation (CNV) is a significant consideration, to detect aberrations in genes that may cause disease when haplo-insufficient and in genes associated with recessive disorders for which the mutation has been identified in only one of the alleles by exome sequencing.[4]. Data from exon-focused arrays have shown that up to 40% of intragenic mutations can involve just one or two exons within a gene, and it is essential to cover all exons within targeted genes.[1]
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