Targeted comparative genomic hybridization array for the detection of single- and multiexon gene deletions and duplications

Tayeh, Marwan K.; Chin, Ephrem; Miller, Vanessa Rangel; Bean, Lora Jh; Coffee, Bradford; Hegde, Madhuri

doi:10.1097/gim.0b013e318195e191

Cited by 39 publications

(41 citation statements)

References 35 publications

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“…This observation of significant analytical sensitivity added by exon aCGH has been elaborated on in other reports. 2 These data also show that a high number of intragenic copy-number mutations encompass just a single exon, thereby setting an expectation of sensitivity for any method used for deletion/duplication analysis. Other groups have also emphasized the need for exon-level CNV detection at disease genes.…”

Section: Discussionmentioning

confidence: 81%

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

Retterer¹,

Scuffins²,

Schmidt³

et al. 2015

Genetics in Medicine

117

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Original research article INTRODUCTIONSignificant 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. Recurrent rearrangements between segmentally duplicated sequences are also associated with a number of syndromic disorders. 3 For these known disorders, targeted gene testing by multiplex ligation-dependent amplification or exon-focused arrays has been useful. 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, not only to detect aberrations in genes that may cause disease when haplo-insufficient but also 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 now routinely used as a first-tier test for children with intellectual disability, developmental delay, or congenital anomalies. 5 In less than 10 years, the CMA designs have evolved from low-resolution arrays containing large bacterial artificial chromosome clones or <100,000 oligonucleotide probes to high-resolution versions with more than 1 million probes. 6 As a result, several groups have identified single-gene pathogenic aberrations that boost the analytical sensitivity of CMA. 7 However, although some of these more recent arrays have higher density at disease genes, they do not all cover every exon in those genes and are therefore not capable of detecting some pathogenic intragenic mutations. Separately, 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 therefore it is essential to cover all exons within targeted genes. 1 Copy-number detection in clinical genetic testing eventually will occur entirely through examination of next-generation data, whereas array comparative genomic hybridization (aCGH) and other assays will serve as complementary and confirmatory methods. 8 To complement whole-exome sequencing (WES) or whole-genome sequencing data in a meaningful way, an array with coverage of virtually all exons is essential. Until the time that WES/whole-genome sequencing can be used routinely and reliably for copy-number detection, a whole-exome array can be used as the ultimate whole-genome CMA platform. 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 ut...

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Section: Discussionmentioning

confidence: 81%

“…1,2 Intragenic deletion mutations are of considerable frequency in many disease genes, such as PAX6, CDKL5, and STXPB1. Recurrent rearrangements between segmentally duplicated sequences are also associated with a number of syndromic disorders.…”

Section: Introductionmentioning

confidence: 99%

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

Retterer¹,

Scuffins²,

Schmidt³

et al. 2015

Genetics in Medicine

117

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show abstract

“…75 This method is not dependent on a single probe and can be extremely sensitive because multiple probes are designed for each exon, thus avoiding allele dropout due to the presence of SNPs under probe, which is a major drawback of MLPA. Refer to ACMG Standards and Guidelines for Clinical Cytogenetics for technical details.…”

Section: Gene-targeted Array-based Comparative Genomic Hybridization mentioning

confidence: 99%

ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis)

Hegde

Ferber

Mao

et al. 2014

Genetics in Medicine

Self Cite

147

105

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“…6 Although the power of next-generation sequencing has opened up the potential to screen all exons or the whole genome for sequence mutations, the analysis algorithms are not, as yet, robust for routine identification of losses or gains of sequence involving a single or a few exons. As the probe capacity on microarrays increases, there is the potential to screen a large number of genes at the exonic level using microarrays [7][8][9][10] providing the means to identify CNVs that are currently missed with whole-genome clinical arrays and nextgeneration sequencing.…”

Section: Introductionmentioning

confidence: 99%

Single exon-resolution targeted chromosomal microarray analysis of known and candidate intellectual disability genes

et al. 2013

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Intellectual disability affects about 3% of individuals globally, withB50% idiopathic. We designed an exonic-resolution array targeting all known submicroscopic chromosomal intellectual disability syndrome loci, causative genes for intellectual disability, and potential candidate genes, all genes encoding glutamate receptors and epigenetic regulators. Using this platform, we performed chromosomal microarray analysis on 165 intellectual disability trios (affected child and both normal parents). We identified and independently validated 36 de novo copy-number changes in 32 trios. In all, 67% of the validated events were intragenic, involving only exon 1 (which includes the promoter sequence according to our design), exon 1 and adjacent exons, or one or more exons excluding exon 1. Seventeen of the 36 copy-number variants involve genes known to cause intellectual disability. Eleven of these, including seven intragenic variants, are clearly pathogenic (involving STXBP1, SHANK3 (3 patients), IL1RAPL1, UBE2A, NRXN1, MEF2C, CHD7, 15q24 and 9p24 microdeletion), two are likely pathogenic (PI4KA, DCX), two are unlikely to be pathogenic (GRIK2, FREM2), and two are unclear (ARID1B, 15q22 microdeletion). Twelve individuals with genomic imbalances identified by our array were tested with a clinical microarray, and six had a normal result. We identified de novo copynumber variants within genes not previously implicated in intellectual disability and uncovered pathogenic variation of known intellectual disability genes below the detection limit of standard clinical diagnostic chromosomal microarray analysis.

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Targeted comparative genomic hybridization array for the detection of single- and multiexon gene deletions and duplications

Cited by 39 publications

References 35 publications

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

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

ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis)

Single exon-resolution targeted chromosomal microarray analysis of known and candidate intellectual disability genes

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