Diagnostic Genome Profiling

Veltman, Joris A.; Vries, Bert B.A. de

doi:10.2353/jmoldx.2006.060131

Cited by 43 publications

(5 citation statements)

References 28 publications

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“…Further improvements in array design, ongoing improvements in AGH software, and continuing enhancement of resources like DECIPHER https://decipher.sanger.ac.uk/ and the Toronto Database of Genomic Variants http://projects.tcag.ca/variation/ are helping to establish AGH as the primary clinical tool for recognition of genomic imbalance that causes ID and other birth defects [33,34,37,41,67-70]. It seems likely, however, that no perfect AGH platform for detection of pathogenic CNVs may ever exist and that effective clinical interpretation of these studies will continue to require considerable skill and experience [33,50,71].…”

Section: Resultsmentioning

confidence: 99%

“…It is clear that AGH using "targeted" arrays that only include probes for genomic regions known to be involved in microdeletion or microduplication syndromes has substantially lower detection rates for CNVs that cause ID than AGH using arrays that provide genome-wide coverage [37,39-41]. Beyond this, however, there is no agreement regarding the kind of array, the distribution of probes across the genome, or the resolution that is most appropriate for clinical use.…”

Section: Discussionmentioning

confidence: 99%

“…Because its detection rate for pathogenic genomic imbalance is much higher than that of conventional cytogenetic analysis, a consensus has developed that AGH should be used clinically for the evaluation of patients with ID and other birth defects [ 31 - 38 ]. It is clear that AGH using "targeted" arrays that only include probes for genomic regions known to be involved in microdeletion or microduplication syndromes has substantially lower detection rates for CNVs that cause ID than AGH using arrays that provide genome-wide coverage [ 37 , 39 - 41 ]. Beyond this, however, there is no agreement regarding the kind of array, the distribution of probes across the genome, or the resolution that is most appropriate for clinical use.…”

Section: Discussionmentioning

confidence: 99%

“…Affymetrix GeneChip ® 500 K array genomic hybridization performed in individuals with idiopathic intellectual disability detected pathogenic genomic imbalance in 10 of 10 patients in whom 100 K GeneChip ® array genomic hybridization found genomic imbalance, 1 of 44 patients in whom 100 K GeneChip ® array genomic hybridization had found no abnormality, and 16 of 100 patients who had not previously been tested. Further improvements in array design, ongoing improvements in AGH software, and continuing enhancement of resources like DECIPHER https://decipher.sanger.ac.uk/ and the Toronto Database of Genomic Variants http://projects.tcag.ca/variation/ are helping to establish AGH as the primary clinical tool for recognition of genomic imbalance that causes ID and other birth defects [ 33 , 34 , 37 , 41 , 67 - 70 ]. It seems likely, however, that no perfect AGH platform for detection of pathogenic CNVs may ever exist and that effective clinical interpretation of these studies will continue to require considerable skill and experience [ 33 , 50 , 71 ].…”

Section: Discussionmentioning

confidence: 99%

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Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization

et al. 2009

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BackgroundArray genomic hybridization is being used clinically to detect pathogenic copy number variants in children with intellectual disability and other birth defects. However, there is no agreement regarding the kind of array, the distribution of probes across the genome, or the resolution that is most appropriate for clinical use.ResultsWe performed 500 K Affymetrix GeneChip® array genomic hybridization in 100 idiopathic intellectual disability trios, each comprised of a child with intellectual disability of unknown cause and both unaffected parents. We found pathogenic genomic imbalance in 16 of these 100 individuals with idiopathic intellectual disability. In comparison, we had found pathogenic genomic imbalance in 11 of 100 children with idiopathic intellectual disability in a previous cohort who had been studied by 100 K GeneChip® array genomic hybridization. Among 54 intellectual disability trios selected from the previous cohort who were re-tested with 500 K GeneChip® array genomic hybridization, we identified all 10 previously-detected pathogenic genomic alterations and at least one additional pathogenic copy number variant that had not been detected with 100 K GeneChip® array genomic hybridization. Many benign copy number variants, including one that was de novo, were also detected with 500 K array genomic hybridization, but it was possible to distinguish the benign and pathogenic copy number variants with confidence in all but 3 (1.9%) of the 154 intellectual disability trios studied.ConclusionAffymetrix GeneChip® 500 K array genomic hybridization detected pathogenic genomic imbalance in 10 of 10 patients with idiopathic developmental disability in whom 100 K GeneChip® array genomic hybridization had found genomic imbalance, 1 of 44 patients in whom 100 K GeneChip® array genomic hybridization had found no abnormality, and 16 of 100 patients who had not previously been tested. Effective clinical interpretation of these studies requires considerable skill and experience.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization

et al. 2009

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“…However, we do know that such costs would rapidly escalate and even then the majority of diagnoses achievable by aCGH would be missed; clinically relevant genomic imbalances found by genome-wide aCGH are rarely recurrent and therefore targeted approaches are unlikely to improve diagnostic yield (Veltman and de Vries 2006). Even if multi-telomere FISH or multi-telomere MLPA are not the tests chosen following karyotyping, costing in only five targeted tests for genomic imbalance at £100/test for every sample with a normal karyotype would raise the overall cost of testing 100 patients to ∼£59,402 (compared with £56,130 for aCGH) and offer negligible improvement in resolution overall.…”

Section: Discussionmentioning

confidence: 99%

Diagnosing idiopathic learning disability: a cost-effectiveness analysis of microarray technology in the National Health Service of the United Kingdom

Wordsworth

Buchanan

Regan

et al. 2007

HUGO J

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Array based comparative genomic hybridisation (aCGH) is a powerful technique for detecting clinically relevant genome imbalance and can offer 40 to > 1000 times the resolution of karyotyping. Indeed, idiopathic learning disability (ILD) studies suggest that a genome-wide aCGH approach makes 10–15% more diagnoses involving genome imbalance than karyotyping. Despite this, aCGH has yet to be implemented as a routine NHS service. One significant obstacle is the perception that the technology is prohibitively expensive for most standard NHS clinical cytogenetics laboratories. To address this, we investigated the cost-effectiveness of aCGH versus standard cytogenetic analysis for diagnosing idiopathic learning disability (ILD) in the NHS. Cost data from four participating genetics centres were collected and analysed. In a single test comparison, the average cost of aCGH was £442 and the average cost of karyotyping was £117 with array costs contributing most to the cost difference. This difference was not a key barrier when the context of follow up diagnostic tests was considered. Indeed, in a hypothetical cohort of 100 ILD children, aCGH was found to cost less per diagnosis (£3,118) than a karyotyping and multi-telomere FISH approach (£4,957). We conclude that testing for genomic imbalances in ILD using microarray technology is likely to be cost-effective because long-term savings can be made regardless of a positive (diagnosis) or negative result. Earlier diagnoses save costs of additional diagnostic tests. Negative results are cost-effective in minimising follow-up test choice. The use of aCGH in routine clinical practice warrants serious consideration by healthcare providers.

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The clinical utility of enhanced subtelomeric coverage in array CGH

Ballif

Sulpizio

Lloyd

et al. 2007

American J of Med Genetics Pt A

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Telomeric chromosome abnormalities are a substantial cause of mental retardation and birth defects. Although subtelomeric fluorescence in situ hybridization (FISH) probes have been widely used to identify submicroscopic telomeric rearrangements, array-based comparative genomic hybridization (array CGH) has emerged as a more efficient and comprehensive detection method. Due to the clinical relevance of telomeric abnormalities, it has been proposed that array CGH using panels of BAC clones that map to regularly spaced intervals along the length of each telomere could be used to characterize subtelomeric aberrations more precisely in a single experiment. We have added 1,120 FISH-mapped BAC clones to our microarray to enhance the coverage of the 41 unique human subtelomeric regions. Contigs of clones were selected in increments of approximately 0.5 Mb beginning with the most distal unique sequence for each subtelomere and extending on average approximately 5.7 Mb toward the centromere. We have used this microarray to characterize 169 clinically significant subtelomeric abnormalities identified out of nearly 7,000 consecutive clinical cases analyzed by array CGH in our diagnostic laboratory. The expanded telomere coverage was sufficient to define the breakpoints of over half (56%) of the chromosome abnormalities. However, 44% of the subtelomeric aberrations extended beyond the size of this expanded coverage suggesting that many subtelomeric abnormalities are >5 Mb in size and that greater representation may be of even more value. In addition to identifying 6 cases of complex rearrangements, we have identified 42 cases of interstitial deletions that would have been missed by subtelomere FISH panels that use a single clone to the most distal unique sequence for each region. Microarrays designed to investigate regions known to be involved in chromosome abnormalities will enhance the detection of cytogenetic abnormalities at unprecedented resolution and frequency.

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Diagnostic Genome Profiling

Cited by 43 publications

References 28 publications

Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization

Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization

Diagnosing idiopathic learning disability: a cost-effectiveness analysis of microarray technology in the National Health Service of the United Kingdom

The clinical utility of enhanced subtelomeric coverage in array CGH

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