Array-based comparative genomic hybridization: clinical contexts for targeted and whole-genome designs

Aradhya, Swaroop; Cherry, Athena M.

doi:10.1097/gim.0b013e318149e354

Cited by 42 publications

(23 citation statements)

References 44 publications

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“…[31][32][33] Some efforts have been made to develop explicit guidelines for clinical uptake of array-based molecular cytogenetics. 34,35 They currently suggest that whole genome analysis not be employed as a firstpass technology in cytogenetic analysis. However, they also note that the main issue is interpretation of findings, given that array methods routinely detect multiple CNVs even in patients without a clear medical ascertainment.…”

Section: Novel Genetic Analysismentioning

confidence: 99%

Is gene discovery research or diagnosis?

Samuels

Orr²,

Guernsey

et al. 2008

Genetics in Medicine

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The criteria that distinguish human genetic research from clinical molecular diagnosis are frequently practical rather than theoretical. They are driven by the availability and costs of the relevant technologies and the systemic level of scientific fluency in interpreting laboratory results. The guiding principle in the practice of medicine is the primacy of patient care. In the service of this overarching goal the defining characteristic of clinical diagnosis is the definition of the disease entity, even when no immediate treatment is possible. For heritable disorders caused by single-gene defects, identifying the putative causal variant is the goal of molecular diagnostics. Current technologies, costs, and standards of institutional infrastructure have not typically permitted novel gene discovery to be performed within the realm of the clinical laboratory. Discovery is usually funded by self-defined research organizations and carried out by self-defined research personnel with the primary intent of publishing findings in research journals. However, exponential improvements in technological capabilities and the concurrent decline in associated costs seem poised to recast this landscape, bringing to clinical medicine some activities now considered research. Even whole genome resequencing of individual patient DNA is within clinical reach in the foreseeable future. Genet Med 2008:10(6):385-390.

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Section: Novel Genetic Analysismentioning

confidence: 99%

Is gene discovery research or diagnosis?

Samuels

Orr²,

Guernsey

et al. 2008

Genetics in Medicine

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“…[27][28][29] The approach described here easily lends itself to future expansion that will blur the distinctions between focused and nonfocused arrays by allowing many options for array design and analysis.…”

mentioning

confidence: 99%

Bacterial artificial chromosome-emulation oligonucleotide arrays for targeted clinical array-comparative genomic hybridization analyses

Kang

Shaw

et al. 2008

Genetics in Medicine

103

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Purpose: The goal of this work was to test the ability of oligonucleotide-based arrays to reproduce the results of focused bacterial artificial chromosome (BAC)-based arrays used clinically in comparative genomic hybridization experiments to detect constitutional copy number changes in genomic DNA. Methods: Custom oligonucleotide (oligo) arrays were designed using the Agilent Technologies platform to give high-resolution coverage of regions within the genome sequence coordinates of BAC/P1 artificial chromosome (PAC) clones that had already been validated for use in previous versions of clone arrays used in clinical practice. Standard array-comparative genomic hybridization experiments, including a simultaneous blind analysis of a set of clinical samples, were conducted on both array platforms to identify copy number differences between patient samples and normal reference controls.Results: Initial experiments successfully demonstrated the capacity of oligo arrays to emulate BAC data without the need for dye-reversal comparisons. Empirical data and computational analyses of oligo response and distribution from a pilot array were used to design an optimized array of 44,000 oligos (44K). This custom 44K oligo array consists of probes localized to the genomic positions of Ͼ1400 fluorescence in situ hybridization-verified BAC/PAC clones covering more than 140 regions implicated in genetic diseases, as well as all clinically relevant subtelomeric and pericentromeric regions. Conclusions: Our data demonstrate that oligo-based arrays offer a valid alternative for focused BAC arrays. Furthermore, they have significant advantages, including better design flexibility, avoidance of repetitive sequences, manufacturing processes amenable to good manufacturing practice standards in the future, increased robustness because of an enhanced dynamic range (signal to background), and increased resolution that allows for detection of smaller regions of change. Genet Med 2008:10(4):278 -289. Key Words: array-CGH, oligonucleotide, focused microarray, CNV, chromosome abnormalities, mosaicismThe advent of array-based copy number analysis using comparative genomic hybridization (CGH) or non-CGH methods, including analysis of single nucleotide polymorphisms, has been a breakthrough in the detection of chromosomal copy number changes in the clinical setting. 1 This approach has been shown to be superior to both classical cytogenetic banding methods and fluorescence in situ hybridization (FISH)-based methods because of the greatly improved resolution and highly multiplexed nature of the method. [2][3][4] It is clear that this "molecular cytogenetic" methodology will continue to expand the capabilities for correlations between chromosomal aberrations and clinical phenotypes. This will be invaluable, not only for the diagnostic potential, but also for eventual discovery of the true genotypic basis for specific syndromic features at the molecular level.Until recently, most clinical applications of array-CGH, other than some cancer studies, have...

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“…In addition to showing the superior analytical sensitivity of oligonucleotide arrays compared with BAC arrays, these studies also demonstrated the convenience of oligonucleotide-array design and manufacturing. Aradhya and Cherry used samples from 20 patients with dysmorphic features, developmental delay, or mental retardation to directly compare the performance of whole-genome BAC arrays of 1-Mb resolution (Spectral Chip 2600; PerkinElmer) with that of Agilent whole-genome oligonucleotide CGH arrays of 35-kb resolution (33 ). All of these patients had a typical karyotype.…”

Section: Individuals With Oligonucleotide Arraysmentioning

confidence: 99%

Microarray-Based Genomic DNA Profiling Technologies in Clinical Molecular Diagnostics

Shen

2009

Clinical Chemistry

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Background: Microarray-based genomic DNA profiling (MGDP) technologies are rapidly moving from translational research to clinical diagnostics and have revolutionized medical practices. Such technologies have shown great advantages in detecting genomic imbalances associated with genomic disorders and single-gene diseases. Content: We discuss the development and applications of the major array platforms that are being used in both academic and commercial laboratories. Although no standardized platform is expected to emerge soon, comprehensive oligonucleotide microarray platforms—both comparative genomic hybridization arrays and genotyping hybrid arrays—are rapidly becoming the methods of choice for their demonstrated analytical validity in detecting genomic imbalances, for their flexibility in incorporating customized designs and updates, and for the advantage of being easily manufactured. Copy number variants (CNVs), the form of genomic deletions/duplications detected through MGDP, are a common etiology for a variety of clinical phenotypes. The widespread distribution of CNVs poses great challenges in interpretation. A broad survey of CNVs in the healthy population, combined with the data accumulated from the patient population in clinical laboratories, will provide a better understanding of the nature of CNVs and enhance the power of identifying genetic risk factors for medical conditions. Summary: MGDP technologies for molecular diagnostics are still at an early stage but are rapidly evolving. We are in the process of extensive clinical validation and utility evaluation of different array designs and technical platforms. CNVs of currently unknown importance will be a rich source of novel discoveries.

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Array-based comparative genomic hybridization: clinical contexts for targeted and whole-genome designs

Cited by 42 publications

References 44 publications

Is gene discovery research or diagnosis?

Is gene discovery research or diagnosis?

Bacterial artificial chromosome-emulation oligonucleotide arrays for targeted clinical array-comparative genomic hybridization analyses

Microarray-Based Genomic DNA Profiling Technologies in Clinical Molecular Diagnostics

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