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May 15, 2010 (Vol. 30, No. 10)

CGH Delivers Insights on Cytogenetics

Technique's Considerable Power Has Led to Extensive Use in Research Laboratories and Clinical Settings

  • Task Force

    Click Image To Enlarge +
    A simple insertional translocation: An aCGH summary table indicating the size of the duplication segment is on the top. To the left are the aCGH results showing the oligonucleotide probes specific for chromosome 1 next to the chromosome 1 ideogram. The probes detecting a gain in copy number are shown in the red circle. To the right is the reversed FISH image showing insertion of chromosome 1p21.3 material (probe RP11-465K1 in red) into chromosome 3q. The control probe is RP11-488L9, labeled in green. [Baylor College of Medicine]

    A large project is under way to optimize and standardize array design and interpretation guidelines for clinical labs worldwide. This project was initiated in 2008 primarily by Emory University but also involved GeneDx, ARUP Laboratories, and Mayo Clinic. Known as the International Standard Cytogenomic Array Consortium (ISCA), this collaborative undertaking has now expanded and includes over 100 labs worldwide.

    “I think this collaborative effort is necessary for the future of array CGH testing in clinical laboratories to ensure its proper use and the necessary education that goes with it,” explains Swaroop Aradhya, Ph.D., director of clinical cytogenetics and vp at GeneDx. In fact, in what amounts to a paradigm shift, ISCA is releasing a consensus statement promoting the use of array CGH as a first-tier test in children with developmental delay, intellectual disability, and/or congenital anomalies.

    Array CGH has also been used outside of the cytogenetics context and in the realm of single-gene Mendelian disorder testing. At the American College of Medical Genetics’ recent “Clinical Genetics” meeting, Dr. Aradhya and his colleagues described an adaptation of the array CGH approach to evaluate individual exons of single genes each associated with a specific genetic disorder.

    The GeneDx exon array can examine more than 560 genes and has now been used to test more than 2,500 patients, Dr. Aradhya says. In approximately 3.5% of these patients, this approach revealed mutations that had either eluded detection or were not identifiable with other methods.

    GeneDx, which started offering cytogenetic postnatal array CGH three years ago, has expanded its array CGH service to offer prenatal cytogenetic testing for fetuses with ultrasound abnormalities, exon-level copy number analysis for single-gene disorders, and mitochondrial genome testing. Its parent company, BioReference Laboratories, also offers array CGH testing for leukemias. A few other clinical laboratories in the U.S., including Emory University and Baylor College of Medicine, now offer a similar breadth of array CGH testing services.

    “Our main effort is to put together a large consortium of clinical diagnostic labs using whole-genome array technology and pool the data into a central public database that will provide a valuable resource for the research and clinical communities,” says David H. Ledbetter, Ph.D., the Robert W. Woodruff professor of human genetics and director of the division of medical genetics at Emory University.

    ISCA makes the information deposited in this massive database available for vendors, registered investigators conducting research on copy number variants, and clinical laboratories. “We expect to have data from 200,000 array CGH patient samples in the next two years,” predicts Dr. Ledbetter.

    The data will help compare findings from individual patients with results already deposited in the database and will help investigators during efforts to distinguish copy number variants that are benign from the ones that have pathogenic effects. “The major problem right now is that we are not sure about the functional consequence for most copy number variants, but large datasets from control and patient populations should enable us to quickly determine which ones have clinical significance.”

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