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AJMG Paper Suggests Signature Genomic Labs Can Identify Rare Syndrome Without Skin Biopsy

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A study published in this month's issue of the American Journal of Medical Genetics by researchers at Signature Genomic Laboratories shows that the company can identify patients with Pallister-Killian disorder using DNA from blood rather than the more invasive skin biopsy that is routinely used.

The development is in line with a general trend in molecular cytogenetics of using array-based methods to replace older technologies.

Pallister-Killian syndrome is a rare genetic disorder characterized by mental retardation, seizures, streaks of hypo- or hyperpigmentation, and coarse facial features. The syndrome results from the presence of four, rather than the normal two, copies of the short arm of chromosome 12 in some of the body's cells, Signature said. The extra fragments of DNA usually cannot be identified in the cultured cells derived from blood used for conventional chromosome analysis, necessitating a skin biopsy for diagnosis.

According to the paper, from March 2004 through July 2008 Signature screened 23,098 individuals with developmental disabilities whose clinical specimens were submitted to its lab from within the US. Using array comparative genomic hybridization, Signature was able to identify a two-copy gain of the short arm of chromosome 12 in eight cases.

Typically, traditional cytogenetic analysis using cultured cells cannot identify the abnormality associated with PKS. According to the paper, this discrepancy arises from the inability of abnormal cells to compete with normal cells during the culturing process required for conventional chromosome analysis. In the paper, Signature suggests that, because it does not require cultured cells for analysis, its array platform can better detect chromosome abnormalities that are not present in every cell.

For example, while Signature's arrays detected the abnormality in eight cases, follow-up confirmation using fluorescence in situ hybridization on blood samples from the eight only found one case with the abnormality.

"PKS is a non-descript syndrome; it just might be one syndrome out of a number of syndromes," Signature CEO Lisa Shaffer told BioArray News this week. "For individuals that may have PKS, clinicians will usually order a karyotype. The problem is that this abnormality is not expressed in key lymphocytes, which is what you look at with a molecular karyotype," she said. "If you take a whole blood sample and extract the DNA, you can detect it because it is there. It just doesn't show up when you culture cells."

Shaffer described PKS as a "fairly rare" syndrome, and BioArray News was unable to determine the rate of incidence in the US after consulting several resources on rare chromosomal diseases. Because of this, Signature's ability to detect PKS on its array platforms is unlikely to result in any major financial benefit to the company, but Shaffer said it gives Signature "great satisfaction" that children with PKS "no longer need a painful skin biopsy to find a diagnosis." Physicians instead can send peripheral blood samples to Signature, where it can detect the abnormality, if present, she said.

One issue that exists is whether or not clinicians will even be aware of the development, or whether they will trust a newer method over the existing route to diagnosis. Shaffer said that Signature believes that the availability of medical literature is the best way to get information to clinicians. "Any clinician that suspects PKS will check the most recent literature and they will find out about this method," she said.

In the study, Signature used versions of both its bacterial artificial chromosome-based SignatureChipWG, which now uses 4,600 BAC contigs to represent regions known in cytogenetics, including those associated with 150 syndromes, the pericentromeric regions, and subtelomeres; as well as the SignatureChipOS, a 105,000-probe oligo chip manufactured by Agilent Technologies with similar coverage. According to Shaffer, Signature can detect PKS in prenatal as well as neonatal samples.

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