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Changing Their Minds, CMDX and Signature Will Now Offer Prenatal Array CGH Testing

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This article has been corrected to accurately describe Signature Genomic Laboratories' prenatal service.
CombiMatrix Molecular Diagnostics and Signature Genomic Laboratories both recently added prenatal testing to their comparative genomic hybridization-based diagnostic menus, changing an earlier stance against using CGH to test the unborn for congenital defects.
 
The change of heart may help build a consensus in the CGH community that it is now appropriate to offer these tests to expectant mothers.
 
The choice of the two CGH innovators follows by more than a year Baylor College of Medicine’s decision to use CGH technology for these indications. It also essentially ends a once-hot debate on the ethics of using CGH in the prenatal setting, and opens the door to newcomers like Empire Genomics to begin offering their own prenatal testing services.
 
Last week CMDX said that its laboratories in Irvine, Calif., will perform the prenatal services on the second version of its Constitutional Genetic Array Test, the CA850, which can identify more than 50 common genetic disorders in one test.
 
The CombiMatrix subsidiary said in a statement that it sees its prenatal testing service as an opportunity for at-risk parents to evaluate the genetic health of the fetus using a method that complements older methods like karyotyping.
 
CMDX's decision to offer CGH-based prenatal tests represents a sea change for CEO Mansoor Mohammed. Less than a year ago he argued that CGH was too immature to provide the kind of information that might result in an abortion. His comments at the time also hinted that Baylor could have been acting irresponsibly.
 
Mohammed said last week that his previous reservations were "never an absolute negation of the utility of the array CGH technology," and that they were influenced by what he perceived to be a "rush by some segments of the clinical genetics community to use a new technology without fully understanding and appreciating its possible ramifications."
 
Last April, Mohammed told BioArray News that "more genotype-phenotype associations need to be [made] before [array CGH] can be used in the prenatal arena. We need to have a wider corpus of data so we can gain appreciation of genotype-phenotype, phenotype-genotype associations. A lot more maturity needs to be put into this before it is used [for prenatal analysis]" (see BAN 4/11/2006).
 
Last week Mohammed, who became CEO of CMBX in February, defended both his earlier warnings of using CGH in the prenatal setting as well as CMDX's recent decision to start offering the technology in its labs.
 
According to Mohammed, recent publications documenting copy number variations in the human genome have given CMDX an adequate roadmap for taking CNVs into account while conducting a prenatal analysis, and have soothed its concerns about the possibility of undocumented CNVs leading to a misdiagnosis.
 
"In the past, I disagreed with the use of array CGH prenatal testing by some groups as I felt that the anxiety generated by the prenatal detection of these CNVs could not be effectively mitigated," Mohammed wrote in an e-mail to BioArray News. "My original position has now been tempered by the much more complete documentation of the location of these CNVs and by practical and reliable methods, such as [fluorescent in situ hybridization], to trace the inheritance or de novo classification of a putative CNV or CNVs," he wrote.
 
"Coupled with the incredibly robust performance of our array CGH tests, our exhaustive clinical validation and strict guidelines for use, I am finally comfortable to offer array CGH for select prenatal cases," Mohammed added.
 
Signature PrenatalChip
 
In February, Signature Genomic Laboratories, a Spokane, Wash.-based company that offers CGH-based diagnostic services for genetic abnormalities, added prenatal to its menu. Its decision also reversed earlier reservations by cofounder and CEO Lisa Shaffer that CGH was too new a technology to be used in the prenatal setting.
 
Signature's new PrenatalChip uses bacterial artificial chromosomes and includes 1,083 clones representing 367 distinct regions of the genome. CMDX has not disclosed how many clones are on its array, but says it tests for 51 congenital syndromes.
 
The PrenatalChip is intended for patients with otherwise normal pregnancies that are coming in for chromosome testing because of advanced maternal age or parental concern, Shaffer wrote in an e-mail to BioArray News last week. Signature also uses its older SignatureChip to screens patients with abnormal ultrasound findings.
 
In October 2005, Shaffer told BioArray News that Signature eventually intended to offer prenatal testing, but that the technology was "absolutely not ready for prime time" (see BAN 11/2/2005).
 
Now Signature is ready to offer prenatal testing based on its own growing experience with the technology, as well as demand.
 
"I always said that just because you can do something doesn't mean you should do it," Shaffer wrote last week. "We now have a lot of experience with our chip — over 12,000 cases tested. We felt that this experience was necessary before moving into prenatal," she wrote.
 

"I always said that just because you can do something doesn't mean you should do it."

Shaffer added that Signature now has a database to which it can refer that contains nearly 1,000 abnormalities. "I can't emphasize enough how important this is for findings with potentially unclear clinical relevance," she wrote. Finally, demand for prenatal service was high, another factor that prompted Signature to add it to menu.
 
"We have had a lot of requests for us to do prenatal and we have referred them to the other labs, but the clinicians or counselors have gotten upset with us. They want prenatal and they want us to do it," she wrote. "So we have entered in slowly and we will continue to monitor the situation to make sure that we are making diagnoses, not creating anxiety."
 
Newbies Take Notice
 
While CMDX and Signature were in the thick of the debate over prenatal CGH testing, newer CGH testing services were entering the marketplace with their own prenatal offerings, arguing that it is irresponsible to not offer the tests.
 
"We believe it is not only ethical but responsible to offer a CGH for prenatal testing," Anthony Johnson, CEO of Buffalo, NY-based CGH service company Empire Genomics, wrote to BioArray News this week. "The responsibility and primary areas of concern are that the lab be certified, very experienced and validate their findings.”
 
Johnson wrote that Empire decided to offer prenatal screening largely because awareness of the technology has increased, the quality of testing is better than it was several years ago, and because CGH has advantages in terms of sample needs and resolution.
 
"While it is not a totally displacing technology to traditional karyotyping, because of some of its inherent faults, it clearly has a place in the clinical arena," Johnson wrote. He was alluding to the inability of BAC array platforms to identify a balanced translocation in patients, an abnormality that occurs when pieces of equal length of two chromosomes are exchanged.
 
Johnson also said that contributing to his firm’s decision was work performed by more established CGH testing firms that helped the technology become acceptable for the application.
 
"In the past two years groups like Spectral Genomics and Signature have been working behind the scenes with the medical industry to gain acceptance of the prenatal tests," he wrote.
 
Johnson added that his company also offered postnatal testing, and was working on a pipeline of tests for other developmental disorders, such as autism.

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