Signature Genomic Laboratories last week said that it has expanded its PrenatalChip-based genetic-testing service in the US to more broadly look for chromosomal imbalances in utero.
Signature debuted the genetic-testing service last year to help identify risk for developing certain genetic diseases in the unborn. The expansion of the service with PrenatalChip version 2.0, which is designed to detect a greater number of genetic disorders, comes as more cytogeneticists begin to accept comparative genomic hybridization as a diagnostic tool, and as demand for the prenatal-testing service is increasing.
Justine Coppinger, a certified genetic counselor at Spokane, Wash.-based Signature, told BioArray News this week that PrenatalChip version 2.0 interrogates more clinical loci than the company’s first PrenatalChip, and retains coverage of the pericentromeric and subtelomeric chromosomal regions, which are more prone to genetic rearrangements.
As such, she said the new chip is intended to be used in pregnancies “in which the suspicion for a chromosome imbalance exists but is relatively low, such as pregnancies referred for advanced maternal age or parental anxiety, but array CGH is desired for additional information or reassurance.”
Among the differences between v. 1 and v. 2 is that the new chip includes 2,108 BAC clones, whereas the first version interrogated 1,083. In addition, the new array tests for the presence of copy-number alterations linked to over 120 disorders compared to roughly 70 touted by the original chip.
“The purpose of the design of the Signature PrenatalChip is to maximize the benefit that prenatal array CGH offers, which is rapid detection of copy-number alterations, including those that may be missed by karyotyping — that may impact pregnancy management and medical decision-making — while minimizing the potential for finding copy-number alterations that have unclear clinical significance,” Coppinger said.
Signature has implemented a two-tier approach for its prenatal testing service. The first tier of the service uses the PrenatalChip, which targets over 100 discrete chromosomal regions, the gain or loss of which results in a genetic disorder. If more coverage is needed, Signature then uses its whole-genome array, the SignatureChipWG, especially in cases in which abnormal findings were discovered by ultrasound.
According to Coppinger, demand for the prenatal-testing service is increasing. The company has received 407 clinical prenatal samples for array CGH testing so far this year, up from the 153 clinical prenatal samples for aCGH Signature received in 2007.
“There is more interest from patients, physicians, and genetic counselors about the applications of microarray technology prenatally, the appropriate use and timing of testing, and insurance coverage,” Coppinger said. “We typically receive several calls a day with questions about our Prenatal Service.”
These questions, she said, “have become more sophisticated over time, beginning with ‘What is array CGH and why should I know about it?’ in spring 2006, to recent questions along the lines of ‘How can I incorporate this technology into my practice?’”
Signature has also diversified its testing options. In addition to its PrenatalChip, Signature last year began using what are essentially different versions of its whole-genome array.
“Any genetic testing in pregnancy is controversial.”
The first was the SignatureChip WG, which the company makes in-house in Spokane using BACs. It is unlikely to detect alterations with unclear clinical significance, an attribute that helps Signature make a higher-confidence diagnosis for its clients.
The second was the SignatureChip OS, manufactured by Agilent Technologies, which contains 105,000 features per array with an average of 50 oligos per clinical target and the same syndrome coverage of the SignatureChip WG. It excels at detecting gene alterations that cannot be found using BACs. However, Signature has warned that it may be impossible to confirm such a finding using fluorescence in situ hybridization, the standard confirmatory technique (see BAN 10/23/2007).
“Our decision to offer different microarray options has allowed physicians and genetic counselors, along with their patients, the ability to choose the prenatal microarray that best meets their diagnostic and philosophic needs,” Coppinger said. “Physicians and genetic counselors have started to incorporate these themes into their counseling sessions to prepare parents for normal or abnormal results.
“Our genetic counselors carefully track prenatal cases, and have become experienced in understanding the different applications of array CGH in prenatal diagnosis,” she added.
In September, Signature published a study in Prenatal Diagnosis that compared the ability of microarray-based tests to detect genetic abnormalities in prenatal and neonatal samples. In the study, company researchers performed CGH analysis on 151 prenatal samples and 1,375 neonatal samples from patients younger than three months. The results showed that while abnormalities were detected in 11.4 percent of neonatal samples, only 1.3 percent of prenatal samples tested revealed genetic abnormalities.
However, the paper determined that many patients were being excluded from CGH testing based on the results of other forms of chromosomal analysis, such as karyotyping. Stating that its rate of detection in neonates was higher than rates of detection by other technologies, Signature concluded that, if more prenatal samples were slated for CGH analysis, the rate of detection would most likely increase, too.
Controversy and Competition
When Signature began offering prenatal testing in early 2007, it was a change from a policy that considered array CGH technology to be too nascent to convince a couple to terminate a pregnancy.
In October 2005, Signature CEO Lisa Shaffer told BioArray News that Signature eventually intended to offer microarray-based prenatal testing, but that the technology was "absolutely not ready for prime time."
Around 18 months later, in April 2007, she said the firm had gained enough expertise to begin performing its services on prenatal samples: "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." (see BAN 4/3/2007).
By jumping into the prenatal CGH-diagnostics market, Signature joined Baylor College of Medicine’s Medical Genetics Laboratories in offering the tests. Baylor’s initial push into the market, which came in 2005, invited some controversy. In a Dec. 8, 2005 editorial, for example, Nature called for increased federal supervision of microarray-based diagnostics.
"Researchers at Baylor College of Medicine … are offering pregnant women a genome-scanning test that checks for abnormalities in developing fetuses, but because of the way this test was developed, it is not currently subject to FDA review," the editorial stated.
According to the editorial, "the introduction of prenatal microarray tests into this picture creates additional urgency for the regulators to act. If misdiagnoses occur, children may be born with an unexpected disease, or fetuses may be terminated on the basis of false information" (see BAN 4/11/2006).
This week, Coppinger said that while Signature is witnessing an increased demand for its tests, big questions remain about its service and those like it. “Any genetic testing in pregnancy is controversial,” Coppinger said. “Most prenatal physicians and genetic counselors would agree that there are applications of array CGH in prenatal medicine [but] many remain uncomfortable with the possibility of results of unclear clinical significance or establishing which prenatal patients might benefit most from being offered array CGH,” she said.
To assuage these concerns, Signature performs follow-up analyses on parental samples if an abnormality is detected in a prenatal sample, which Coppinger said enables the lab to make a “more complete interpretation in nearly all cases.”
She added that as more studies like the one in Prenatal Diagnosis appear, questions about the technology should gradually subside. “As physicians and genetic counselors become more familiar with the technology and its appropriate uses, and as more studies are published, we anticipate that the controversy will lessen,” she said.
Arthur Beaudet, chair of the department of human medical genetics at Baylor who oversees its Chromosomal Microarray Analysis service, this week agreed with Coppinger’s assessment of the market. Like Signature, Baylor has seen an increase in demand for its prenatal testing service, and expects to perform CMA on around 230 samples this year, compared to 130 samples last year.
In terms of the questions surrounding prenatal testing using CGH, Beaudet acknowledged that the services are still controversial, but said that there will be “slow acceptance” of the technology over time.
He also said that Baylor will soon introduce an upgraded version of the array it uses in prenatal testing.
Baylor last year began using a 44,000-feature oligonucleotide array manufactured by Agilent Technologies, replacing an older BAC-based platform it printed in-house. Baylor will now upgrade to a 105,000-feature array with “better backbone coverage over the great majority of the genome,” Beaudet said.
A paper describing the use of Baylor’s new platform has been submitted to Prenatal Diagnosis and is awaiting publication, he said.