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Bio-Reference Laboratories’ GeneDx to Launch Genetic Test Based on Illumina GA This Fall

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This article has been updated to reflect the fact that the hypertrophic cardiomyopathy test offered by the Harvard Medical School – Partners Healthcare Laboratory for Molecular Medicine has changed. Rather than Sanger dideoxy sequencing alone, it now uses a combination of array-based resequencing and Sanger sequencing.
 
GeneDx, a genetic-testing laboratory and subsidiary of Bio-Reference Laboratories, has developed a sequencing-based test for hypertrophic cardiomyopathy on Illumina’s Genome Analyzer.
 
The homebrew assay, currently in early-access testing and scheduled to be launched in October, is among the first commercial diagnostic tests to be offered on a next-generation sequencing platform.
 
Though not the first genetic test for HCM, the company claims it will be less expensive than rival assays. It is the first of several tests that GeneDx plans to offer on the Illumina GA eventually.
 
GeneDx acquired an Illumina GA about a year ago and has since validated all aspects of the platform for genetic testing, initially for cardiomyopathies, according to Amar Kamath, vice president of marketing for Bio-Reference Laboratories.
 
“The reason we are investing in this is that we believe that this particular platform can be used for many other conditions where mutations in any one of a large number of genes cause a specific clinical condition,” he said. “We believe that over time, we will launch similar assays for other diseases where one needs to sequence a large number of genes to come up with a diagnosis.”
 
The test involves sequencing 16 genes known to be involved in HCM and is expected to have a clinical sensitivity of approximately 60 percent. The company’s goal is to make the test, which will be run in its CLIA-certified laboratory, widely available to physicians in October, Kamath said.
 
The initial target price is approximately $2,500, though the company will seek eventually to reduce it to $2,000. Bio-Reference Laboratories is “still figuring out” insurance coverage for the test, whose turnaround time has yet to be determined, according to Kamath.
 
GeneDx developed the test using PCR amplification but is also considering exon amplification methods, such as those made by Roche NimbleGen or Agilent Technologies.
 
“If the exon method works, and if it is cost-effective, we will continue using that. If it doesn’t, we will continue using the PCR method,” Kamath said.
 
Right now, GeneDx can analyze eight samples per run on the Illumina GA — one per lane on the flow cell — but the company, anticipating increasing demand for the test, is working on barcoding methods to increase the number of samples per run. 
 
GeneDx developed the test on the “Classic” Genome Analyzer it owns and has not decided yet whether it will upgrade to a GA II. “It’s a business decision,” Kamath said. “If the throughput is beneficial, then we will do it.”
 
HCM is a relatively common genetic disease marked by a thickening of the heart muscle. It affects about 1 in 500 people in the US and is often diagnosed by an echocardiogram that reveals hypertrophy of the left ventricle.
 
However, HCM is often asymptomatic, especially in younger people, and therefore goes undiagnosed. Several genetic tests have recently become available to confirm a diagnosis and to test individuals with a family history of HCM who are at risk for the disease. HCM is the most common cause of heart-related sudden death in young adults.
 
Over 200 HCM mutations in more than 10 genes encoding components of the cardiac sarcomere — the basic contractile unit of a heart muscle cell — have been identified to date.  
 
According to Kamath, GeneDx chose the condition because it is common and serious enough to have a diagnostic need, and because it requires sequencing multiple genes, “which would be very expensive using traditional methods.”
 
Using the Illumina platform, “we are able to sequence a larger number of genes in a very short period of time at a very low cost,” he said. The price, he added, is “significantly lower than [what] our competitors charge.”
 
At least three other testing labs already offer commercial genetic tests for HCM, according to their websites. These tests are based on Sanger sequencing, or a combination of microarray-based resequencing and Sanger sequencing, of multiple HCM-related genes.
 

“The reason we are investing in this is that we believe that this particular platform can be used for many other conditions where mutations in any one of a large number of genes cause a specific clinical condition.”

Correlagen Diagnostics, a genetic testing company based in Waltham, Mass., launched several HCM tests in July of 2007, though a company official told In Sequence that the firm has “been doing full sequencing for HCM for 18 months.” The company offers single-gene tests for one of 10 genes, or multi-gene tests of several of these. Each test, which involves sequencing the genes’ exons, has a typical turnaround time of one to three weeks. Specific pricing information for the tests was not available, though the official said that the “average charge to a patient with insurance is $500 to $700.”
 
PGxHealth, a division of Clinical Data, released its HCM test in May. The test, part of the company’s Familion brand of genetic tests for cardiac syndromes, involves sequencing all exons of nine cardiac sarcomeric genes at a price of $5,400. In its press release, the company points out that its test, which has a clinical sensitivity of 50 to 60 percent, is the only one that includes the Troponin-C gene. Results for genetic tests are generally available within four to six weeks, according to PGxHealth.
 
The Laboratory for Molecular Medicine at Harvard Medical School – Partners Healthcare Center for Genetics and Genomics has been offering HCM testing since March 2004. The lab’s current test, called HCM CardioChip test, combines array-based resequencing and Sanger sequencing. It examines coding regions and splice sites of 158 exons from 11 genes that are involved in HCM using the Affymetrix GeneChip platform and analyzes one of these genes by Sanger dideoxy sequencing. In addition, any genes for which the array shows a mutation or an ambiguous result are followed up by dideoxy sequencing. The complete test costs $3,000, the turnaround time is five weeks, and the test has a detection rate of 50 to 60 percent among patients with clinically evident HCM.
 
At present, GeneDx has made its HCM test available to a small number of undisclosed cardiomyopathy experts to gain experience for the test’s launch this fall.
 
According to Barry Maron, director of the Hypertrophic Cardiomyopathy Center at the Minneapolis Heart Institute Foundation and one of the early-access experts, GeneDx’s test is comparable in reliability to diagnose HCM to existing genetic tests. Its success will rely on a number of factors, including its cost and whether it will be covered by health insurance, he told In Sequence this week.
 
Genetic testing for HCM is “a powerful tool” he said, used to ascertain diagnoses of the disease when other clinical tools fail, and to determine whether family members of a patient are affected even before they develop clinical symptoms.
 
He noted, though, that none of the tests is exhaustive and that as new genes involved in HCM are identified, testing panels will need to be expanded.
 
Kamath declined to estimate the market size for its HCM test but said that initially, the test is geared at cardiologists who specialize in the disease. However, he said “we do believe that over time, the general cardiologist who suspects that the patient has an inherited condition will probably send out the test.”
 
Following the HCM test, GeneDx plans to launch a test for dilated cardiomyopathy, though it has not yet determined the number of genes to be assayed. Also on the list are tests for non-compaction cardiomyopathy and arrythmogenic right-ventricular dysplasia.
 
Additional tests for other inherited diseases involving multiple genes will follow, according to Kamath.
 
GeneDx is on track to be among the first testing laboratories to commercialize a genetic test based on a next-generation sequencing platform, though several institutions and companies are also working on such assays.
 
Correlagen, for example, is “working aggressively with next-generation sequencing technology,” David Margulies, the company’s CEO, told In Sequence by e-mail this week. He did not elaborate.
 
According to Margulies, “there is no particular advantage of using [next-generation sequencing] for an oligogenic test such as HCM. The bioinformatics around NGS are challenging and will slow adoption, but are ultimately manageable.” The challenge of HCM testing, he said, is to “manage novel variants” and provide accurate interpretations to clinicians. “The sequencing method is independent of this challenge.”
 
Another company, Myriad Genetics, has been using 454 Life Sciences’ sequencer for about two years as part of agricultural research projects. The company is now developing 454-based testing products for cancer personalized medicine (see In Sequence 3/11/2008) but has not yet announced any commercial tests.
 
And earlier this month, Roche Diagnostics, which owns 454, said that researchers at the Oxford Biomedical Research Centre, a partnership between the Oxford Radcliffe Hospitals NHS Trust and the University of Oxford, will evaluate the 454 platform for clinical genetic testing, in particular for sequencing several genes harboring familial mutations and, in combination with Roche NimbleGen capture arrays, to screen for mutations in larger numbers of genes (see Short Reads in this issue).
 
Last month, Roche said that researchers at the Blood Center Linz in Austria have acquired a 454 GS FLX that they plan to use to make human leukocyte antigen, or HLA, typing “significantly quicker and more efficient” (see In Sequence 7/1/2008).
 
GeneDx decided more than a year ago which second-generation sequencing platform to choose for its internal development. At the time, the company sent samples for sequencing to Illumina, 454 Life Sciences, and Applied Biosystems and compared the technologies in terms of ease and cost of sample preparation, sequencing, and analysis, according to Kamath. “Solexa, for our applications, turned out to be the most appropriate,” he said.
 
“The disadvantage [of being first to market] is that we had to select a platform a year ahead of anybody else. Therefore, the rest of the industry will benefit from what we learned,” he added.
 
The company will keep an eye on new developments in sequencing technology but is unlikely to switch platforms in the near future. “It’s very painful to switch, because now you have to revalidate the whole process,” Kamath said. “Switching technologies is a serious consideration, and we would only do that when things change significantly in the market, and I don’t believe things have changed that much.”
 
GeneDx, based in Gaithersburg, Md., offers genetic testing for rare and complex hereditary disorders. Most of its tests involve DNA sequencing, according to its website.
 
Bio-Reference Laboratories, which is based in Elmwood Park, NJ, and says it is the largest independent regional clinical laboratory servicing the greater New York metropolitan area, acquired the company in 2006 for approximately $17 million.
 
In 2005, GeneDx had about $5 million in revenues, but its annual revenues “have grown substantially,” according to Kamath, who said Bio-Reference Laboratories does not break out revenues by business unit.
 
During its last fiscal year, which ended Oct. 31, 2007, Bio-Reference Laboratories had $250 million in total revenues. During its fiscal 2008 second quarter, it booked $75.2 million in revenues.
 
Bio-Reference Laboratories CEO Marc Grodman said in a statement last month that GeneDx’s fiscal 2008 second-quarter revenues had increased 80 percent year over year.
 
The company said it has invested “substantially” in infrastructure, marketing, and R&D for its GeneDx genetic testing and GenPath oncology laboratory units “in order to take advantage of growth opportunities in those markets.”
 
“While these investments may have an impact on near-term margin growth, they are critical to secure the long-term value of Bio-Reference,” according to Grodman.
 
“We have invested in the development of new testing platforms at our GeneDx division because of our belief in the value of genetic testing,” he said.

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