The National Center for Genome Resources has teamed up with the Beyond Batten Disease Foundation to develop an inexpensive carrier screening test for approximately 400 rare genetic disorders, possibly using second-generation sequencing.
The partners are still deciding whether to run the multiplex test on an array-based or a sequencing platform, a decision they plan to make in the near future. Second-generation sequencing, in which NCGR has considerable in-house expertise, is a strong contender, according to the foundation. Factors in the decision include the complexity of the test and the technical feasibility of multiplexed, targeted resequencing.
The goal of the project is for NCGR, a non-profit genomic research institute based in Santa Fe, NM, to develop and validate a single carrier genetic test for about 400 rare or orphan diseases for which the genetic defect is known, with the hope that it will be adopted widely by women, and by their partners prior to pregnancy.
The panel will almost exclusively test for autosomal recessive conditions, such as cystic fibrosis, which afflicts 30,000 people in the US, and Batten disease, a fatal neurodegenerative disorder that affects several hundred children in the US, and for which no treatment is available today.
"We plan to eradicate these and other [diseases] through prevention, [through] this carrier screening panel," said Craig Benson, president and CEO of Rules-Based Medicine of Austin, Tex. Benson recently founded the Beyond Batten Disease Foundation with his wife after their daughter was diagnosed with Batten disease last year.
Besides funding and helping to develop the multi-disease carrier test, the foundation also plans to sponsor research towards a treatment for juvenile Batten disease. It has already obtained several million dollars in funding commitments for these projects.
The foundation expects to offer the test through a non-profit, CLIA-certified testing lab at a low cost — the aim is under $250 — as early as next year. Benson hopes that it will become part of the first routine visit of a young woman to the gynecologist, and will also be used by their partners prior to pregnancy if they turn out to be carriers for one of the diseases.
NCGR and the foundation came together through Mark Chandler, CEO of Austin-Based Biophysical Corporation, who sits on the board of directors of both NCGR and Rules-Based Medicine.
NCGR's expertise with DNA analysis and Benson's background in biological testing made the pair a good match, according to Benson. "We have a lot of experience with CLIA labs and rolling out a testing services operation and diagnostics," he said.
According to Stephen Kingsmore, president of NCGR, the project is "the logical extension" of the center's research in genomics over the last few years, taking it in a more translational direction. "Unlike a university genome center, we have the flexibility to be able to go in that direction and create either a new entity or have that be a new operating part of NCGR," he said.
Until a few years ago, NCGR focused on bioinformatics research. But in 2007, the center started investing in second-generation sequencing technology and runs a genome center with six Illumina Genome Analyzers today (see interview with Greg May, director of the genome center, in this issue).
Developing and introducing the carrier test will likely cost several million dollars, according to Benson, though the final budget has not yet been determined. He declined to reveal how much funding NCGR is receiving under the partnership.
So far, the partners have assessed the field and determined the first 100 or so diseases, prioritizing them based on how serious and how prevalent they are, according to Kingsmore.
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NCGR researchers are currently conducting pilot projects in order to determine whether to develop the test on a microarray or a sequencing platform.
For example, they have looked at the allelic variation of the genes mutated in each of the diseases as one factor that will determine which platform is more suitable.
"If the average disorder has 10 or 100 allelic variants, it becomes very difficult to design an array that's going to comprehensively test for those, and it probably makes more sense to do targeted sequencing of those genes, both exonic and intronic regions," Kingsmore said.
Another factor in deciding which type of platform to use is technical feasibility. Array-based genotyping platforms are "well established," he said, whereas with sequencing, "there are still some issues we need to look at," including the feasibility of multiplexing and targeted selection of DNA for sequencing.
Both of these are "still really new, and still really 'researchy'," Kingsmore said. "We have to spend, probably, a month or two looking at feasibility and really understand whether sequencing is ready for that."
Multiplexing by barcoding, he explained, is necessary to ensure the cost for the test is low. "If you could run in a single channel, say, of an Illumina GA II, 64 samples, you could see how you could get that to be a test that you could offer for $100."
And while several companies — including Roche NimbleGen, Agilent Technologies, and RainDance Technologies — are starting to offer kits for selecting DNA regions, these need to be compatible with barcoded sequencing, introduce little bias, and offer "substantial" enrichment, according to Kingsmore.
In principle, he said, the test could run on any of the existing second-generation sequencing platforms, but NCGR's in-house experience is with the Illumina Genome Analyzer. "We are really happy with the Illumina sequencing system, and this particular test — the way it would be configured — would fit very well with that," Kingsmore said. "If we wind up continuing to develop the test for [the] Batten [Foundation], and if it is a sequencing test, we would push for Illumina, just because we are very experienced in that."
According to Benson, the partners are leaning towards a sequencing platform. "My guess, as we sit here today, is that we will go down the sequencing route," he told In Sequence this week.
If that is the case, the carrier test would be one of the first medical applications of Illumina's sequencing technology. Last October, genetic testing company GeneDx launched a test for hypertrophic cardiomyopathy that runs on the Illumina Genome Analyzer (see In Sequence 7/22/2008). The test involves sequencing 150 exons, including their splice junctions, from 17 genes, amplified by multiplexed PCR. Potential mutations are then verified by Sanger sequencing.
The company plans to offer similar test panels for dilated cardiomyopathy and arrhythmia in the near future, according to its website.
"To our knowledge, there is no one else using this or another next-gen platform in a clinical setting," Yuriy Shevchenko, director of research and development at GeneDx, told In Sequence by e-mail this week.
Once Kingsmore and colleagues have determined the technology platform, the next step for NCGR will be to develop the test for 75 conditions and validate it on 1,000 DNA samples from carriers and controls.
The aim is to develop and validate a test for up to100 diseases by the fall, and to expand it to the entire panel of about 400 diseases by early next year, according to Benson.
To do this, the Beyond Batten Disease Foundation plans to team up with other foundations that focus on specific rare diseases that will be included in the test. Not only could they help promote the test to physicians, patients, and payors, Benson said, but also help the researchers gain access to DNA samples of disease carriers to validate the test.
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He said the foundation is also currently negotiating with institutions interested in housing the non-profit CLIA lab, and hopes to come to an agreement within the next few months.
According to Kingsmore, no multiplexed genetic carrier tests are available today other than for the Ashkenazi Jewish population, where certain genetic disorders, like Tay-Sachs disease, are more common than in other populations. "By and large, there is nothing like what we are describing," he said.
"In the US, patients and doctors would probably readily adopt such tests," said Harry Ostrer, director of the Human Genetics program at the New York University Medical Center, in an e-mail message. "The biggest challenge is going to be getting around certain patents that are being enforced and that drive up the cost of testing," he said. Ostrer added that his molecular diagnostics laboratory is also working on an inexpensive multiplexed genetic test.
Benson said the foundation is aware of patent issues, "but we believe we will be able to favorably resolve these issues before launching."