By Monica Heger
Emory Genetics Laboratory recently began offering sequencing-based genetic testing for X-linked intellectual disability, congenital muscular dystrophy, and congenital disorders of glycosylation. Additionally, over the next two to three months, Emory plans to add sequencing-based genetic testing for other diseases including mitochondrial diseases, prostate cancer, hearing loss, cardiomyopathy, and various types of mental retardation, In Sequence has learned.
The Emory Genetics Laboratory, housed within the Department of Human Genetics at Emory University School of Medicine, is performing the sequencing in its CLIA- and CAP-certified laboratory on Applied Biosystems' SOLiD in combination with RainDance capture technology. For each disease, they will sequence the targeted genes to between 30- and 100-fold coverage using single-end sequencing with 50-base reads.
To analyze the results, Emory has partnered with SoftGenetics and will use the company's NextGene software to detect mutations, including large and small deletions, duplications, and SNPs.
Madhuri Hegde, senior director of the Emory Genetics Laboratory, said that the lab has already received its first samples. The tests must be prescribed by a physician and the turnaround time is about 12 weeks, although Hegde said that the time will drop significantly over the next six months as the lab becomes more adept at analyzing the results.
For each of the tests, there is a "comprehensive" option, where all known genes will be sequenced, and more targeted options, which will sequence fewer genes at a lower cost. For instance, Emory is offering three different sequencing options for XLID: a 90-gene panel test for $6,500; a 60-gene panel for $5,500; or a 30-gene panel for $4,500. Similarly, there are two panels offered for CMD, and three for CDG, priced at $5,500 or $4,500.
Hegde said the lab is offering a range of options because often the children will have already had extensive testing, so the full sequencing of all known genes would be redundant.
For the XLID test, "we have also created a gene-selection tool. A physician goes online, puts in the phenotype of the child, and then a gene priority list will pop up," Hegde said. The tool will help physicians determine whether to order the full 90-gene panel, or one of the pared-down 60- or 30-gene panels.
The researchers at Emory partnered with experts in each disease to develop the tests. For the XLID tests, they collaborated with Greenwood Genetic Center; for the CDG tests, they worked with Hudson Freeze, an expert in CDG at Sanford Children’s Health Research Center at the Burnham Institute for Medical Research; and to develop the CMD tests, they worked with the Muscular Dystrophy Association, which also funded the research along with the National Institute of Neurological Disorders and Stroke.
Funding to develop the XLID and CDG tests came from the Collaboration Education and Test Translation program, which is part of the Office of Rare Disorders.
Emory joins a growing number of companies and non-profit organizations that are offering sequencing-based genetic tests for specific diseases. Ambry, for example, currently offers a sequencing test for X-linked mental retardation, and has plans to release a broad screen for multiple genetic diseases sometime in the next few months (IS 5/18/2010).
GeneDx, meantime, offers sequencing-based tests for hypertrophic cardiomyopathy, while the National Center for Genome Resources is developing a carrier screening test for over 400 genetic disorders with next-generation sequencing technology (IS 3/30/2010), and Sequenom is developing a sequencing-based prenatal test for Down syndrome (IS 5/18/2010).
Emory's tests will look for both known and novel variants, and will sequence the entire gene, which is why they will require such deep sequencing, said Ephrem Chin, supervisor of the molecular genetics laboratory at Emory.
"If you are looking at only specific mutations [rather than the entire gene], the test may not be able to pick up any other changes that may be present in the patient sample," said Chin.
Callum Bell, program lead at the NCGR, said that deciding which mutations to report has been controversial among experts and organizations offering testing services. On the one hand, if the test reports only known mutations, it will likely miss important variants, particularly in the case of a rare disease, he said. "The other extreme is reporting everything. And if you have a panel of 400 genes, the report will be thick. Everyone will have something," he said.
He said that the NCGR has not figured out exactly which mutations it will report for the sequencing based genetic screen it is developing, but will likely fall somewhere in the middle of the spectrum.
Bell added that tests for specific diseases, like the ones being offered by Emory, will eventually be overtaken by whole-genome sequencing, due to sequencing's falling price.
"When it costs $1,000 to sequence a genome, why would you take a test that costs $5,000?" he said.
He acknowledged, however, that the interpretation of the genome still poses many challenges, and will be the biggest hurdle in bringing sequencing-based genetic tests to the clinic.
"Many physicians will be ill-equipped to interpret this test for a patient, and I'm not sure that there are enough genetic counselors," he said. Nevertheless, he said the goal was to make sequencing-based genetic tests broadly available, and to have organizations like the American College of Medical Genetics endorse the tests for certain diseases. "We would like to see this become the standard of care," he said.