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GeneDx Adds Diagnostic Exome Sequencing to Portfolio; Says Disease Gene Panels Still Have Role


By Julia Karow

Although GeneDx is planning to launch a diagnostic exome sequencing test to provide answers for patients who have gone through a "diagnostic odyssey", the company does not believe exome sequencing will replace more focused disease gene panels anytime soon.

GeneDx, a subsidiary of Bio-Reference Laboratories, said last week that it will start offering its XomeDx test early next year (CSN 10/12/2011), accepting requests to receive the test Jan. 3.

The test is offered for patients who have gone through "all the routine diagnostic tests" with no definite molecular diagnosis, and GeneDx may recommend other tests first if they have not yet been exhausted, according to its website.

The XomeDx test does not only include exome sequencing, but also mitochondrial DNA sequencing, and in some cases array-based copy number variant analysis, according to Sherri Bale, GeneDx's managing director.

Exome sequencing will be performed on the Illumina HiSeq using a capture method that is still being finalized. At the moment, between 80 percent and 95 percent of the exome is expected to be captured by the test, though this number might improve over time, Bale said.

For the analysis, the company has been developing algorithms that sequentially filter variants based on the patient's family history and the probable inheritance pattern of the disease, and is in the process of automating these. Company scientists are also working on bioinformatic methods to identify deletions that are not picked up by CNV arrays.

The test, which is prescription-only and requires a "more detailed" consent than GeneDx's other genetic tests, is expected to have a turnaround time of around three months, which does not include confirmation of clinical variants by Sanger sequencing.

Depending on the family structure and inheritance mode, the company may sequence the exomes of several family members — for example of the patient and his or her parents, or of several affected members.

The price of the test — including sequencing, analysis, and interpretation — will likely be on the order of $5,000 per sample, which Bale said is in line with what other labs have said they are planning to charge for similar tests.

The company states on its website that it does not yet know whether or when XomeDx will be covered by insurance.

Although GeneDx has not pinned down its own costs yet, the lion's share will be in the interpretation. While the bioinformatic variant analysis is expensive to develop, it will be inexpensive to run, but the interpretation will require the expertise and experience of clinical geneticists. The company is using tools like PolyPhen to help streamline the interpretation, but there is currently nothing to replace the analytical abilities of a human expert, Bale said.

In fact, GeneDx, which employs about 20 board-certified clinical geneticists with different specialties, sees its strength in its expertise with rare disorders — a capability that Bale said is not available from sequencing services that merely provide a list of filtered variants.

"I don't want to see people spend $5,000 and get something that's filtered against the OMIM genes, and that's all you get," Bale said, referring to the Online Mendelian Inheritance in Man database. "I hope that people understand that this is still not a purely technical exercise. There is a lot of intellectual thought and background that people need to have to be able to do a clinically relevant analysis and give actionable information back to the physician."

The company will not report incidental findings that are not related to the patient's phenotype, she said.

While GeneDx does not know yet how many XomeDx tests it will run next year or whether insurance will reimburse for it, it plans to limit the cases it takes on to a couple per week initially in order to insure a fast turnaround time, Bale said.

The company is in the process of validating the test and is still changing aspects of it — for example capture or indel analysis methods — as they improve. "The gold standard is not yet set, and we want to be able to come out with something that is useful to patients," she said.

Validation includes running samples with different types of variants that GeneDx has previously analyzed to see if the exome analysis pipeline picks them up, too.

The fact that the capture efficiency is currently only between 80 percent and 95 percent of the exome is a limitation of the test, Bale said, but many other clinical tests are also not 100 percent sensitive. For example, she noted that an existing test for Gorlin syndrome that involves sequencing and deletion testing of a single gene, PTCH, is only about 75 percent sensitive, probably in part because the gene's introns are not included in the analysis.

Exome vs. Gene Panels

Bale said she does not believe the exome test will replace focused disease gene panels anytime soon. At the moment, GeneDx offers close to 20 diagnostic gene panels that use next-generation sequencing, including several for cardiology and mitochondrial disorders.

The difference between these panels and the XomeDx test is that the genes in the panels are sequenced 100 percent, meaning that areas of low coverage or low-quality reads are filled in with Sanger sequencing. For the exome, on the other hand, the missing 15 percent or so are not supplemented by Sanger, as that would drive up the cost significantly.

For focused clinical phenotypes, sequencing subsets of genes completely would be the preferred approach, she said. While it would be possible to focus only on the genes of interest in an analysis of the exome sequence, that would increase both price and turnaround time.

"At the moment, I don't think that … the exome is going to replace the panels," she said. This might change if panels get up to 150 or 200 genes, she said, but for the current panels of 20 or so genes, targeted sequencing will likely prevail.

GeneDx is not alone in offering diagnostic exome sequencing. Ambry Genetics, for example, launched a similar test, called Clinical Diagnostic Exome, earlier this month (CSN 10/5/2011).

Have topics you'd like to see covered in Clinical Sequencing News? Contact the editor at jkarow [at] genomeweb [.] com.

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