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UMDNJ Offering CF Carrier Screening and Mitochondrial Testing on Ion Torrent; Plans to Add More Tests


The University of Medicine and Dentistry of New Jersey's Institute for Genomic Medicine is now offering two sequencing-based tests: one for cystic fibrosis carrier testing and another to identify mutations in the mitochondrial genome of children suspected of having a mitochondrial disorder.

Researchers at the university developed the two tests to run on the Ion Torrent PGM and expect to develop additional carrier screening tests and other diagnostics in the near future, according to the institute's director, Marvin Schwalb.

The group's CF carrier screening test is based on a targeted panel that covers the coding regions of the CFTR gene and includes around 1,000 of the disease's most well-defined causal mutations.

For mitochondrial diseases, the institute is offering a sequencing test covering the whole mitochondrial genome.

Schwalb told Clinical Sequencing News that the Ion Torrent sequencer has enabled the group to dramatically reduce the cost of CF testing from several thousand dollars per test using traditional nucleic acid amplification methods to an estimated $200 per test.

"Using the Ion Torrent system, their smallest chip … is $99," Schwalb said. "[But] we can put 16 [cystic fibrosis] samples on there, so the chip itself now becomes a minor cost."

Schwalb noted that the American College of Obstetrics and Gynecology recommends CF carrier screening for all pregnant women. "It's a very common test. For any one hospital, getting 16 samples at a time is no big deal, so we really can fill up the chip," he said.

According to Schwalb, the UMDNJ group has been involved in cystic fibrosis testing since the identification of the first causal mutations in the disease. Adapting the team's previous CF mutation testing method, which was based on Luminex beads, to the Ion Torrent was "not particularly difficult," he said.

Schwalb acknowledged that ACOG's guidelines do not recommend sequencing-based carrier screening because of the potential for false positives. To address this issue, he said the UMDNJ group designed its target capture strategy to limit sequencing to only the coding regions of the gene, which harbor around 1,000 of the most definitive causal mutations in the disease.

"There are so many polymorphic variants and things that are difficult to interpret [if you sequence the whole gene]," Schwalb said. "So our computer program only looks at the little over 1,000 mutations that are absolutely known in the international database. [Also] some regions are left out because they are intronic regions … It just doesn’t make sense to bother sequencing areas that have no chance of producing a mutation that fits our tight criteria."

As a result, the test is "98 percent and not 100 percent sensitive," he said. "[Statistically,] we'll miss one, once every couple of years ... but it was necessary to make sure we only evaluate known mutations."

According to Schwalb, as new mutations are added to the database, it will be easy for the group to update the test, potentially increasing accuracy even further over time.

The test's 98 percent detection rate is an improvement over the ACOG-recommended 23-mutation panel, which has a detection rate of around 88 percent for the non-Hispanic white population. Furthermore, the sensitivity of the 23-mutation panel varies widely among different ethnic groups, ranging from less than 50 percent in the Asian American population to 94 percent in the Ashkenazi Jewish population, according to ACOG.

As a result, the improved rate of the UMDNJ test "is particularly valuable for minorities," Schwalb said in a statement.

The UMDNJ group is not the first to offer sequencing-based CF screening. Good Start Genetics announced last year that it would offer sequencing-based carrier testing for cystic fibrosis as part of a larger preconception carrier testing panel. The company reported at the time that its CF test would target "hundreds" of pathogenic variants (CSN 10/26/2011).

While the primary purpose of the UMDNJ's CF test is currently carrier screening, Schwalb said it is possible the institute could also offer diagnostic testing with some tweaks to procedure and pricing.

"The practical reality of carrier screening is that most of the time the result is negative, he said. But when you are looking at diagnosis, you usually have to spend an hour looking at the data and making sure you have the correct evaluation," he explained.

"We anticipate getting enough samples, [though,] to fill a couple of chips every single week [just for carrier screening]. So adding a rare sample for diagnosis is no big deal," he said.

For the group's mitochondrial disorder test, Schwalb said the price tag will be higher, because it will likely only be running one sample at a time due to the relative rarity of this type of testing.

Schwalb said his team has been doing mitochondrial mutation analysis for issues like optic neuropathy for a long time, and occasionally for newborn screening targeting specific mutations. "We have a clinical genetics program and [we] are the reflex testing lab for New Jersey for newborn screening that the state does," he said.

When problems pop up that look like they are mitochondrial, Schwalb said there is a "tremendous limitation in getting them analyzed because the sequencing is so expensive." However, he said his group will be able to sequence the whole mitochondrial genome with the Ion Torrent for about $500.

According to Schwalb, the institute is currently offering both tests, first for in-house and then in-state patients, but hopefully in the future for a broader population through partnerships with other institutions.

He said the team is planning to incorporate some new equipment for automation, which will allow it to sequence more samples.

The group is also developing additional sequencing-based tests, Schwalb said. "We are aware of the fact that there are lots of [diseases] that could use sequencing either because [they involve] many mutations, or they are relatively uncommon and don't have a test currently," he said.

Currently the team is working on four new tests. Schwalb declined to detail these next offerings, but said the group is generally interested in additional newborn screening tools, in blood disorders like hemophilia, and in cancer.

"The biggest problem for these, [at least for] relatively rare disorders," he said, "is getting positive samples. We have these four [new tests] up and running. We're just searching for samples to test them."

Researchers from the group will also be looking for outside input on other diagnostic areas of need. "Clinicians will come up with things that we don’t think about," Schwalb said.

"When I present this sequencing story [in grand rounds], I'm going to [list] all the tests we are doing [and] developing, and then the last line will say 'and anything else you want,'" he said.

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