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Columbia Clinical Exome Test Approved by NY State as Demand for Exome, Gene Panels Grows

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NEW YORK (GenomeWeb) – Columbia University Medical Center's Laboratory of Personalized Genomic Medicine has received final approval from the New York State Department of Health for its diagnostic whole-exome sequencing test for inherited disorders after submitting its application a year and a half ago.

Demand for the exome test, as well as for a targeted diagnostic sequencing test called the Columbia Combined Genetic Panel, has grown over the past year as clinicians from different specialties are getting more familiar with the new options, according to lab representatives.

In several cases, results from the exome test had dramatic consequences, preventing bone marrow transplants that would have been ineffective.

Columbia originally submitted the exome sequencing test, which runs on the Illumina HiSeq 2500 and uses Agilent SureSelect capture reagents, to New York state officials in early 2013 and received conditional approval shortly thereafter.

Last month, the PGM lab received final approval for the test, making it one of the first academic centers in the state with such an offering. Mount Sinai's Genetic Testing Laboratory also received final approval for its whole-exome sequencing test, as well as for its whole-genome sequencing test, in late September.

Other centers are close behind – the New York Genome Center, for example, said in August that it was about to submit an exome test and planned to submit whole-genome and transcriptome sequencing tests later this year.

Final approval from the state for Columbia's CCGP test is still pending, and the lab plans to submit a whole-genome sequencing test by the end of this year.

The CCGP test, which runs on the Illumina MiSeq or HiSeq with Agilent SureSelect capture, covers about 1,300 genes in total. Physicians can choose between 11 panels when they order the test, each comprising dozens of genes, or they can order a custom panel, and only genes in those panels will be reported.

Each panel covers a different disease area, such as autism or hearing loss. Depending on how many panels or genes are ordered, the price of the test ranges between $2,000 and $4,000, which is what insurance companies are billed. Prices might differ for institutions and hospitals that send samples to Columbia on a regular basis and are "very competitive" to prices of commercial laboratories, according to Anthony Sireci, physician manager of the PGM laboratory. The CCGP test has a turnaround time of about two months.

Physicians usually order the CCGP test when a patient's phenotype is pretty well defined and there is a limited number of candidate genes, said Peter Nagy, associate director of the PGM laboratory. When that is not the case, or the CCGP test does not yield an answer, the lab recommends the whole-exome sequencing test, which is more comprehensive but also more expensive – insurance companies are billed $6,000 for the test, which includes sequencing of patient-parent trios.

For the exome test, Columbia guarantees reporting on 95 percent of the regions captured by the Agilent reagents, the so-called "reportable range" of the test, and has a long list of disease-associated genes and mutations that are not covered because they are in the remaining 5 percent. To decrease its false-negative rate, the lab has dropped coverage requirements for calling mutations from initially 15-fold to 10-fold, which it found to be sufficient to make high-quality calls.

The test has a maximum turnaround time of four months, though more than half the results were returned within two months. The lab also is able to expedite the test in urgent cases, such as prenatal samples, to less than two weeks.

It reports secondary findings for about 30 genes associated with either cancer predisposition syndromes or life-threatening conditions, and patients can opt out of such incidental findings. The consent form also offers choices about whether results will go into the electronic medical record, and how long the raw data and DNA samples will be kept.

One feature that sets Columbia's exome test apart from those offered by commercial testing labs is that ordering clinicians are involved in the interpretation of the results during the so-called sign-out session or consensus conference. "We definitely factor in their input very heavily [and] they like it very much," Nagy said. "I do believe that results in greater precision and more relevant results being given back."

Overall, the lab has received orders for about 250 whole-exome sequencing tests and more than 150 CCGP tests, and it expects orders for another 400 tests or so by the end of this year, Nagy said. Following the final approval from New York state, the lab plans to advertise the exome test more widely outside of New York, starting with the American Society of Human Genetics annual meeting next week.

The diagnostic yield for the exome test has been around 25 percent, and cases get reanalyzed every few months, Nagy said. The lab only reports back pathogenic or likely pathogenic variants. "We don't report back anything that we don't feel very strongly could be the cause," he said.

So far, the lab has reported secondary findings in a couple of cases, "but it's not as common as one would have thought," he added.

Among the exome cases were prenatal samples from amniocentesis material, which the lab was able to turn around in less than two weeks. "We don't market ourselves as being able to do that for everyone," Sireci said, but "we're a smaller laboratory that can do that type of stuff."

In several cases, results from the exome test have prevented bone marrow transplants because it turned out that the patient had a syndrome that cannot be treated by a transplant, or because the donor had the same mutation as the proband. "We had multiple cases where we saved the institution probably hundreds of thousands of dollars," Nagy said.

The lab is currently working on speeding up the test interpretation, for example, by letting clinicians put in specific terms, which a computer can match with specific disease descriptions and their associated genes. In addition, it is making its website more user-friendly and is further standardizing test reports and rendering them more accessible to non-geneticists.

In addition, the lab is annotating genes that have not been previously associated with disease based on their associations – either physical or functional – with known disease genes. "We currently do not really have a good way to routinely report out pathogenic mutations that we find in not previously disease-associated genes, but I think that will change in the future," Nagy said.

"Cleaning up" the databases of incorrect information about pathogenic mutations also remains an important task, he added.

Most orders for the CCGP and exome tests have come from Columbia physicians, though some doctors from other institutions have ordered them as well. Pediatric geneticists have ordered the tests most frequently, but users have also included neurologists and ophthalmologists, and test volumes have steadily increased over the last year or so.

After an order comes in, the lab submits it to the patient's health insurance for preauthorization, so patients know about any out-of-pocket expenses before the test is conducted. So far, of the about 450 cases submitted for preauthorization, 59, or 13 percent, have been turned down. "There are insurance carriers who routinely say 'no', and it's not the Medicaid [managed care cases]," Sireci said. "They have actually been very supportive of this type of testing."

In cases where insurance has reimbursed for the exome test, the payment has not completely covered the lab's internal costs, Sireci said, "but we do it because it's important clinically and because it's the test of last resort for a lot of our patients."

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