The Children's Hospital of Philadelphia said last week that it plans to begin offering clinical sequencing services through two different labs. It will offer targeted sequencing-based tests through its Clinical Molecular Genetics Laboratory, as well as exome sequencing through its [email protected] Joint Genome Center, which recently became CAP accredited and CLIA certified.
Avni Santani, the scientific director of the Clinical Molecular Genetics Lab, told Clinical Sequencing News that the lab will offer gene panel tests on both the Illumina MiSeq and Life Technologies' Ion Torrent PGM for a range of disorders including hearing loss, neurological disorders, and cancer predisposition.
Two MiSeqs and one PGM are currently housed in the clinical lab. Santani added that the tests would use both platforms as well as a variety of different capture technologies.
Clinical exome sequencing will be done within the Joint Genome Center on the Illumina HiSeq 2000. The center currently has five machines but plans to eventually scale up to 20. Santani said the team had not yet decided on a capture technology for clinical exome sequencing but is evaluating Agilent SureSelect, Nimblegen, and Illumina's TruSeq.
The services will be broadly available, not just for the patients within CHOP, and will require a physician prescription. Prices for the tests have not yet been determined, but will be comparable to other clinical exome sequencing tests, Santani said.
For instance, the University of California, Los Angeles, offers clinical exomes at $4,500 for an individual or $6,500 for a trio and Ambry Genetics offers clinical exomes between $5,000 for an individual and $7,999 for a trio.
CHOP's exome sequencing test will be used for patients who have already gone through so-called "diagnostic odysseys" to determine the cause of their disease, as well as for first-line testing in patients with multiple congenital disorders in order to avoid such odysseys.
The targeted tests will be used in cases where physicians have made or suspect a certain diagnosis, but want to confirm the molecular basis of the disorder. Additionally, said Santani, many physicians do not want to do exome sequencing because of the added burden of dealing with incidental findings. Such findings are less likely using a more targeted approach.
Catherine Stolle, the director of the Molecular Genetics Laboratory, told CSN that the team is still working on strategies for dealing with variants of unknown significance and findings unrelated to the patient's phenotype.
For unrelated findings, Santani said that actionable variants will likely be returned to the physician. The team is currently working on a list of conditions for which medically actionable variants exist that could be reported back.
Variants of unknown significance are trickier. For instance, said Stolle, if a known mutation is not found with exome sequencing, but a novel variant in a "suggestive pathway" is found, it "creates a clinical dilemma," she said. While the variant cannot be reported as causative, the information is still valuable and "should not be buried."
Stolle said she envisions a scenario for cases like this where the information could be anonymized, and then functional studies could be done within a basic research setting. The challenge in this case, then, is finding the personnel and funding to do the functional studies.
Theoretically, patients' sequencing data could be stored and revisited as new information became available, but storing raw sequence data is not trivial, and could quickly become more costly than the sequencing itself, said Santani.
Santani said that CHOP has not yet figured out exactly what types of information would be stored and for how long. The raw sequence data, because it takes up so much storage capacity, may just be kept on file for a short period of time, after which the raw data could be discarded and the FastQ files stored longer term.
Eventually, said Stolle, it will be cheaper to simply resequence rather than store the data.
Going forward, Stolle said, the lab will consider implementing whole-genome sequencing in a clinical setting, although that would not happen for another several years.
CHOP joins a growing list of academic institutions and commercial companies offering clinical sequencing services. Aside from Ambry and UCLA's clinical exome sequencing tests (CSN 3/7/2012), Emory University also offers an array of gene panels and exome sequencing, while Washington University's Genomics and Pathology Services group and Baylor College of Medicine both offer targeted cancer sequencing and exome sequencing (CSN 2/29/2012 and CSN 11/16/2011).
The Medical College of Wisconsin and Children's Hospital Wisconsin, meantime, is one of the few places to currently offer diagnostic whole-genome sequencing (CSN 8/24/2012).