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Partners HealthCare Launches Clinical WGS Test; Clinical Exome to Follow Later this Year

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After two years of development, Partners HealthCare launched a clinical whole-genome sequencing test for rare genetic disorders this summer and plans to offer a lower-priced clinical exome test by the end of the year.

The genome sequencing test, which has been in the making since 2011 (CSN 6/15/2011), is available through the Partners Laboratory for Molecular Medicine and can be ordered by doctors across the US. The LMM recommends it for patients with a suspected genetic disease where existing genetic tests have either failed to come up with an answer, or are unlikely to do so.

The test costs $9,000 for a single genome, or $18,000 for a parent-child trio, an option that is recommended if a de novo mutation is suspected as the disease cause.

In addition, the LMM provides an interpretation-only service of genome or exome sequencing data from other CLIA laboratories for $5,000 for one or more family members.

The lab has not yet billed any health insurance providers for the test, but according to Heidi Rehm, chief laboratory director of the LMM, other laboratories have found that clinical exome tests are often reimbursed when there is a documented medical need.

The turnaround time of the genome test is expected to be at least 16 weeks, depending on the lab's case load, but the LMM can prioritize urgent cases when a result is needed quickly to decide on a treatment.

Sequencing for the test is performed at Illumina's CLIA-certified laboratory in San Diego, currently the only provider of CLIA whole-genome sequencing services, according to Rehm.

Illumina sequences the genomes on the HiSeq platform, using 100-base paired-end reads, to at least 30x mean coverage, such that at least 95 percent of bases are covered at least eight-fold.

The LMM then analyzes the data and interprets the results, which includes read alignment, variant calling, variant annotation, and data filtering. Variants that are reported back are confirmed by an orthogonal method like Sanger sequencing, and the raw data is stored by Partners HealthCare for at least two years.

Ordering physicians receive two reports, a primary report with findings related to the patient's condition and symptoms, and a so-called General Genome Report with secondary or incidental findings that may not be related to the patient's disorder but still have potential medical value.

Rehm said the general report includes all variants recommended by the American College of Medical Genetics and Genomics earlier this year (CSN 5/8/2013) – recommendations she co-authored – as well as variants with medical relevance in "thousands of other genes." These include risk factors for highly penetrant monogenic diseases, carrier status for recessive disorders, pharmacogenomic markers, and blood group type.

While the full genome report is the default option, patients can choose to obtain only the incidental findings recommended by the ACMG – variants in about 60 genes related to 24 conditions. If patients opt out of that as well, the lab will document their reasons for further study.

Patients can obtain a copy of the sequence alignment files for a small fee to cover the cost of the hard drive, so they can obtain a second opinion from another data interpretation service or enroll in a research study, particularly if the LMM analysis was inconclusive.

Rehm said Partners HealthCare's clinical whole-genome test is likely very similar to the one offered by the Medical College of Wisconsin (CSN 5/22/2013), which initially used Illumina's CLIA lab for sequencing but has since moved to in-house sequencing, but she noted that LMM's test might offer a broader incidental findings report.

Besides offering it as a diagnostic test, the LMM is applying its genome sequencing test to the MedSeq study, a project led by Brigham and Women's Hospital that is funded with $9.6 million from the National Human Genome Research Institute under the Clinical Sequencing Exploratory Research Project program (CSN 1/4/2012). In total, the lab will sequence the genomes of 100 probands for MedSeq, half of them healthy, the other half suffering from cardiomyopathy.

In addition, the LMM will provide genome interpretations for a pilot project on sequencing-based newborn screening led by BWH and Boston Children's Hospital that was recently funded by the National Institutes of Health (CSN 9/4/2013).

Rehm said the LMM started to offer the clinical genome test in early July, initially only to its internal physicians. So far, it has completed about 10 cases, most of them for the MedSeq study, and another 15 or so cases are in the queue.

So far, her team has completed the analysis for three clinical cases. For two of those, a family afflicted by hearing loss and a patient with distal arthrogryposis type 5, they were able to find causative mutations (CSN 6/26/2013), and for the third, they have identified a candidate gene. While the gene defects causing the hearing loss were already in the literature, the arthrogryposis results were new.

Right now, the LMM has capacity to analyze about 10 cases per week, though the testing volume will likely be lower at first. The lab expects to analyze more than 100 patient genomes during the first year.

The LMM is also developing an exome sequencing test, both in house and in collaboration with the Broad Institute, which it plans to launch by the end of the year. The main advantage of that test will be its lower cost, Rehm said.

At the time the LMM decided to develop the whole-genome test, "we made the assumption that sequencing costs would continue to drop, and that by the time we launched our platform, the cost of the exome and genome would not be significantly different," she said.

However, sequencing costs have not dropped much over the last two years, and "there is still a pretty reasonable difference in the cost between a genome and exome," she added. "For that reason, we decided a number of months ago to pursue an exome platform."

Once both tests are available, the exome test might be used more often for analyzing parent-child trios, whereas the genome test might be more popular for genomes of single patients, Rehm said.

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