NEW YORK – As clinical whole-genome sequencing (WGS) is becoming more of a routine diagnostic test for certain patients with genetic disorders, the Broad Institute has launched a new end-to-end WGS and variant interpretation service in partnership with genome analysis company Fabric Genomics.
Priced at $1,000 per sample, the new test promises to be competitive with other offerings in the market while offering better cost transparency.
"We've been offering clinical genome sequencing for many years but without an interpretation," said Heidi Rehm, medical director of the Broad’s clinical sequencing platform and chief genomics officer at Massachusetts General Hospital's department of medicine. "Having an end-to-end service really allows us to help move the field forward in all aspects of genomic analysis."
While not a direct-to-consumer test, the new service caters to any healthcare provider or researcher who needs clinical WGS and data interpretation. According to Rehm, target customers include clinicians ordering genomic tests for patients, scientists conducting clinical research trials, pharmaceutical companies, and academic researchers.
After ordering the test, customers can submit whole blood, saliva, or extracted DNA to the Broad, where the samples are processed by the institute’s CLIA-licensed, CAP-accredited clinical sequencing lab. In addition to these sample types, Rehm said her team is working on accepting buccal swabs.
For a diagnostic test, clinicians also submit any phenotypic information relevant to the patient, which will be used downstream to help with variant interpretation. Rehm said the service currently does not include a “healthy genome” offering, where every genetic element that might put a person at future disease risk is analyzed, but that option will come in the future.
Sequencing of the test is performed using the Illumina NovaSeq 6000 platform, with a minimum of 30X average coverage for each sample and 95 percent of the genome sequenced with at least 20X coverage. As the Broad currently operates multiple Illumina NovaSeq X instruments, Rehm noted that her group is also hoping to transition the test to that new platform down the line.
Following sequencing, the data is processed using pipelines such as Illumina DRAGEN-GATK (Genomic Analysis Toolkit) and Manta Structural Variant Caller to call single-nucleotide variants (SNVs), indels, copy number variants (CNVs), and mitochondrial variants, as well as short tandem repeats (STRs). After that, the variants are transferred to Fabric Genomics' platforms for prioritization and annotation.
For a diagnostic test, Rehm said, the data is analyzed using Fabric’s AI-driven GEM platform to help prioritize and rank the variants based on their match to the patient's phenotype. While the entire genome is analyzed, the diagnostic WGS service only tries to identify the cause of the phenotype, she noted.
"The actual algorithm can help prioritize variants based on how good a match the phenotype is to a gene," she explained. "Those are the kinds of things that enable the process to be quicker and more scalable, even though it still requires geneticists to look at what's been ranked."
For other analyses, such as for secondary findings, Rehm said Fabric’s Artificial Intelligence Classification Engine (ACE) software can automatically classify variants in predefined panels according to American College of Medical Genetics and Genomics (ACMG) guidelines.
Even though incorporating Fabric’s algorithms can help expedite and scale up the data analysis component of the test to some extent, Rehm stressed that the test still relies on human expertise to ensure its quality and accuracy.
"Some of the data can be automated and other data can't," she said. "The algorithm can't go out and interpret functional assays in papers or look at pedigrees … so some of that data we have to add to the case manually." Before the test result is returned to the customer, the final report is reviewed and signed out by a team of board-certified clinical geneticists at the Broad under Rehm's supervision.
The team also offers customized data analysis services to support individual needs for each project. "We anticipate there will be a fair bit of customization to the services that we provide," she said.
Customers can also request that their data be reanalyzed a year after the initial test.
Currently, the turnaround time for the assay, from sample to report, is about four weeks, Rehm said. However, she noted that the team is hoping to decrease this time to support more urgent cases, such as infants in the neonatal intensive care unit.
The Broad has also adopted a transparent pricing strategy. Generally speaking, Rehm said the price for the WGS test including targeted variant interpretation is $1,000. For trio sequencing, the test is priced at $2,500 for all three samples.
"One of the ways that we bring the price down is [by filling] all of our instruments to capacity," Rehm said, claiming that the test is cheaper than similar assays from commercial labs. "We have a huge volume every week."
However, she noted that because the test does not involve third-party billing, the Broad cannot accept health insurance. "A lot of the routine clinical care business today competes significantly on the ability to do third-party billing," she said. "I actually don't think it's likely that we will capture as much of the single-patient diagnostic testing and instead primarily contract with larger projects."
While her team "endeavor[s] to partner and work with exciting clinical opportunities," the largest business opportunity for the new test is likely to be clinical research programs, she said. Moreover, the test can be an attractive option for patients who are paying out of pocket, given its relatively low cost and transparent pricing, Rehm noted
A number of commercial laboratories have already been offering clinical WGS services with variant interpretations. GeneDx, for instance, currently offers whole-genome and rapid whole-genome sequencing services, both including variant analysis.
According to a GeneDx spokesperson, the turnaround time for the company’s rapid testing is an average of five days for verbal diagnosis followed by a written report issued within 14 days. For non-rapid testing, the turnaround time is six to eight weeks. For genome testing, the firm accepts blood samples for patients and blood or buccal samples for relatives.
GeneDx also said it has contracted with “many hospitals and health systems for genomic testing” and has seen “an increase in commercial coverage for genome testing, including the most recent coverage announcements from UnitedHealthcare and Cigna.” The company did not disclose the price for its whole-genome tests but said it has a patient assistance program that "will work with patients" to cover out-of-pocket expenses.
Illumina Laboratory Services, Illumina’s CAP-accredited, CLIA-certified clinical sequencing branch, also offers a clinical whole-genome sequencing test, for patients with rare and undiagnosed genetic diseases, with full interpretation and clinical report.
An Illumina spokesperson noted that the test, named TruGenome Undiagnosed Disease Test, is offered to institutions that provide a physician test order — such as hospitals, clinical labs, and institutions with an institutional review board (IRB) — to help with the diagnosis of rare and undiagnosed genetic diseases. The service accepts blood samples and can return the interpreted results within 14 days of the sample's arrival, but Illumina also did not disclose the price of the test.
Currently, the Broad has one signed contract for the new service while others are in the process, Rehm said. As the institute continues to offer the test to more and more customers, Rehm said her team plans to expand the content of the assay, adding pharmacogenomics and a broader array of panel options, for instance. In addition, the team will continue to validate and add other variant types that are not currently available as part of the test, including tandem repeat expansions.
Besides short-read sequencing, Rehm said her group is also exploring long-read sequencing technologies to develop a potentially more cost-effective way to confirm copy number variations (CNVs) and other structural variants.
Furthermore, the team is working to add optional RNA sequencing to the test, given that the transcriptome can help with the interpretation of certain variants.
Rehm said her team is also hoping to establish a framework to enroll participants whose WGS test comes back negative in the Broad’s vast research network.
"It is my hope that there'll be a nice flow of subjects from the clinical service into our research service," she said. "Patients who test negative but have a high suspicion for genetic disease will have the opportunity to enroll in our research programs where we can use other techniques."