NEW YORK – Baylor College of Medicine (BCM) this month launched a new medical research laboratory dedicated to developing multiomic clinical assays in collaboration with Baylor Genetics.
The Medical Genetic Multiomics Laboratory (MGML) is a CLIA-certified and CAP-accredited clinical lab within Baylor College of Medicine's Department of Molecular and Human Genetics. Baylor Genetics and that department recently signed a lab agreement under which the MGML and Baylor Genetics will jointly develop tests that Baylor Genetics can exclusively offer commercially.
In the event that Baylor Genetics — itself a joint venture of BCM and Japanese clinical diagnostics firm H.U. Group — decides not to commercialize a test, the MGML may still offer it for research use only.
The MGML plans to take on projects with great potential clinical impact but that may be considered high risk for not initially having a large market due to the tests' cutting-edge nature.
"The lab agreement is the product of what has been done informally for [some] time, but now formalizes the process," said Brendan Lee, professor of molecular and human genetics at Baylor College of Medicine and chair of the Department of Molecular and Human Genetics.
Although the MGML will develop tests for commercial ends, the lab itself is an academic institution and receives its funding from traditional sources such as public grants and philanthropic donations, and directly from collaborators such as Baylor Genetics, on a per-project basis.
In this respect, the MGML functions similarly to the Broad Institute's Broad Clinical Labs, which is also a CLIA-licensed and CAP-accredited clinical lab housed within the Broad Institute, but focuses on offering lab services to customers rather than developing new assays.
The MGML recently launched its first clinical test, Whole Transcriptomic RNA Sequencing (WT RNAseq), and provides it to the Undiagnosed Diseases Network (UDN) through Baylor Genetics.
The test analyzes all RNA transcripts for outliers –– transcripts with unusually high or low expression compared to controls, or with unusual isoforms.
"The transcriptome is quite complex," Lee said. "There could be over 100,000 isoforms that derive from [our] 20,000 genes. If a gene is expressed at a much-reduced level, it may reflect a variation or a mutation in that gene that's deep [inside an intron], or because of a structural variation that was missed."
For a firm diagnosis, however, any gene identified by the assay would have to be analyzed via another method, such as whole-genome or whole-exome sequencing.
"The greatest value of such an independent analysis is that it can point to a gene not previously associated with the disease being tested for and could lead the way to new research studies to establish this new gene-disease correlation," Lee said.
He cautioned, however, that it remains best practice to order whole-transcriptome sequencing either after a negative WGS or WES test or in parallel with one, as WT RNAseq results alone are insufficient for making a diagnosis.
Nonetheless, Lee expects that complementing other genomic testing with WT RNAseq can increase diagnostic yields.
"This assay fills a critical space for cases where DNA-based tests have not provided answers, enabling a deeper exploration of the molecular basis of diseases," May Malicdan, associate investigator for the National Human Genome Research Institute and the UDN, said via email. "Overall, it is [likely] to increase the diagnostic rate."
Lee said that with certain challenging cases, such as diagnosing a child with developmental delay, clinicians might find a diagnosis in roughly 25 to 30 percent of cases, possibly due to structural variations in gene products, rearrangements, and rare isoforms that are missed using whole-genome and whole-exome sequencing.
Malicdan said that the UDN initially began using the WT RNAseq assay as a research tool, "its success in uncovering elusive diagnoses has led to its adoption as a clinical tool."
"WT RNAseq is [now] offered to patients and physicians within the UDN, particularly when other genomic tests fail to provide clear answers," she said.
WT RNAseq is entering a somewhat sparse field in terms of commercially available clinical whole-transcriptome RNA-seq assays. Many commercially available assays that include RNA transcript sequencing, such as Ambry Genetics' +RNAinsight, consist of focused panels of defined transcription targets.
Caris Life Sciences is among the few others who do offer such an assay via its tissue-based Whole Transcriptome Sequencing. In contrast to the MGML's focused whole-transcriptome assay, Caris said through a spokesperson that the company's current next-generation sequencing approach "features a combined whole-exome and whole-transcriptome sequencing assay, versus two individual tests."
Although relatively few clinical whole-transcriptome RNA-seq assays exist commercially, developing these assays for diagnosing rare disorders and classifying cancers is an area of active research, with numerous published methods available.
One study, for instance, found whole-transcriptome RNA-seq to be feasible and clinically useful in classifying and prognostically stratifying patients with childhood acute lymphoblastic leukemia, while another found evidence that it could be a reliable first-tier diagnostic approach among patients with heritable skin diseases.
Lee said that the MGML is currently working on "several" other assays, but that it remains too early to comment on their details. The lab's primary focus, at least in the near term, will be on RNA sequencing.
"RNA is the first clinical target that we're focused on," he said.
Given Baylor Medicine's experience developing other omics tests, Lee said that he can envision future collaborations geared toward combining RNA sequencing with genomics and metabolomics.
"There are targeted epigenetic tests out there, for example," he said, "but can we do whole-genome epigenetic testing?"
Lee said that the MGML's overall strategy is to move forward slowly and thoughtfully, with the current deal with the UDN being something of an early step in the lab's growth.
"It's our expectation and intention that [the MGML] will grow beyond the UDN," he said.