Genomic diagnostic startup Medomics plans to launch next month a mitochondrial genome sequence-analysis test for mitochondrial diseases that runs on a second-generation sequencing platform. The test, it says, will be more sensitive than current sequencing-based mitochondrial genome tests.
Developed on Medomics' Applied Biosystems SOLiD system, the test will be the firm's first targeted sequencing-based assay. The company also offers a test called the "diagnostic genome" that involves whole-genome sequencing and interpretation of medically relevant variants, as well as research services for academic groups.
Medomics, based in Azusa, Calif., was founded last July by a number of scientists and clinicians working, at the time, at the City of Hope. The privately held company, which became certified under the Clinical Laboratory Improvements Amendments earlier this year and is licensed by the state of California, has less than 20 employees. Funding came from the founders and through loans.
The company's goal is "to apply massively parallel sequencing to diagnosis," Medomics chairman and founder Steve Sommer told In Sequence. At City of Hope, which he left last year, he headed the Clinical Molecular Diagnostic Laboratory, now called the Molecular Diagnostic Laboratory, until 2006.
The company's SOLiD instrument is its sole sequencing platform at the moment. When the company decided to acquire the instrument last September, "it was my sense that the error rate was much lower [than that of other sequencing platforms] and that ABI would dominate on throughput," Sommer said. However, other platforms have made "enormous progress" in the meantime, he said, adding that "each of the technologies has a sweet spot."
"I see complementary instrumentation providing the most flexibility for diagnostic labs," he said.
The firm's mitochondrial genome-sequencing test will be sensitive enough to pick up mutations present at a level of 3 percent or less of all mitochondrial DNA present — a state called heteroplasmy.
Mitochondrial diseases can affect a variety of organs and can lead to neurological dysfunction, muscle weakness, gastrointestinal problems, migraine headaches, blindness, deafness, or diabetes. It is caused by mutations in either the 16.5-kilobase mitochondrial genome — which encodes 37 genes and is inherited through the mother — or the nuclear genome, which harbors over a thousand mitochondrial genes. Each cell contains on the order of 1,000 mitochondria, each of which harbors several copies of the mitochondrial genome, and sometimes only a fraction of them contains a disease-causing mutation.
Medomics' tests will be used to screen patients suspected to suffer from mitochondrial disease, or those suffering from a disease that follow a maternal pattern of inheritance, by analyzing mitochondrial mutations from their blood. It can "offer physicians confirmation of a possible mitochondrial disease diagnosis, enable rational therapy decisions, provide guidance on the prognosis of disease, and allow for accurate risk counseling," according to a company statement.
Heteroplasmy can differ between tissues, and "screening of a patient's blood sample for the presence of even very low levels of heteroplasmy can serve as an important initial step in assessing whether additional tissue biopsy is warranted," according to the company statement.
Sequencing the mitochondrial genome by traditional Sanger sequencing — which Medomics estimates is currently offered by just a handful of laboratories — can only detect 30 percent heteroplasmy, potentially leading to many false negative results. Its test, which offers "deep heteroplasmy analysis," will be able to pick up mutations that are at least tenfold rarer.
Other, more targeted tests already offer the same level of sensitivity as Medomics' test, but for specific mutations. For example, Transgenomic's MitoScreen assay promises to detect less than 1 percent heteroplasmy for certain mutations.
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Medomics says its test could help increase the number of patients with mitochondrial disease who are diagnosed correctly. "It's a feeling of many in the field that only a small fraction of those with true mitochondrial disease are detected," Sommer said.
Its test will have a similar cost to that of other tests that sequence the entire mitochondrial genome, but exact pricing information is not yet available. For comparison, the Emory Genetics Lab at Emory University Medical School, for example, charges $3,500 for a mitochondrial genome sequence analysis test, according to its website.
The 'Diagnostic Genome'
Besides the mitochondrial genome, Medomics offers — at an undisclosed price — whole-genome sequencing and interpretation of medically relevant variants, a test it calls the "diagnostic genome." It also offers a less comprehensive version of this test called the "medically relevant genome."
For the "diagnostic genome," the company plans to sequence an individual's genome with sufficient coverage to detect 99.999 percent of all variants. "The amount of sequence that will be necessary is not clear, because no one has done it, but it will be approximately a terabase of sequencing," Sommer said, or more than 300-fold coverage.
The company plans to use mate-pair reads from its SOLiD platform as its core sequencing method, but "in all likelihood," the service will require more than one sequencing technology, Sommer said, noting that Medomics would probably outsource this additional work.
More challenging than generating the data is its medical interpretation, a strength of the company, according to Sommer. "We have a team of mutation experts and genetic counselors" on staff, he said.
The analysis will focus on variants "that are extremely likely to substantially alter the function of one of the genes," including miRNA genes.
Sommer believes that the service "will lead to unanticipated and important medical insights" for individuals and their families, including previously unrecognized disease predispositions, or pharmacogenomic variants that affect response to certain drugs.
In contrast to Knome, which offers whole-genome and exome sequencing and analysis services directly to consumers (see In Sequence 5/19/2009), Medomics offers its whole-genome analysis only through physicians.
Sommer said he could not comment on how the two companies' analyses differ since he has not seen details of Knome's offering.
Medomics has not yet sequenced a patient's genome but is "in serious discussions" with individuals interested in the service, he said.
In addition to whole-genome sequencing and its mitochondrial genome test, the company is working on other diagnostic tests that are driven by massively parallel sequencing, such as analyses of specific chromosomes or of cancer-relevant genes, he said.
Besides providing genetic testing, the company, through its services division, is involved in a number of research collaborations with undisclosed academic groups, for example on a project that analyzes rearrangements, amplifications, and copy-number variations in select cancers, and one that involves the analysis of microRNA expression in cells infected with HIV. For these collaborations, Medomics provides sequencing services as well as bioinformatics analyses and variant interpretation.
"Some of that work is going to help us with the various specific diagnostic tests" Medomics wants to develop, Sommer said, such as analyses of the epigenome or the cancer genome.
The company also offers a warfarin sensitivity test that is not based on sequencing, as well as genetic-counseling services for physicians and other diagnostic labs.