Emboldened by the rapidly decreasing cost of DNA sequencing, direct-to-consumer personal genomics company Navigenics said it plans to add rare-variant interpretation of sequence-based data to its service offering.
Starting later this year, under a partnership with genetic testing company Correlagen Diagnostics, the company wants to offer Sanger-sequencing-based tests of selected genes known to be involved in certain diseases.
Next year, Navigenics expects to add the analysis of entire exomes, followed by whole-genome analysis several years from now when the cost of sequencing has further fallen.
“You are going to see a transition in the molecular diagnostics space, over the next couple of years, to sequencing just the genome,” as opposed to many separate genetic tests, Navigenics CSO Dietrich Stephan told In Sequence last month. “We all know it’s going to happen; that’s just the trajectory of the technologies.”
Earlier this year, Navigenics started offering its service, called Health Compass, which uses whole-genome genotyping on Affymetrix microarrays to provide consumers with an analysis that gauges their genetic predispositions to a number of common diseases and conditions, ranging from Alzheimer’s disease to stomach cancer. The service costs $2,500 for the first year, and an additional $250 per year thereafter.
Array-based genotyping scans the genome only for common variants. But researchers involved in the 1000 Genomes Project, the Personal Genome Project, and other efforts have been developing sequence capture or genome partitioning methods that, in combination with second-generation sequencing, will enable low-cost exon sequencing. The sequence data will likely uncover rare sequence variants contained in the gene-coding portion of an individual’s genome.
“We are going to be faced with interpreting these millions of variations between individuals, and defining the functional consequence of any of these changes is going to be incredibly difficult,” according to Stephan.
To get a first stab at it, Navigenics has teamed up with Correlagen Diagnostics, a genetic testing company that offers DNA-sequence-based tests for a variety of genes that contribute to, for example, hypertrophic cardiomyopathy, severe combined immunodeficiency, or primary adrenal insufficiency.
Correlagen maintains a database of gene variants, which Navigenics intends to use to aid its interpretation services. According to Stephan, the database contains data from Correlagen’s own sequencing services as well as from the scientific literature.
“As we see a variant, we can pass it across this database and say, ‘That’s been seen before, and that patient had this disease,’ so we can assign a better weight to that variant,” he explained.
“You are going to see a transition in the molecular diagnostics space, over the next couple of years, to sequencing just the genome.”
In many cases, though, a rare gene variant will never have been seen before and, thus, be more difficult to interpret. Based on the variant’s properties, like its evolutionary conservation, or whether it results in an amino acid change, Navigenics will attempt to assign it a probability score that predicts its clinical relevance. “And that’s a really, really hard problem,” Stephan said.
What is needed, he said, is sequencing-based genome-wide association studies. “What you ideally would want to do is take thousands of people with a complex genetic disease and thousands of people without one, sequence their entire exomes, and look for hotspots of accumulation of rare variants in certain regions of the genome [of cases vs. controls, where] the specific variants look like they have some sort of functional consequences.”
“Then, the next time a person comes through the door, you can start to informatically stratify the loci that you see variants in ... based on sequencing all these genomes.”
In terms of cost, large-scale exome-sequencing studies will soon become feasible, Stephan predicted. Within months from now, “in one lane of an Illumina Genome Analyzer, we will be able to sequence the exome of one individual, probably, for about $2,000,” he said.
Within five years or less, he added, whole-genome sequencing will be possible for an even lower price. “Navigenics will be the interpretative engine that matures alongside of the technologies, so that in this three- to five-year timeframe, we can really rely on this comprehensively in the clinic,” Stephan said.
For now, Navigenics and Correlagen will start offering sequencing of selected genes to customers with a strong family history in a certain disease, such as type-2 diabetes, or to customers who are “particularly concerned about one indication and want to understand the rare variant contribution of that.”
That service will use PCR-based Sanger sequencing, which Correlagen will provide. “We will use that as a starting point and a platform for building the rules for interpretation, and then we will slowly expand across multiple genes, and then all genes,” Stephan said.
The company has not yet decided how many different genes it will initially cover, for example, if it will include genes involved in monogenic disorders or only those that are known to contribute to complex genetic diseases.
It has also not yet decided how much it will charge its customers for the additional service.
Other direct-to-consumer personal genomics companies are thinking along similar lines but are not yet revealing specific steps. “23andMe is closely following the next-generation sequencing field and will offer an expanded service when the data quality, balanced by the cost, of these offerings meets our criteria,” said Linda Avey, co-founder of 23andMe, in an e-mail message. Once the company decides to include sequencing analysis in its service, “we will examine any and all sequencing companies in determining which would work best with our platform,” she said.