HOLLYWOOD BEACH, Florida (GenomeWeb) – Bionano Genomics has launched a new genome mapping instrument, Saphyr, that it says is higher throughput, faster, and more accurate than its Irys system.
The instrument is based on the same optical mapping technology that is used in Irys, CEO Erik Holmlin said in an interview, but the increased throughput "opens the door to population-based studies" as well as to the clinical and translational research market, he said.
In a presentation at the Advances in Genome Biology and Technology meeting here, Eric Vilain, chief of medical genetics at the University of California, Los Angeles, supported Holmlin's suggestion as he described using the system in a clinical research study to identify large pathogenic structural variants in individuals with unknown disease who had received a negative exome or whole-genome sequencing test.
The Saphyr system is based on the same nanochannel-based single-molecule optical mapping technology as the Irys, but the new system includes the latest generation in high-speed scanning optics as well as a higher-capacity chip, Holmlin said. The result is that throughput will increase from being able to map several genomes per week, depending on the genome size, to being able to do multiple genomes per day, Holmlin said. The exact number will vary depending on the genome's size, the scientific question trying to be answered, and how the run is set up, he added. In addition, the system will be able to detect structural variants with a sensitivity of around 90 percent, Holmlin said.
The Saphyr will be priced in a similar range as Irys, with cost per sample significantly reduced. Again, depending on the genome and the set-up, the cost per sample could be around six times less on the Saphyr, Holmlin said.
Bionano will continue to fully support Irys, which Holmlin said is "suited for smaller-scale studies." Nonetheless, he anticipates that many of the firm's 100 Irys customers would be interested in converting to Saphyr to take advantage of its "higher throughput, speed, and data quality when their research programs expand to need those enhancements."
Already, the company has placed three systems — two with China's Berry Genomics and one with the UCLA. Berry Genomics has been generating data with the Saphyr, including for detecting large structural variants in cancer patients. Last year, Berry and Bionano struck an agreement to codevelop Bionano's technology for China Food and Drug Administration approval. Holmlin said that the clinical system would be "based more closely on Saphyr than on Irys."
In addition, Erich Jarvis and Olivier Fedrigo from Rockefeller University plan to use a system in the vertebrate G10K and bird B10K projects to create reference genome assemblies. James Broach, director of the Penn State Institute for Personalized Medicine, plans to use the Saphyr for thyroid cancer studies and other clinical studies.
During his AGBT presentation, UCLA's Vilain said that his lab, which is part of the National Institutes of Health's Undiagnosed Diseases Network, has been testing Saphyr for its ability to call pathogenic structural variants in patients with unknown diseases.
As an initial validation test, he verified that it could first detect structural variants in individuals with known disease. To do this, he focused on patients diagnosed with Duchenne muscular dystrophy, since the disorder is caused by structural variants in the DMD gene. He said that the Saphyr was able to detect structural variants in a cohort of patients, even in some of the less straightforward cases.
For instance, he described a patient who had a Duchenne muscular dystrophy phenotype, but a PCR assay of the gene as well as an exome sequencing test were both negative. Whole-genome sequencing had identified several deep intronic variants, but their significance was unknown. After that, the patient was referred to a muscle biopsy and researchers also performed transcriptome sequencing.
The RNA sequencing identified a drop off in gene expression after exon 37 in the DMD gene and the muscle biopsy confirmed the diagnosis. But, Vilain said that when they performed mapping with the Saphyr, they detected a large 5.1 megabase inversion that began just after exon 37. "So, this patient could have been diagnosed in a noninvasive fashion," he said.
Since the initial validation of the technology, Vilain said that the lab has now gone on to test Saphyr's ability to discover variants in patients who have not been diagnosed. The team is first analyzing patients who have already received an exome or whole-genome sequencing test through the Undiagnosed Diseases Network program. The group has so far tested affected individuals from 11 trios.
One case was an 8-year-old male whose symptoms included severe developmental delay, hypotonia, and microcephaly. The boy also had an affected sister. A microarray had identified a 190-kilobase deletion that had been inherited from the father, but exome sequencing had not found anything that matched the phenotype.
Using next-generation mapping, the team identified a 3.5-kilobase deletion in both siblings that included the MED17 gene, which is involved in regulating transcription of RNA polymerase-dependent genes. However, the variant was present only on one allele, the allele from the father. Looking back at the sequence data from the other allele, the team found two intronic variants in the gene inherited from the mother. Vilain said that the group has not yet confirmed this molecular diagnosis but are in the process of doing further analysis, like RNA sequencing, to see if gene expression results confirm the finding.
Vilain described a second case, which he said also still needs to be confirmed, that involved a 13-year-old female who presented with development delay, seizures, and autism. She also had features suggestive of an overgrowth disorder, including a head circumference way above average and precocious puberty.
Whole-genome sequencing had not identified anything that seemed clinically relevant. But mapping revealed a 1.6-kilobase deletion in the EZH1 gene. "That's never been associated with a clinical diagnosis," Vilain said, but its closest homolog EZH2 is associated Weaver syndrome, an overgrowth syndrome.
Recent research also has shown that EZH1 and EZH2 work synergistically to promote growth and both are needed to promote skeletal growth, he said. "This is an interesting potential clinical result that we're still waiting to confirm," Vilain said.
He said that mapping could be a good additional tool to detect structural variants, which "account for a significant fraction of variation." Currently, the short-read NGS tests used to diagnose rare disease have a diagnostic rate around of 25 percent to 35 percent.
"That leaves us with frustration of having a negative sequence and no diagnosis," he said. "Next-generation mapping can identify novel structural variants and could soon be integrated into a clinical diagnostic strategy."