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New Consortium Aims to Demonstrate Strengths of PacBio Revio Platform for Genetic Disease Research


WASHINGTON – Researchers from over a dozen institutions across the world have formed a new consortium with Pacific Biosciences to explore the utility of HiFi sequencing for analyzing rare genetic diseases.

Unveiled at the American Society of Human Genetics (ASHG) annual meeting here on Thursday, the consortium, dubbed HiFi Solves, aims to develop and share best practices for use of the PacBio Revio sequencer for clinical research applications.

"The genesis [of the initiative] was to pull together the various key opinion leaders that we have been working with around the world in various aspects of rare disease research," PacBio Chief Commercial Officer Jeff Eidel told GenomeWeb. "Rather than having those efforts be somewhat disparate and siloed, the goal was to bring them together into one consortium and be able to have a function to share those findings and discoveries."

The consortium includes 15 genomics research institutions across 11 countries and is divided into regional sub-efforts in Europe, North America, and Asia-Pacific, according to the company. "The idea is not to duplicate efforts across the various regions and to make sure that we are covering as much ground as possible," Eidel said.

During a PacBio-sponsored workshop on Thursday, Alexander Hoischen, a genomics researcher at Radboud University Medical Center in the Netherlands who is leading the HiFi Solves effort in Europe, outlined some of the goals of his group of collaborators.

"The essence of [our effort] is just asking two very simple questions," Hoischen said. "One is: 'Can HiFi genomes replace old tests?' … And then maybe scientifically more intriguing is, 'How many extra potential diagnoses can we make by using HiFi genomes in undiagnosed cases?'"

Besides Radboud UMC, other European HiFi Solves members include the Max Planck Institute for Molecular Genetics and the Bioscientia Institute for Medical Diagnostics in Germany, Karolinska University Hospital and the Karolinska Institutet in Sweden, the University of Leuven in Belgium, and SciLifeLab in Sweden.

Hoischen said the collaborators will be using HiFi sequencing to re-analyze about 100 "tricky" mutations that had been previously identified with standard methods in areas of high sequence homology such as pseudogenes or segmental duplications.

The aim of that analysis, which will cover all variant types — single nucleotide variants (SNV), copy number variations (CNV), structural variations (SV), and gene conversions — is to demonstrate the potential advantages of long-read HiFi sequencing for identifying mutations that have been previously hard to detect using traditional technologies, including short-read sequencing.

As for showing the technology’s utility for solving undiagnosed diseases, the group plans to perform whole-genome sequencing on around 300 rare disease samples on the Revio platform, he said.

"The real ambition here would be to make this the first-tier test and stop almost all the other tests for germline testing," Hoischen told GenomeWeb on the sidelines of the conference.

Radboud UMC has already developed and validated an in-house amplicon-sequencing-based clinical test on the PacBio Sequel II platform, he said, and has been using that to analyze thousands of clinical samples annually "for quite some years" now.

However, Hoischen said that before the launch of Revio, which promises to enable HiFi sequencing at higher throughput and lower cost, it has always been cost-prohibitive to perform large-scale whole-genome sequencing studies using the technology.

"We were always excited about the HiFi quality, but only with Revio, I think we can do the genome-wide studies now," he pointed out.

Even so, to achieve the ultimate goal of offering a HiFi-based germline mutation test in place of traditional assays to every patient suspected of having a rare disease at Radboud UMC — which can amount to about 25,000 samples a year, Hoischen said — the cost of HiFi sequencing still has to come down while throughput needs to increase.

In addition, he underscored the importance of improving data analysis tools for the technology.

"We have to realize that the tools for long reads are where we were for short reads 10 years ago," he said. "There are still improvements possible for mapping [and] variant calling of different variant types, in particular for structural variants and cytogenetic aberrations."

This is also true for the visualization of mutation events, Hoischen said. "Some of these structural variants are so complex that you want to have a very nice visualization for that, which is also not routine yet," he pointed out.

Commenting on other commercially available long-read technologies, such as nanopore sequencing, Hoischen said that "competition is always important" and that each method has its "own advantages and potentially disadvantages and caveats to it."

"It's more of a strategic choice at some stage that you go for one or the other," he said. "We learned the lesson many years ago that you rather do one or two innovations very well than three or five innovations and not so well."

The goal is to "contribute with our experience to best practices of HiFi genomic sequencing in genetic disease," Tomi Pastinen, director of the Genomic Medicine Center at Children's Mercy Kansas City who is leading the HiFi Solves efforts in North America, wrote in an email.

Children's Mercy has also validated a laboratory-developed test using PacBio sequencing to help diagnose critically ill newborns. In addition, Pastinen said his group is able to provide Revio HiFi sequencing services for the consortium as needed.

In terms of Children’s Mercy's disease areas of interest for the consortium, Pastinen said the immediate applications of HiFi sequencing that his team is considering are infant hypotonia, ataxias and other movement disorders, as well as growth disorders. They already have hundreds of patients enrolled at Children’s Mercy that may be suitable for studying these diseases, he added.

In addition, Pastinen disclosed that PacBio is providing in-kind contributions for sequencing consumables for the consortium.

Considering the company somewhat as a "quarterback" for HiFi Solves, Eidel said the role of PacBio is to "make sure the centers are all communicating well, and information is being shared across the institutions."

Beyond that, PacBio CSO Jonas Korlach said, the company will also provide technical help and workflows for the consortium members, such as computational analysis pipelines, automation support, and connecting them with the appropriate vendors based on their workflows.

While the goal for HiFi Solves is to demonstrate PacBio sequencing’s potential utility for clinical genetics, PacBio management made clear that its platforms are still for research use only, and that the company’s current strategy is to still focus on that side of the business, though it strives to support customers to develop and validate their own clinical tests.

"Our tools will continue to be used in research-use-only fashion," Eidel said. "I think you are going to start seeing more and more of our customers start to develop lab-developed tests based on those platforms. What we might choose to do in terms of FDA-cleared or IVDR-cleared platforms, I think that may evolve over time."