The human genetics division of German laboratory diagnostics company Bioscientia has launched a clinical long-read, whole-genome sequencing (WGS) test to diagnose patients with certain sensory disorders, its first such test for routine diagnostics.
The company plans to expand the test, which runs on the PacBio Revio platform and uses HiFi reads, to other inherited conditions in the near future.
“I have been waiting for a platform that could be used routinely at affordable costs for diagnostics in sensory disorders,” said Hanno Bolz, Head of Bioscientia's Human Genetics Division. "With the Revio machines, … this became an option."
According to Bolz, Bioscientia installed its first Revio platform in May of last year, followed by a second one in September, and launched the HiFi WGS assay in mid-December.
Compared with previous sequencing tests offered by the company, which include short-read whole-exome and whole-genome sequencing assays, Bolz noted that the long-read WGS assay comes with several advantages.
For one, long-read sequencing can better detect complex exonic regions or complex aberrations affecting an exon.
In some cases, the new test is also able to capture targets that have not been accessible by short-read WES at all. For instance, long-read sequencing was capable of profiling the highly repetitive ORF15 exon, a mutational hotspot of the RPGR gene that is associated with retinal degeneration and has been difficult to analyse by Sanger or short-read sequencing.
Additionally, HiFi long-read sequencing provides phasing information, which can be important in cases where patients want to know if they have mutations in both copies of RPE65, a gene involved in a recessive form of retinal dystrophy that can be treated with gene therapy.
"Usually, you need some first-degree relatives to check this, and those are not always available or can take a long time," Bolz said. "With long-read sequencing, you can right away tell the phasing [of the gene]," adds Boltz.
Bioscientia developed the HiFi WGS test as a laboratory-developed test (LDT) according to the standards of the US College of American Pathologists (CAP), the German national accreditation body Deutsche Akkreditierungsstelle (DAkkS), and the EU In Vitro Diagnostic Regulation (IVDR).
As an LDT, validation of the test did not require the involvement of a notified body under IVDR, Bolz noted. The test validation included all variant types, such as single-nucleotide variants (SNVs), copy number variants (CNVs), structural variants (SVs), repeat expansions, complex and pseudogene-shadowed regions, as well as methylation patterns.
Bioscientia’s bioinformatics team developed a complete analysis pipeline, consisting of publicly available and in-house developed tools to perform variant analysis, annotation, and curation for a clinical report. The report is checked and signed off by at least one clinician, and the results are returned to the patient’s referring physician or Bioscientia’s medical geneticists for in-house genetic counselling.
Bolz said his group collaborated closely with PacBio to develop the test, which offered technical and bioinformatics support.
Additionally, Bioscientia belongs to the recently established HiFi Solves consortium, which was formed by research labs from over a dozen institutions across the world and PacBio to explore the utility of HiFi sequencing for analysing rare genetic diseases.
On average, Bolz said Bioscientia performs about 5,000 short-read WES tests per year.
While the HiFi WGS test will not replace these assays, he considers long-read sequencing "the way to go" for many rare diseases, noting that many patients who typically receive WES testing at Bioscientia will be switched to the long-read test moving forward.