NEW YORK (GenomeWeb) – With 1,000 and rising genomes sequenced per month, the Garvan Institute of Medical Research in Sydney is taking the strategy of focusing on clinical applications first, with the idea that the research will necessarily follow.
Garvan was one of the first three sites to acquire Illumina's HiSeq X Ten instruments, and it did so in order to focus on clinical whole-genome sequencing. Garvan Executive Director John Mattick told GenomeWeb during a recent visit to the institute that by designing whole-genome sequencing pipelines for clinical purposes and engaging with the clinical community to sequence patient cohorts, the institute essentially "get[s] the research for free."
Such focus on clinical applications first also distinguishes Garvan from genome centers in the US, which were first designed with the research community in mind, Mattick said.
The institute has a number of clinical whole-genome sequencing projects it is working on internally and in collaboration with other academic institutes and hospitals in Sydney and throughout the world. It has a clinical whole-genome sequencing collaboration with Liverpool Hospital to diagnose unsolved cases of genetic disease in children.
The New South Wales government has invested $24 million in three different research projects, including a project to sequence around 4,000 genomes from healthy individuals over the age of 75 in order to serve as references for disease risk alleles; a Genomic Cancer Medicine research program to identify inherited risk factors, as well as variants associated with early detection, prevention, and disease management; and a third that provides grants to clinicians to obtain whole-genome sequencing for patient cohorts in order to understand genetic causes of disease.
Diagnostic whole-genome sequencing
The Garvan Institute has been offering whole-genome sequencing to children with unknown genetic diseases for the last two and a half years, and has thus far achieved a diagnostic rate of more than 50 percent, which is significantly higher than diagnostic rates achieved by other academic medical centers offering exome sequencing.
Marcel Dinger, who heads the Kinghorn Center for Clinical Genomics at Garvan, told GenomeWeb that the center achieves higher rates in part because it does whole-genome as opposed to exome sequencing. Whole-genome sequencing not only enables the team to identify disease-causing variants in regulatory regions and structural variants that are more difficult to detect with exome sequencing, but it also provides better coverage of the exome than exome sequencing.
In addition, he said, certain phenotypes have higher success rates with whole-genome sequencing. For instance, he said, patients with polycystic kidney disease have close to a 90 percent diagnostic rate. Some of the genes involved with that disease also have highly homologous pseudogenes. While whole-genome sequencing is able to sequence through those areas and distinguish the gene from its pseudogene, exome sequencing typically struggles in that area, Dinger said.
The HiSeq X Ten is housed at the Kinghorn Center, which has ISO 15189 certification, and researchers there have validated some of the units for clinical purposes, while keeping others as research boxes. Dinger said this enabled the researchers to make changes to their whole-genome sequencing protocols and perform upgrades on the research boxes, while keeping the pipelines locked down on the clinical instruments.
Recently, Garvan spun out Genome.One, a company that provides whole-genome sequencing to diagnose children with severe, likely genetic disorders. Genome.One also plans to soon begin offering services to adults as well as to patients with cardiac and renal disease.
Dinger said that clinical whole-genome sequencing costs around $4,300. Currently, Australia's federal health insurance program does not cover that cost, but typically the cost is born by the local state budgets, he said, through funding to hospitals. The clinicians at the hospitals have "quite a bit of discretion" on which tests to order for their patients, he added.
Mattick added that he anticipates federal insurance will soon cover whole-genome sequencing for babies born with unknown but suspected severe genetic disease, since there is so much evidence demonstrating that it can be a cost-effective and fast test. "The value proposition is so high that it will likely be covered by public insurance soon," he said.
From clinical to research
Garvan's clinical sequencing work also provides an opening into genomic research, Mattick said. For instance, while the researchers are able to diagnose 55 percent of cases who receive diagnostic whole-genome sequencing, 45 percent of patients do not get an answer and "can immediately be fed back into a research domain" and the sequencing has already "been paid for by the clinical portion," Dinger said.
Unlike other clinical pursuits, genomics provides a "prime opportunity to set up a different platform for research to be carried out," he added. Researchers rarely get access to pathology tests or other types of diagnostic or healthcare information, he said, but frameworks are already being established in the realm of genomics to enable easier transfer of genomic data generated for clinical purposes to also be used for research.
Mattick said that Garvan would continue to focus on technologies that would enable genomic data generated for clinical purposes to be used for research. That would require patient consent, as well as secure databases.
He said Garvan is testing out new software called Patient Archive that will better enable genomic, phenotypic, and medical data to be easily stored and converted into a format that makes it machine readable. Then, machine-learning algorithms can query the data.
The Australian Genome Health Alliance is now running a pilot, using the software to figure out how genomic data could be collected, stored, and accessed in the future. The pilot, which will run for five years, started at the beginning of this year. The project will also study the economics of such a project to see whether it saves money or improves outcomes.
Several hospitals in Japan are also testing the Patient Archive software and Genomics England is considering implementing it, Mattick noted.