Higher detection rates for HSP mutations
Researchers at the Garvan Institute of Medical Research in Australia said last week that they can diagnose rare, monogenic diseases (such as HSP) more than 50% of the time using whole-genome sequencing (WGS). According to Mark Cowley this diagnostic rate is much better that the 25% rate typically observed with whole-exome sequencing (WES).
Whole genome sequencing (WGS) is where a person’s complete DNA sequence is identified and described. Whole exome sequencing (WES) is where all the active (expressed) genes that encode proteins are identified. This represents about 1% of the whole human genome (180,000 exons out of 30 million base pairs). WGS has until now been much less available and much more expensive than WES, but it does have some distinct advantages.
The Garvan lab is currently undergoing an assessment by the Australian National Association of Testing Authorities to offer clinical whole-genome sequencing to diagnose patients with rare genetic disorders. It has already used this approach to diagnose patients with autosomal dominant polycystic kidney disease, hereditary spastic paraplegia, and other disorders.
“Ultimately, the goal we are trying to achieve here is to start off in a clinical environment with patients and their families seeing clinical geneticists, being counselled for the test, going through sequencing, bioinformatics, and clinical interpretation [to produce] a clinical report,” Cowley said. “Hopefully, this clinical report returns a positive diagnosis for the patient … and improves the clinical management of that patient.”
While whole-genome sequencing picks up coding and structural variation that exome sequencing may miss, clinicians and researchers often turn to exome sequencing because of the reduced cost. In the US, Cowley noted, a genome sequence could cost three times as much as an exome sequence.
However, Cowley said that because of Illumina’s pricing strategy, the difference in cost between whole-genome sequencing and whole-exome sequencing is smaller in his lab than in others. It boils down to a clinical genome in the Garvan lab costing only 1.1 times as much as a clinical exome.
With their HiSeq X Ten, The Garvan lab has run nearly 5,000 genomes and worked out some of the growing pains. They have been able to diagnose some 53.5 percent of a cohort of 308 patients. In hereditary spastic paraplegia, Cowley and his team were able to pinpoint the disease cause in four out of five consanguineous families. One family, he noted, had a mutation in the PEX16 gene, which isn’t a traditional hereditary spastic paraplegia gene and likely wouldn’t have been caught by a targeted screen.
The approach can be used to end patients’ diagnostic odysseys, which can go on for years with misdiagnosis or lack of a confirmed diagnosis. This can be used to power gene prioritization algorithms and for sharing of de-identified patient data for patient matchmaking. He noted that it is to be rolled out through the Australian Genomics Health Alliance and the Undiagnosed Disease Networks in Japan and Australia.
SOURCE: GenomeWeb, May18 2016
Whole-Genome Sequencing Has Better Dx Rate Than Exome at Similar Cost, Australian Team Finds