Whole genome sequencing can help pinpoint diagnoses

The use of whole genome sequencing could save parents of children with rare diseases from some heartache by helping to pinpoint a diagnosis earlier, Canadian researchers say.

Whole genome sequencing is a laboratory tool to find genetic variants in a person's entire genome sequence instead of just sections, the current standard.

In a study on 100 patients published Wednesday by Nature Partner Journals Genomic Medicine, researchers from Toronto's Hospital for Sick Children found four times as many molecular diagnoses compared with the current standard technology.

In 34 per cent of the cases, whole genome sequencing provided a genetic diagnosis compared with eight to 13 per cent with conventional testing, the researchers found.

"We uncovered several different extremely rare disorder that the clinicians themselves would never have thought of," said Christian Marshall, the study's principal investigator. 

Bryson McArthur's parents first noticed something was different with their son when he was two months old and couldn't hold his head up. 

"There were at least a dozen that were genetics tests but they also had muscle biopsies where they cut into his leg and MRIs," recalled his father, Keith McArthur. Each time, the family was told the tests were probably not for what he had but to rule out a possibility.

Last month, the Toronto family was able to put a name to it: GRIN1 after the misspelled gene. Now they communicate regularly with seven other affected families worldwide for support and to learn from each other.

Clinical usefulness unknown

But the shift in applications of the technology from the research lab to the clinical genetics clinic introduces a host of issues.

These include unproven clinical usefulness, patient privacy concerns, insurability, a child's choice to remain unaware of potential future health risks, and the costs of interpreting all the data generated in a meaningful way.

In patients with significant symptoms such as those with developmental delay but no clinical diagnosis as in the study, the arguments for whole genome sequencing as a first diagnostic strategy are the strongest, said Christopher McCabe, a health economist at the University of Alberta in Edmonton.

McCabe is highly cautious about expanding the use of whole genome sequencing beyond a case-by-case basis. Once a child receives a genetic diagnosis, other family members without symptoms rightly deserve genetic answers, too.

"Until we have expanded the capacity of the clinical professionals that we need in order to respond to the information appropriately, then actually we're not helping at all. We're quite possibly damaging the quality of the health-care service that will be provided to the parents and to children because of this risk of swamping them," said McCabe, who holds a Capital Health research chair. 

"It might be seen as if we're putting the cart before the horse."

In the study, about 35 per cent of individuals were uncomfortable with life or employment insurance implications of incidental findings because Canada doesn't have a law against discriminating and 35 per cent declined because they felt overwhelmed with the medical complexity in neonatal intensive care. 

The study was funded by the Centre for Genetic Medicine, the Centre for Applied Genomics, the Hospital for Sick Children, Genome Canada, the University of Toronto McLaughlin Centre and Complete Genomics.