Study suggests whole genome sequencing should be primary genetic test for patients

Test identifies child’s one in a million disease

TORONTO – In the last decade, thousands of genetic discoveries have been made thanks to advanced technologies that have given researchers the tools to look at segments of the human genome. The goal is to use this genetic information to enable early diagnosis and to potentially inform on which therapies and medicines provide the most targeted treatment for patients. While the merits of whole genome testing have been recognized by researchers, it has yet to become a standard practice for clinicians looking for a diagnosis.

When investigating a potential genetic condition in a child, the current standard-of-care genetic test is chromosome microarray analysis (CMA) which only looks at copy number changes in genes and misses smaller genetic changes. Families often go through an odyssey of tests, which can take months to years, is costly to the overall health-care system, and many still end up with many unanswered questions.

A new study compared standard genetic testing to whole genome sequencing in 100 patient cases at The Hospital for Sick Children (SickKids) and found that whole genome sequencing identified genetic variants that could help with diagnosis in more than a third of the patients. This represented a four-fold increase compared to the diagnostic rate using the standard chromosome microarray analysis which only found genetic variants in eight per cent of the cases. The study was led by the Centre for Genetic Medicine at SickKids and is published in the Jan. 13, 2016 online edition of Nature Partner Journals (NPJ) Genomic Medicine.

Whole genome sequencing is a laboratory process that looks at a person’s entire DNA sequence at one time rather than just parts of it.

While chromosome microarray analysis can be very useful for some, in 80 to 85 per cent of cases a diagnosis cannot be reached with this test alone which leads physicians to additional genetic tests. The number of genetic tests per patient typically ranges from three to five with a total cost to the health-care system of $3,325 to $5,280. The physicians in this study ordered on average three tests per patient which generated a diagnostic rate half of that achieved by whole genome sequencing. The cost of whole genome sequencing is approximately $3,000 per patient, and experts say that as the technology becomes more accessible, the cost is expected to decrease.

Although full economic evaluations are required, Dr. Christian Marshall, principal investigator of the study and Associate Director in the Department of Paediatric Laboratory Medicine at SickKids says the clinical use of whole genome sequencing is likely to reduce the number of genetic investigations and potentially the time to diagnosis, ultimately acting as a more cost-effective approach.

He adds, “In order to provide the best possible care clinicians need to determine the underlying genetic cause. In one test, whole genome sequencing can achieve this. This will help doctors determine prognosis, guide treatment or begin appropriate surveillance and prevention programs if needed.”

Six-year-old Zahra had had several genetic tests with no significant results before she came to SickKids and was offered whole genome sequencing as part of the research study. “The frustration of not being able to find out what was going on with our daughter was overwhelming,” says Syed, Zahra’s father.

When Zahra turned four years old, her parents noticed that she was not developing like other children her age, but as first time parents, people told them that they were being overly cautious and that all children develop at different rates. As time went on, they knew something was off. Whole genome sequencing revealed that Zahra had a very rare condition called Pantothenate kinase-associated neurodegeneration (PKAN); the incidence is literally one in a million. PKAN is a progressive neurodegenerative condition caused by a mutation in the PANK2 gene that leads to an excess of iron that progressively builds up in the brain. There is presently no known cure for this disorder and some of the major symptoms include problems with development, speech and movement (sudden falls).

“Now, it feels like getting a diagnosis for Zahra was just the beginning of our journey. While it was not easy, it helped my wife and I understand why our daughter is different, and gave us the opportunity to do the best we can for her and find therapies that will improve her quality of life now and as she gets older,” says Syed, who has since become very involved in advocacy and awareness for families affected by PKAN.

The diagnostic laboratory at SickKids receives more than 600 chromosome microarray analysis requests from the Division of Clinical and Metabolic Genetics per year and greater than 3,000 from across the province of Ontario. A diagnosis is identified in just eight to 12 per cent of these cases.

“The results of this study indicate that whole genome sequencing can and should be used at the first-tier genetic test in individuals with developmental delay and/or congenital abnormalities,” says Marshall who is also Assistant Professor in Laboratory Medicine & Pathobiology at the University of Toronto.

This study was funded by SickKids’ Centre for Genetic Medicine, The Centre for Applied Genomics, Genome Canada, the University of Toronto McLaughlin Centre, Complete Genomics, Inc., and SickKids Foundation.

This paper is an example of how SickKids is contributing to making Ontario Healthier, Wealthier and Smarter.