Genome-wide sequencing pilot project helps Ontario families get answers

More than one-third of the estimated930,000 Ontarians with a rare disease lack a genetic diagnosis, despite lengthy and costly investigations, which was the case for most of Anna’s life.  

Anna had a childhood filled with regular injuries as a result of persistent muscle weakness, with hundreds of doctor’s visits. Her clinical team at CHEO completed dozens of tests, including muscle biopsies, metabolic testing and at least five different genetic tests, but no conclusive diagnosis was reached. 

Conventional genetic testing involves testing subsets of genes, often leading to multiple tests and investigations, which can present a complicated and time-consuming process for clinicians, patients and families. In contrast, GWS can search all known genes for variants that could be disease-causing, providing a much more comprehensive look at a patient’s genetic data. 

Isla had severe jaundice, skin rashes, extremely low energy, difficulty feeding and problems with growth associated with high levels of inflammation markers in her blood at just one week of age. She spent over a year in and out of SickKids with high fevers, infections, breathing issues and extreme acid reflux. Her clinical team addressed the symptoms while they searched to find the underlying cause, but tests to check her blood, bone marrow, immune system, DNA and more yielded nothing. 

Diagnoses provide clarity and open the door to treatment plans and relief for patients and their families 

A diagnosis can often be the first step to accessing targeted care and for families, it can provide emotional relief and improved access to support and resources. 

Isla was started on a biologic drug to reduce her inflammation levels with the hopes it would help address her other health issues. Still, her clinical team and her family wanted an explanation for all of Isla’s health concerns to help optimize treatment and prevent complications. Isla had exome sequencing as one of the last diagnostic options, which found aa new DNA change in a gene called CDC42, which is known to cause severe inflammation. Armed with this knowledge, Isla’s family and clinical team were confident that their treatment plan was the right one. 

Anna had genome sequencing as part of GSO’s quality improvement study to evaluate the benefit of interrogating the entire genome. GSO reported that she has a rare genetic condition because of two variants affecting a gene called SELENON. She inherited one variant from her mother and one from her father. Genome sequencing was critical to the identification of these variants in Anna as they were not detectable via the previous testing technologies and would not have been identified using exome sequencing. Although she is small for her age and her bone development is delayed, she takes swimming lessons, does her best to keep up with friends at recess, gets good grades and is an avid reader. Like any 12-year-old, she loves spending time on her tablet playing games. “More than I probably should,” Anna says.  

“It took 12 years to finally put a name to what Anna was experiencing every day sinceshe was an infant. When we got the genome sequencing results and diagnosis, it was the first time in 12 years that we were able to read something with a name on it and say, ‘That’s it! That’s what we’ve been dealing with,’” said Mallory Boileau, Anna’s mother. “It would be great for families to get this type of answer at the beginning of their journey. Twelve years is a long road not to have answers.” 

Now, Anna’s family and care team can keep an eye out for potential complications that are associated with her diagnosis. Mallory says, “The not knowing is sometimes more terrifying than anything. We’re no longer guessing all the time and can address things before they become an issue. It’s such a relief.” 

Isla’s family is thankful, too.   “After Isla started her treatment, you could tell how much better she was feeling. Isla started to have more energy and began smiling and even laughing,” says Miki Simmons, Isla’s mother. “At four years old, Isla’s keeping up with all her older siblings and I’m not sure where we would be if we didn’t have the treatment plan and diagnostic answers that we did when she was a baby.” 

GSO to investigate the cost and feasibility of genome sequencing compared to exome sequencing 

A subset of 650 families will form the basis of a quality improvement pilot, with half of those receiving genome sequencing rather than the current standard of care, exome sequencing. Exome sequencing focuses on the one to two per cent of DNA that encodes proteins, because genetic variants that alter the normal function of proteins are the most likely cause of severe disease.  Genome sequencing, while currently a costlier technology, determines almost the entire sequence of a person’s DNA. 

Through this quality improvement project, GSO will compare the results of each sequencing type and the findings will inform a robust assessment of diagnostic utility, cost effectiveness, and timeliness of exome sequencing and genome sequencing, which will hopefully inform provincial and cross-provincial policy related to genome-based diagnostics for rare diseases. 

GSO is funded by the Ontario Ministry of Health and Genome Canada, via Ontario Genomics.  

Genome Canada’s funding is part of its All for One precision health initiative that advances a new standard of health care for Canadians, expanding access to genome-wide sequencing for diagnosis and treatment of life-threatening genetic diseases. Now with pan-Canadian reach, and significant investment and strong partnership from provincial and regional health services authorities, All for One is deployed across six implementation projects serving nine provinces. 

More information and resources on GSO can be found at https://gsontario.ca/. 

Partner quotations 

“Our government is proud to support this pilot with CHEO and SickKids, which is already helping Ontario families just one year into implementation. This promising project will improve patient outcomes by providing timely access to genetic diagnoses, which is another way Ontario is building a better connected health-care system, centred on the needs of patients.” 
– Christine Elliott, Ontario’s Deputy Premier and Minister of Health 

“Quick access to comprehensive genetic testing, like exome or genome sequencing, must be a cornerstone of health care for children and youth who have suspected, but undiagnosed, genetic conditions. With GSO, not only are we able to provide this testing, but we’re also preparing for the future when genome sequencing may become the new standard-of-care clinical test for these patients. This pilot is another step in the path to achieve SickKids’ vision of Precision Child Health, where every patient and family receives individualized care.” 
– Dr. Martin Somerville, Division Head of Genome Diagnostics, SickKids