Imagine having a terrible medical condition and not knowing what it was.
More than 400,000 Albertans have a rare disease. Many of them face challenges getting the right diagnosis, let alone finding the right specialist and obtaining effective treatment. Some cases are deadly; others can have a major impact on a patient’s day-to-day life.
Advances in genetic screening in the last two decades mean a higher percentage of these diseases are diagnosed. But current tests—which rely largely on DNA sequencing—have their limitations, said Peter Kannu, associate professor and chair of the University of Alberta’s Department of Medical Genetics.
Kannu is leading a team of U of A researchers who are developing more sensitive and dynamic genetic tests that will add the sequencing of RNA (responsible for gene expression or messaging) to the current practice of genome sequencing (which explores mutations in the DNA). The team will also look for changes in small molecules called metabolites, which are involved in metabolism.
The first stage of the work will take place in a research lab in the Department of Medical Genetics, with the goal of validating the new protocols in a diagnostic lab at Alberta Precision Laboratories. The pilot project received financial support from a U of A Precision Health Seed Fund Award.
Tackling ‘orphan diseases’
There are various definitions of what constitutes a rare disease, but one describes it as a condition that affects fewer than one person in 2,000.
“These are the diseases no one has heard of,” said Kannu, who is also a member of the Women and Children’s Health Research Institute (WCHRI). “We often call them orphan diseases because they have no home. Most doctors throw their hands up when a patient walks through the door with one of these conditions.”
Before genetic testing, doctors were able to diagnose rare diseases in fewer than 10 per cent of patients with unexplained conditions. The situation improved by the early 2000s, with the progress in DNA testing. “We transitioned from our ability to sequence a few genes at a time to being able to sequence thousands of genes very quickly,” said Kannu. “That was amazing for us.”
Diagnosis rates rose significantly but even today, 60 to 65 per cent of patients with a rare medical condition remain undiagnosed. “We’ve reached a ceiling” using current strategies, said Kannu.
“The basic problem is that it takes decades for a gene to tell its story,” said collaborator Sherry Taylor, associate professor in the Department of Medical Genetics, molecular geneticist and north sector medical lead for genetics and genomics at Alberta Precision Laboratories. Even genes that have been studied for 25 years—such as the BRCA1 and BRCA2 genes linked to familial breast and ovarian cancer—are not yet fully understood by scientists.
“When we look at variations in genes,” Taylor added, “sometimes we can look at it and say, ‘No problem here,’ or we can say, ‘Yes, this really causes a problem.’ And then there’s a whole class in between called variants of uncertain significance, where we are not really sure what they do.”
A more dynamic approach
Sequencing DNA alone is not enough. “We need to look beyond the DNA to make genetic diagnoses,” said Kannu. “The simple reason is that the DNA is a static representation of the information. It doesn’t change very much in time. We need a more dynamic approach to look at changes that are happening in the body with genetic information.”
One of those changes is in gene expression, which is coded by RNA. Adding RNA sequencing to the genetic tests should result in considerable gains in rare-disease diagnosis, said Kannu.
The pilot project will use the latest RNA sequencing technologies on genetic samples from 15 patients. The new RNA testing platform will be validated in the diagnostic laboratory and the results will allow the collaborators to apply for larger grants. The research results will build a rich digital library of patient gene-expression profiles for future use.
The more sensitive, dynamic genetic tests could be in use within three to five years, said Kannu, who is already running a pilot project for the detection of rare diseases in children in Alberta through the Undiagnosed Disease Program.
Improved and comprehensive testing will result in cost savings for the health-care system, since patients with rare diseases typically undergo multiple rounds of expensive tests. More important, it will give answers to thousands of patients living with the uncertainty and stress of having an undiagnosed condition.
“For some of these cases, there may be nothing that can be done, but at least you are providing an answer and some closure,” said Taylor. “In other cases, you are providing a means by which a clinician can actually help the patient with the condition, providing a route to treatment or therapy. That’s the ultimate goal.”