Improving diagnosis of rare congenital disorders

Eye on Innovation

Eye on Innovation features exciting advances taking place at Mayo Clinic Laboratories. This monthly series shines a spotlight on recently developed tests and highlights how Mayo Clinic translates ideas and discoveries into testing resources that improve diagnosis and care for patients across the globe.

When a child falls ill, two questions quickly come front and center for parents: What’s the problem, and what can be done to fix it? For families whose children have certain congenital disorders, the answers to those questions can be maddeningly elusive.

Laboratory tests to diagnose congenital disorders of methylation, such as Beckwith-Wiedemann, Silver-Russell, Prader-Willi, and Angelman syndromes, often come back without a definitive result.  

“We can have up to 25% of our results be equivocal for these conditions, and that's just not acceptable,” says Linda Hasadsri, M.D., Ph.D., director of Mayo Clinic’s Molecular Technologies Laboratory in the Department of Laboratory Medicine and Pathology’s Division of Genetics and Genomics. “These are typically pediatric patients, and their parents are already in an anxious and stressful state, hoping to get an answer through testing. With an unclear result, we haven't solved anything. And we may have even added to their anxiety.”   

Linda Hasadsri, M.D., Ph.D.

The need to improve those tests is particularly pressing at Mayo Clinic because it has one of the largest volumes in the world of molecular testing for rare congenital conditions involving abnormal methylation. In 2020, Dr. Hasadsri and a team in Mayo Clinic’s Advanced Diagnostics Laboratory launched a project to create a replacement for the current method of testing, which has been the gold standard for more than 20 years. Over the last two years, that project has produced remarkable results.

“Once we had it ready to go, we ran samples that were previously called equivocal and used the new method to see if it yielded the same result. It correctly yielded the diagnosis on the first attempt. That’s a fantastic finding,” Dr. Hasadsri says.

“With this method, patients will be able to get the answer they need in one try, rather than having to embark on a potential diagnostic odyssey.”

Uncovering key changes

To create enhanced testing for these rare congenital conditions, the team crafted a novel bioinformatics tool and paired it with new technology — a methylation array — that increased the sensitivity and specificity of the test results.

As an added bonus, they were able to include more disorders beyond the four that were first identified, including fragile X syndrome and Huntington’s disease. All the disorders involve abnormal methylation, a process that basically turns a gene off and results in a genetic defect. Methylation disorders are one form of an epigenetic change.   

“Epigenetics changes the expression of genes without altering the base sequence of the DNA itself,” Dr. Hasadsri says. “Methylation is a natural process in development and tissue differentiation. But it may be altered due to environmental exposures or disease, and methylation changes also can be inherited.”

Detecting methylation changes is key to the success of the new testing method, which looks at the whole methylome, not just a single targeted region of methylation in the genome. So when there’s strong clinical suspicion that a patient has a potentially heritable disorder, but whole genome or exome sequencing doesn’t reveal an answer, whole methylome analysis may uncover the problem.

“There’s increasing evidence in those cases that they might actually have abnormalities in the epigenome instead, and traditional forms of genetic testing don’t catch that,” Dr. Hasadsri says.

Applying advanced bioinformatics

For the test to appropriately identify abnormalities in a person’s epigenome, Mayo Clinic bioinformaticians Garrett Jenkinson, Ph.D., and Jesse Walsh, Ph.D., developed statistical modeling that took into account the fact that the epigenome varies based on biological sex and age. They then developed reference ranges for the test that could be matched to the individual.

“We’ve shown if you were to run this testing on a known Silver-Russell case, but you use a reference range based on a different age group, you could get a false negative because, epigenetically, these life stages are different,” Dr. Hasadsri says.

“What Mayo Clinic has done here bioinformatically is what elevates and sets this test apart. What we have is unique. This isn’t just a Mayo first. It’s a Mayo only and a Mayo best.”

With the success of this project, the test has now moved into the development phase, and the team anticipates that it will become commercially available in the future.

Making a life-changing difference

Using the new method to identify these rare disorders more quickly and accurately will yield significant benefits for patients and their families. For example, when a test result comes back as “equivocal,” it means the sample may be abnormal, but the limits of the testing technology have been reached, and a definitive diagnosis can’t be made.

“In those cases, another sample may be sent later for repeat testing in the hopes that an answer can be reached then,” Dr. Hasadsri says. “But in the meantime, providers usually just continue to manage the patient as if they have that disorder. Without the official diagnosis, however, it can be a struggle to get insurance coverage for certain treatments. And more worrisome, treatments may be inappropriate if the diagnosis is incorrect.”

Conversely, a proper diagnosis puts patients on the road to better long-term health. People who have Beckwith-Wiedemann syndrome, for instance, are predisposed to a certain type of cancer.

“For them, having the proper diagnosis means they can receive the heightened surveillance they need to watch for that cancer,” Dr. Hasadsri says. “Catching it early on, just as it begins, can be lifesaving for those individuals. That’s the life-changing difference putting the time and effort into building a superior test like this can have for patients.”

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Tracy Will

Tracy Will is a senior marketing specialist at Mayo Clinic Laboratories where she covers innovation, specialty testing, and advances in laboratory medicine. Tracy has worked at Mayo Clinic since 2016.