Understanding Complex Neurological Disorders- DEE

To properly treat an illness or disorder, clinicians must first identify the underlying cause. Such is the situation with developmental and epileptic encephalopathies (DEEs), whose underlying causes can be quite complicated and diverse. Scientists at St. Jude Children’s Research Hospital highlighted the utility of DNA methylation patterns in determining the root cause of DEEs, demonstrating that specific gene methylation and genome-wide methylation “episignatures” can assist identify the genes that cause DEE. The results were published in Nature Communications.

DEEs afflict one in every 590 children and involve more than 825 genes. Current testing methods can clinically identify the fundamental cause, or etiology, of around 50% of people’ DEEs, directing clinicians and families to the most appropriate treatment and support. However, the remaining half of all patients’ cases have still to be resolved.

About half of the patients with DEE will get a diagnosis, and half of them won’t.”

Heather Mefford, MD, PhD, Study Co-Corresponding Author and Member, Department of Cell & Molecular Biology, St. Jude Children’s Research Hospital

When a kid is diagnosed with DEE, tying the encephalopathy to a specific gene can help the doctor provide appropriate treatment or control for the disorder’s symptoms. This knowledge is also extremely beneficial to the family.

“The half who do not receive diagnosis not only won’t be able to get gene-specific recommendations in their therapy, they won’t be able to link with family organizations that can connect them with other families with children that also have mutations in that gene,” explained Mefford.

The importance of detecting unusual genetic connections to DEE

Mefford’s long-term goal has been to address the genetic underlying causes of DEEs, and he was helpful in increasing the number of diagnosable cases to 50%, up from about 5% just ten years ago.

Currently, 27 genes account for 80% of all recognized DEEs. To address the remaining unexplained instances, Christy LaFlamme, co-first author and St. Jude Graduate School of Biomedical Sciences student, accepted the challenge of identifying the disorder’s multiple unusual occurrences.

“One way we can get at the remaining 50% is by exploring what traditional tests don’t look at,” said LaFlamme. “Current tests don’t look at noncoding space that regulates gene expression. A lot of these disorders are due to losing expression of epilepsy genes.”

DNA methylation fingerprint offers a solution.

Mefford is looking into epigenetics, which are changes in gene expression that may or may not include DNA modifications, as a potential remedy. One example of an epigenetic alteration is DNA methylation, which is essential for gene expression. This approach is similar to a chef placing notes next to a recipe telling the reader to skip or repeat a stage.

“For some genetic disorders, everyone with a mutation in the same gene has a methylation profile across their genome that puts them in a category with all the others with the same genetic disorder,” said Mefford. This methylation landscape is called an “episignature” and is akin to a DEE fingerprint.

While episignatures enabled the researchers to discover DEE-causing variations in a broad sense, a deeper look at individual methylation events, known as rare methylation analysis, provided another opportunity. “The underlying cause of the disease ends up manifesting into an episignature that can serve as a marker for that gene,” LaFlamme says. “With rare methylation events, their analysis can point directly to the cause of the disease.”

New methods help detect uncommon methylations.

Exploring these unusual methylation events across the genome using long-read DNA sequencing led the researchers to DNA areas that are rarely studied, providing a solution to the etiology of these occurrences.

This one-two punch enabled the researchers to uncover the causal and potential etiologies of DEEs in 2% of previously undiagnosed instances. This is another crucial step in identifying rare cases of DEEs, as well as another tool for diagnosing children with DEE.

Mefford is determined to keep chipping away in earnest. Her inclusion in the St. Jude Pediatric Translational Neuroscience Initiative implies that the so-called “N of few,” or rarer incidences of neurological illnesses such as DEE, can continue to be addressed.

“We are still dedicated to trying to solve the remaining cases. We’ve always leveraged new technologies, such as next-generation sequencing 10 years ago and now methylation analysis and long-read sequencing,” said Mefford. “We are always looking for technologies that will give us new information to try and solve those cases.”​