To effectively treat a disease or disorder, physicians must first know the root cause. Such is the case with epileptic and developmental encephalopathies (EDEs), the causes of which can be enormously complex and heterogeneous. Scientists at St. Jude Children’s Research Hospital demonstrated the value of DNA methylation patterns in identifying the root cause of EDEs, showing that methylation of specific genes and genome-wide methylation “episignatures” can help identify the genes that cause EDEs. The findings were published today in Nature Communications.
DEEs affect 1 in 590 children and involve more than 825 genes. Current testing methods can clinically identify the root cause, or etiology, of about 50% of people’s DEEs, guiding clinicians and families toward appropriate care and support. However, the remaining half of all patients remain unresolved.
“About half of patients with EED will receive a diagnosis, and half will not,” said co-corresponding author Heather Mefford, MD, PhD, of the St. Jude Pediatric Neurological Disease Research Center and Department of Cellular and Molecular Biology.
When a child is diagnosed with EED, linking the encephalopathy to a specific gene can allow the doctor to provide appropriate treatment or manage the symptoms of the disorder. This knowledge is also invaluable to the family.
“The half who are not diagnosed will not only be unable to obtain specific genetic recommendations for their therapy, but they will also not be able to connect with family organizations that can connect them with other families with children who also have mutations in that gene,” Mefford explained.
The value of identifying rare genetic links to DEE
Addressing the genetic causes of EED has been a long-term goal for Mefford, who was instrumental in increasing the number of diagnosable cases to 50%, up from about 5% just a decade ago.
Currently, 80% of identifiable personality disorders can be explained by 27 genes. Addressing the remaining unsolved cases requires identifying the many rare occurrences of the disorder — a challenge that co-lead author and St. Jude Graduate School of Biomedical Sciences student Christy LaFlamme embraced.
“One way to get to the remaining 50% is to explore what traditional tests don’t look at,” LaFlamme said. “Current tests don’t look at the non-coding space that regulates gene expression. Many of these disorders are due to loss of expression of epilepsy genes.”
DNA methylation fingerprinting offers a solution
Mefford is exploring epigenetics — changes in gene expression that may or may not involve alterations to DNA — as a possible solution. One such epigenetic change involves a process vital to gene expression called DNA methylation. This process is similar to a chef leaving notes next to a recipe telling the reader to skip or repeat a step.
“For some genetic disorders, all people with a mutation in the same gene have a methylation profile across their genome that puts them in a category with all other people with the same genetic disorder,” Mefford said. This methylation landscape is called an “episignature,” and is similar to a DEE fingerprint.
While episignatures allowed researchers to broadly identify variants that cause DEE, looking more closely at individual methylation instances — known as rare methylation analysis — presented another opportunity. “The underlying cause of the disease ends up manifesting itself in an episignature that can serve as a marker for that gene,” LaFlamme explained. “With rare methylation events, their analysis can directly point to the cause of the disease.”
New technologies help detect rare cases of methylation
Exploring these rare methylation events across the genome using long-read DNA sequencing directed researchers toward regions of DNA that are not commonly assessed, offering an answer to the cause of these cases.
This double whammy allowed researchers to identify causal and candidate etiologies of EED in 2% of previously unidentified cases. This represents another significant step in identifying rare cases of EED and another tool to aid in the diagnosis of children with EED.
Mefford is determined to keep working hard. Her position with the St. Jude Pediatric Translational Neuroscience Initiative means she can continue to address the so-called “N of few,” the rarest incidences of neurological disorders like DEE.
“We remain dedicated to trying to solve the remaining cases. We’ve always taken advantage of new technologies, such as next-generation sequencing 10 years ago and now methylation analysis and long-read sequencing,” Mefford said. “We’re always looking for technologies that will give us new information to try to solve those cases.”