Sophia Ceulemans, MS, Medical Science Liaison at GeneDx offered a high-level overview of the problem of unexplained epilepsy and the rapidly advancing field of genetic testing for this challenging disorder. Ms. Ceulemans co-authored the current guidelines from the National Society of Genetic Counselors (NSGC).
One in 26 people will develop epilepsy in their lifetime. For the vast portion of patients with seizures, the underlying cause of the epilepsy is unknown. In younger patients, there may be linkages to other disorders, such as autism and cystic fibrosis, whereas in older patients, the seizures are more frequently linked to acquired causes, such as trauma or neurologic complications of other diseases (e.g., cancer).
With improved gene-testing techniques, including exome sequencing (ES) and genomic sequencing (GS), we are beginning to fill some diagnostic gaps in patients with unexplained epilepsy, and associate a host of pathogenic variants in young and old patients with seizures. Of the hundreds of pathogenic variants identified to date, the majority are autosomal dominant (that is, not inherited). To further complicate the picture, not every person found to have a pathogenetic variant will go on to develop epilepsy. It may well take the action of a combination of pathogenic variants to cause epileptic seizure. Genetic testing is often only offered when seizures are not adequately controlled by medical therapy.
Being able to zero-in on the diagnostic cause of the unexplained epilepsy may finally provide a pathway to better management for these patients. For example, a potential therapeutic approach for a patient with SCN2A, a gain-of-function variant, would be the use of sodium-channel blocking medications. In contrast, a patient with the SCN1A loss-of-function pathogenic variant may benefit from the avoidance of sodium-channel blockers. Another example would be employing a ketogenic diet in patients with a SLC2A1 variant.
Incredible advances have occurred in genetic technology and in our ability to interpret the results of testing. The advent of exome and genomic sequencing has allowed the care team to cast a far wider net and identify pathogenic variants that were missed by conventional gene-panel testing. For example, ES sequences thousands of genes in the coding region; GS also includes noncoding regions and mitochondrial DNA: ES covers up to 2% of the total genome; GS covers the entire DNA sequence.
One study of more than 16,000 patients with seizures and a diagnostic finding on ES showed that 75% had previously undergone panel testing, which missed their genetic-based diagnosis.
The NSGC guideline strongly recommends genetic testing for all individuals with unexplained epilepsy, regardless of age. Either ES or GS are conditionally recommended first line over the conventional gene-panel tests.
The guideline emphasizes the need for a provider who is knowledgeable about genetic tests and can interpret the results in the context of an individual’s presentation.
Knowing the molecular reason for the unexplained epilepsy diagnosis can help inform management and may help guide medical therapy and possible surgical treatments. Furthermore, it may even drive future gene-replacement therapies.
To learn more about the role of genetics in epilepsy, visit https://checkrare.com/the-genetics-of-epilepsy-the-importance-of-identifying-underlying-causes/
