ORLANDO — , new research suggests. Investigators found that pathogenic genetic variants were identified in over 40% of patients with epilepsy of unknown cause who underwent genetic testing.
Such testing is particularly beneficial for those with early-onset epilepsy and those with comorbid developmental delay, said study investigator Yi Li, MD, PhD, clinical assistant professor, Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, California.
But every patient with epilepsy of unknown etiology needs to consider genetic testing as part of their standard workup.
Dr. Li noted research showing that a diagnosis of a genetic epilepsy leads to alteration of treatment in about 20% of cases — for example, starting a specific antiseizure medication or avoiding a treatment such as a sodium channel blocker in patients diagnosed with Dravet syndrome. A genetic diagnosis also may make patients eligible for clinical trials investigating gene therapies.
Genetic testing results may end a long and exhausting “diagnostic odyssey” that families have been on, she said. Patients often wait more than a decade to get genetic testing, the study found.
The findings were presented at the annual meeting of the American Epilepsy Society.
Major Delays
About 20%-30% of epilepsy is caused by acquired conditions such as stroke, tumor, or head injury. The remaining 70%-80% is believed to be due to one or more genetic factors.
Genetic testing has become standard for children with early-onset epilepsy, but it’s not common practice among adults with the condition — at least not yet.
The retrospective study involved a chart review of patient electronic health records from 2018-2023. Researchers used the Stanford electronic health record Cohort Discovery tool (STARR) database to identify 286 patients over age 16 years with epilepsy who had records of genetic testing.
Of the 286 patients, 148 were male and 138 female, and mean age was approximately 30 years. Among those with known epilepsy types, 53.6% had focal epilepsy and 28.8% had generalized epilpesy.
The mean age of seizure onset was 11.9 years, but the mean age at genetic testing was 25.1 years. “There’s a gap of about 13 or 14 years for genetic workup after a patient has a first seizure,” said Dr. Li.
Such a “huge delay” means patients may miss out on “potential precision treatment choices,” she said.
And having a diagnosis can connect patients to others with the same condition as well as to related organizations and communities that offer support, she added.
Types of genetic testing identified in the study included panel testing, which looks at the genes associated with epilepsy; whole exome sequencing (WES), which includes all 20,000 genes in one test; and microarray testing, which assesses missing sections of chromosomes. WES had the highest diagnostic yield (48%), followed by genetic panel testing (32.7%) and microarray testing (20.9%).
These tests collectively identified pathogenic variants in 40.9% of patients. In addition, test results showed that 53.10% of patients had variants of uncertain significance.
In the full cohort, the most commonly identified variants were mutations in TSC1 (which causes tuberous sclerosis, SCN1A (which causes Dravet syndrome), and MECP2. Among patients with seizure onset after age 1 year, MECP2 and DEPDC5 were the two most commonly identified pathogenic variants.
Researchers examined factors possibly associated with a higher risk for genetic epilepsy, including family history, comorbid developmental delay, febrile seizures, status epilepticus, perinatal injury, and seizure onset age. In an adjusted analysis, comorbid developmental delay (estimate 2.338; 95% confidence interval [CI], 1.402-3.900; P =.001) and seizure onset before 1 year (estimate 2.365; 95% CI, 1.282-4.366; P =.006) predicted higher yield of pathogenic variants related to epilepsy.
Dr. Li noted that study participants with a family history of epilepsy were not more likely to test positive for a genetic link, so doctors shouldn’t rule out testing in patients if there’s no family history.
Both the International League Against Epilepsy (ILAE) and the National Society of Genetic Counselors (NSGC) recommend genetic testing in adult epilepsy patients, with the AES endorsing the NSGC guideline.
Although testing is becoming increasingly accessible, insurance companies don’t always cover the cost.
Dr. Li said she hopes her research raises awareness among clinicians that there’s more they can do to improve care for epilepsy patients. “We should offer patients genetic testing if we don’t have a clear etiology.”
