Next-Gen Sequencing Has Significant Utility for Drug-Resistant Epilepsy

Next-generation sequencing improves definitive diagnoses for children with drug-resistant epilepsy, according to a pilot study published online June 22 in CNS Neuroscience & Therapeutics. Furthermore, use of both genetic panels and whole-exome sequencing, can improve treatment efficacy and reduce hospitalizations.

Despite development of new drugs, medications still fail to control seizures in 20 percent to 30 percent of patients. Drug selection remains largely a function of trial and error. Furthermore, drug-resistant epilepsy accounts for the vast majority—estimated to be nearly 80 percent—of the cost of all epilepsy treatment.

“Etiology is a major determinant of treatment, prognosis, and clinical course in epilepsy patients,” write the authors led by Jing Peng, from Central South University in China. “During the last few years, accumulated evidence supports the strong role of genetics in unexplained drug-resistant epilepsy patients.”

In the current study, 273 pediatric patients (average age 13.2 years) with drug-resistant epilepsy and no obvious cause of acquired epilepsy were evaluated (2012 to 2016), with 74 undergoing whole-exome sequencing (WES), 141 patients an epilepsy-related gene panel testing, and 58 patients clinical whole-exome gene panel testing (clinical WES; 3,994 Mendelian disease-related genes). The researchers developed the first version of the epilepsy-related gene panel in 2012 and included 308 genes. However, as genetic knowledge evolved, so did the panel, which now includes 540 genes. Follow-up assessed patients’ seizure and hospitalization frequency.

The researchers found that 86 patients received a genetic diagnosis—a diagnostic yield of 31.5 percent. Clinical WES had the highest detection rate 44.8 percent, followed by the epilepsy-related gene panel) (32.6 percent), and WES (17.3 percent). The tests cost $570 for the gene panel, $720 for clinical WES, and $1,450 for WES, none of which would be covered by insurance in China.

Diagnoses involved 93 likely disease-causing mutations in 33 genes. Of these, mutations in 20 actionable genes that could direct therapy were identified in 62 patients. More than half of patients with actionable gene mutations (34 of 62) immediately accepted the treatment (12 percent of patients overall). After six months of corrective therapy, 52.9 percent of these patients became seizure-free (6.4 percent of the whole cohort) and 38.2 percent with actionable mutations achieved seizure reduction. Over the follow-up period, patients with either positive or negative genetic results had significantly fewer hospitalization incidents.

“Considering both cost and detection rate, we believe that a larger gene panel approach, such as clinical WES, can be a comparable alternative to WES analysis in most cases,” write the authors. “However, reflex testing to WES is an option when a gene panel is negative. It is also important to realize that there is no single best NGS approach.”

Takeaway: NGS-based testing can improve diagnostic accuracy, treatment efficiency, and health care utilization among children with drug-resistant epilepsy.