Advantages of Exome Sequencing Over Panel Testing for Individuals With a Seizure Indication

Our aim was to investigate the advantages of exome sequencing versus panel testing for patients with unexplained seizures.

We reviewed the diagnostic outcomes of exome sequencing by a commercial genetics laboratory for more than 16 000 individuals with a clinical history of seizures or suspected seizures.

Exome sequencing identified diagnostic variants (pathogenic and/or likely pathogenic; L/PATH) in 778 seizure-related genes, resulting in diagnoses in 4035 individuals (24.6% of the cohort). Of the 778 genes, 454 (58.4%) were not present on a comparison sample of six commercially available epilepsy panel tests. The analysis predicted that the epilepsy panels would have missed 52%-63% of diagnostic cases reported by exome sequencing. Nineteen percent (753/4035) of the cohort had a previous epilepsy panel. Exome sequencing added new diagnostic information in this panel-tested sub-cohort, including L/PATH variants not reported on the epilepsy panel (74.2% of patients) and L/PATH variants that were originally classified as variants of uncertain significance by the panel (11.2% of patients). Exome sequencing identified L/PATH variants likely to have immediate implications for clinical intervention in 17.9% of diagnostic cases and in 10.0% of cases with a previous nondiagnostic epilepsy panel.

The data demonstrated limitations of epilepsy panels and several advantages of exome sequencing over panels for patients with unexplained seizures. Exome sequencing offered a higher diagnostic rate than previously published for panels and the identification of variants with implications for clinical intervention among patients with prior nondiagnostic epilepsy panels. Another advantage of exome sequencing was the identification of clinically relevant findings unrelated to seizures. Together, these data further support the use of exome sequencing as a first-tier test for patients with unexplained seizures and demonstrate the potential clinical benefits of comprehensive genetic testing.

Not applicable.