Abstract
Targeted whole-exome sequencing (WES) is a powerful diagnostic tool for a broad spectrum of heterogeneous neurological disorders. Here, we aim to examine the impact on diagnosis, treatment and cost with early use of targeted WES in early-onset epilepsy. WES was performed on 180 patients with early-onset epilepsy (≤5 years) of unknown cause. Patients were classified as Retrospective (epilepsy diagnosis >6 months) or Prospective (epilepsy diagnosis <6 months). WES was performed on an Ion Proton™ and variant reporting was restricted to the sequences of 620 known epilepsy genes. Diagnostic yield and time to diagnosis were calculated. An analysis of cost and impact on treatment was also performed. A molecular diagnoses (pathogenic/likely pathogenic variants) was achieved in 59/180 patients (33%). Clinical management changed following WES findings in 23 of 59 diagnosed patients (39%) or 13% of all patients. A possible diagnosis was identified in 21 additional patients (12%) for whom supporting evidence is pending. Time from epilepsy onset to a genetic diagnosis was faster when WES was performed early in the diagnostic process (mean: 145 days Prospective vs. 2,882 days Retrospective). Costs of prior negative tests averaged $8,344 per patient in the Retrospective group, suggesting savings of $5,110 per patient using WES. These results highlight the diagnostic yield, clinical utility and potential cost-effectiveness of using targeted WES early in the diagnostic workup of patients with unexplained early-onset epilepsy. The costs and clinical benefits are likely to continue to improve. Advances in precision medicine and further studies regarding impact on long-term clinical outcome will be important.
Highlights
Epilepsy is a common pediatric neurological disorder associated with an increased risk of developmental delay, autism and psychiatric illness; and for which treatment is ineffective in 30– 40% of patients
A variant of uncertain significance (VUS) possibly explaining the clinical symptoms of the index patient was identified in 21 cases (12%) (Supplementary Table 3)
High-throughput sequencing has been proven to be a great diagnostic tool in clinical practice in a variety of genetic conditions, and if used early in the diagnostic workup can lead to a reduction of costs associated with obtaining a molecular diagnosis [22]
Summary
Epilepsy is a common pediatric neurological disorder associated with an increased risk of developmental delay, autism and psychiatric illness; and for which treatment is ineffective in 30– 40% of patients. High-throughput sequencing (HTS) has become a widespread diagnostic tool in various genetic conditions, including epilepsy [1], vastly improving molecular diagnosis. A genetic diagnosis of epilepsy may enable more accurate counseling regarding prognosis and recurrence risk, avoids unnecessary medical investigations and may change care. Recent studies have demonstrated the potential cost savings of WES in the diagnostic workup of children with suspected monogenic disorders [15,16,17,18,19,20,21,22]. In Canada, access to such technology in clinical care is variable. In this British Columbia study, we assess the effectiveness of using WES by comparing diagnostic yield, time to diagnosis, and cost to current clinical practices. The potential treatment impact of a genetic diagnosis is described
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