Diagnostic Yield and Treatment Impact of Targeted Exome Sequencing in Early-Onset Epilepsy

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.

Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy

“…First, despite growing numbers of cases of FCD type II being explained by somatic variants in the PI3K-AKT-mTOR pathway, raising the possibility that mTOR modulation might be a treatment possibility, our data suggest that not all FCD can summarily be classified as uniquely related to this pathway, although a downstream effect on the mTOR pathway cannot be conclusively ruled out. Second, 2 previously reported patients with SLC35A2 variants were reported to have a positive response to treatment with exogenous galactose, 47,53 raising an interesting possibility for treatment of epilepsy if variants in this gene can be identified early in patients with intractable epilepsy. Collectively, our findings advance our understanding of the pathophysiology of intractable focal epilepsy and the role of somatic mutation in both lesional and nonlesional epilepsy.…”

Genepanel.iobio - an easy to use web tool for generating disease- and phenotype-associated gene lists

“…We chose an ambitious test setting, selecting cases for which diagnostic conclusions had been reached previously at the Penelope Undiagnosed and Rare Disease Program at the University of Utah. The rate of diagnosis in this setting remains between 35 and 45%, often complicated by complex clinical presentations and ambiguous or blended phenotypes [1, 3]. Two analysts, blinded to the causal variants, independently analyzed 16 previously diagnosed clinical cases to see if genepanel.iobio could correctly prioritize the gene containing the diagnostic variant within the final gene list.…”

Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions

“…8 To date, 24 individuals have been identified with pathogenic de novo variants in ALG13 resulting in a neurodevelopmental disorder primarily characterized by early infantile epileptic encephalopathy. [1][2][3][4][5][10][11][12][13][14][15][16][17][18][19][20] Most of these cases were identified in sequencing studies where clinical and variant information is summarized in the supplemental material. Nearly all reported affected persons are female and harbor an apparently recurrent de novo variant (c.320G>A; p.N107S).…”

“…Within the LLO pathway, at least 35 genes have been identified to cause a glycosylation related disorder 8 . To date, 24 individuals have been identified with pathogenic de novo variants in ALG13 resulting in a neurodevelopmental disorder primarily characterized by early infantile epileptic encephalopathy 1‐5,10‐20 . Most of these cases were identified in sequencing studies where clinical and variant information is summarized in the supplemental material.…”