Diagnostic Yield and Treatment Impact of Targeted Whole Exome Sequencing in Early Onset Epilepsy (I14.001)
Bibliographic record
Abstract
Objective: To report the results of whole exome sequencing (WES) on 63 patients with early onset epilepsy of unknown cause, evaluating diagnostic yield and possible treatment implications. Background: Modern genomic technologies, such as targeted high throughput next generation sequencing (tHTS) and WES, enable the identification of pathogenic variants in 10 - 78 [percnt] of selected patients with unexplained epilepsy. The clinical impact is significant, including an earlier diagnosis of disorders with specific treatment implications. Methods: Between December 2014 - September 2015 WES was performed in 63 patients with early onset epilepsy (≤ 5 years) of unknown cause. Patients were classified as retrospective (epilepsy > 6 months) or prospective (epilepsy < 6 months). WES was performed using the Ion AmpliSeq™ Exome Kit and Ion Proton™ System within 2 weeks of receiving samples. Reporting was restricted to variants of 539 genes implicated in epilepsy, including 47 genes with treatment implications. Putative causative mutations were validated by Sanger sequencing. Results: A genetic diagnosis was made in 19 of 63 patients (30[percnt]: 6/15 prospective; 13/48 retrospective), a possible diagnosis was identified in 12 additional patients. Twelve of 63 patients (19[percnt]: 4/12 prospective, 8/12 retrospective; mean age of seizure onset 11 months (range 0-60)) had a diagnosis with treatment implications (SCN1A, POLG, KCNQ2 x6, ATP1A2, SCN1B, BTD, SCN5A). This included initiation of recommended specific treatment or avoidance of anti-seizure medication worsening seizures (e.g. sodium channel antagonists in SCN1A). Of these 12 patients, four (1 prospective, 3 retrospective) had neonatal seizures and six had an epileptic encephalopathy; epilepsy syndromes included Dravet (2), Lennox-Gastaut (1), and Landau-Kleffner (1). Conclusions: Clinical utility of WES in this epilepsy patient cohort was supported with a potential genetic diagnosis in nearly half of the cohort. The genetic diagnosis in 12/63 (19[percnt]) patients with variable epilepsy phenotypes had immediate treatment impacts.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".