Authors :
Michael Doyle, MRCPI - Beaumont Hospital, RCSI, FutureNeuro, Blackrock Clinic; Katherine Benson - FutureNeuro SFI Research Centre; Patrick Moloney - Beaumont Hospital; Robert Carton - FutureNeuro SFI Research Centre; Hugh Kearney - FutureNeuro SFI Research Centre; Hany El Naggar - Beaumont Hospital; Peter Widdess-Walsh - Beaumont Hospital; Gianpiero Cavalleri - FutureNeuro SFI Research Centre; Norman Delanty - Beaumont Hospital
Rationale: The diagnostic yield of whole exome sequencing can be as high as 40% in people with intellectual disability (ID) and seizures. However, the utility of exome sequencing is currently unclear for people with epilepsy without ID. The aim of this study was to evaluate the yield (percentage) of genomic testing, following American College of Medical Genetics (ACMG) guidelines, for pathogenicity in people with epilepsy without learning disability, stratified by response to anti-epileptic drug treatment.
Methods: Cases, identified via the Beaumont Hospital Electronic Patient Record (EPR) system, were clinically phenotyped and sub-divided into 4 groups: super-refractory focal epilepsy (who have failed five or more medications), super-refractory generalized epilepsy (who have failed three or more medications), ILAE-defined refractory epilepsy (despite trials of two medications) and responders (who have achieved seizure freedom with medication). Exome data was analyzed using a genomic analysis toolkit (GATK/in house pipeline and Congenica) and were discussed at an epilepsy-genetics multidisciplinary team meeting.
Results:
| | Super refractory focal epilepsy | Super refractory generalized epilepsy | Super refractory epilepsy combined | ILAE defined refractory epilepsy | Responders | Total |
| Number of cases | 108 | 32 | 140 | 87 | 100 | 327 |
| Pathogenic variants | 1 | 1 | 2 | 0 | 1 | 3 |
| Likely pathogenic variants | 5 | 1 | 6 | 1 | 0 | 7 |
| VUS | 33 | 9 | 42 | 8 | 24 | 74 |
| Benign/Likely benign | 5 | 0 | 5 | 1 | 2 | 8 |
| Yield | 5.55% | 6.25% | 5.71% | 1.15% | 1% | 3.06% |
P Value
| 0.12 | 0.14 | 0.08 | 1 | N/A | |
A total of 327 individuals were included in the study, of whom 3.06% had an identifiable genetic cause for their epilepsy. Of 140 patients with super-refractory epilepsy (combined focal and generalized), the diagnostic yield was 5.71%, elevated beyond the level observed in responsive patients (1%) although the difference was not significant (p = 0.08).
Conclusions: We have suggestive evidence that super-refractory epilepsy may be enriched for cases with an identifiable ACMG-satisfying mutation. We are currently extending the study to a larger patient group and analysis is ongoing.
Funding: Please list any funding that was received in support of this abstract.: N/A.