Annual Meeting Abstracts: View

  • (Abst. 1.402), 2018
  • Comprehensive Phenotyping and Genotyping in a Scottish Population-Based Cohort of Children Presenting With Epilepsy <3 Years
  • Authors: Joseph D. Symonds, Royal Hospital for Children, Glasgow; Katherine S. Elliott, Wellcome Trust Centre for Human Genetics, University of Oxford; Julian C. Knight, Wellcome Trust Centre for Human Genetics, University of Oxford; Andreas Brunklaus, Paediatric Neurosciences Research Group; Sarah Gardiner, West of Scotland Regional Genetics Department; Shelagh Joss, West of Scotland Regional Genetics Department; Stewart McLeod, Paediatric Neurosciences Research Group; Mary O'Regan, Paediatric Neurosciences Research Group; Daniela T. Pilz, Paediatric Neurosciences Research Group; Kirsty Stewart, West of Scotland Regional Genetics Department; and Sameer M. Zuberi, Paediatric Neurosciences Research Group
  • Content:

    Rationale: Early childhood is associated with a high age-specific incidence of epilepsy. Epilepsy is an etiologically heterogeneous condition, though genetic factors are thought to underpin a significant proportion of cases. Next generation sequencing (NGS) genetic testing allows a greater proportion of cases to be etiologically resolved than previously. Early onset of seizures is associated with high diagnostic yield from genetic testing. In the absence of population-based data, it is not clear how much of a difference genetic testing makes to overall yield from etiology-focussed investigations. Methods: Early-onset epilepsy cases in the West of Scotland (population 2.65 million; 27,000 births per year) were identified from two independent sources: a prospective study of gene panel testing in all new epilepsy cases, and review of the clinical notes of all children who had been investigated with EEG. Criteria for inclusion wereDiagnosis of epilepsy made before third birthday, andDiagnosis of epilepsy made between May 8th 2014 and May 7th 2017.All cases who remained without identified etiology after neuroimaging, karyotype, microarray, and metabolic tests were tested on a 104 gene epilepsy panel. After panel testing, all drug-resistant cases with still unidentified etiology were offered "trio" (both parents and child) Whole Genome Sequencing (WGS).Capture-recapture analysis was used to estimate missing cases.  Patients were followed up for a minimum of 12 months. Details of initial presentation, subsequent seizure evolution, investigations, therapeutic management, and development were gathered in all cases. Associations between clinical features of presentation, etiology, and the development of drug-resistance and/or global developmental delay (GDD) were investigated. Drug-resistance was defined as failure of two adequately trialled anti-epileptic drug regimens. Developmental data was gathered from clinical review and from parent-completed validated questionnaires (ABASII). Results: The estimated total was 218 cases (208 identified with 5% under ascertainment), making the incidence of epilepsy under three years 1 per 380 live births. At most recent follow-up 34% had developed drug-resistant epilepsy and 50% had GDD.Fifty-one percent of the cohort had an etiology identified prior to WGS: 33% of all cases had a genetic cause; 23% a structural cause; 4% a metabolic cause; and 1% an immune cause. 10% fell into >1 etiological category. Of the genetic causes: 10% were trisomies; 23% were chromosomal microdeletions/duplications; and 67% were single gene variants. Without microarray, single gene, or panel testing, only 28% of cases would have been resolved. These tests increased diagnostic yield by 82% (p < 0.001).Identification of a genetic cause was associated with drug-resistance (odds ratio [OR] 4.34; 95% confidence intervals [CI] 2.34-8.07) and GDD (OR 2.54; 95% CI 1.40-4.63). Structural etiology was associated with GDD (OR 3.12, 95% CI 1.56-6.27) but not drug-resistance (OR 1.36, 95% CI 0.70-2.65). 13 drug-resistant cases without identified cause underwent trio WGS, which identified a strong candidate variant in 75% (not included in odds ratios above). Several novel candidate epilepsy genes were identified. Conclusions: One in 380 children will develop epilepsy before their third birthday, of whom one third develop drug resistance and half have GDD. Etiology can be resolved in more than half of cases. Genetic testing has increased etiological yield by 82%. Identifying a genetic etiology is predictive of both drug-resistance and developmental impairment. WGS is useful in unexplained drug-resistant cases. Funding: This research was supported by charitable grants from Epilepsy Research UK and Glasgow Children's Hospital Charity.
  • Figures:
  • Figure 1
  • Figure 2