UCL Great Ormond Street Institute of Child Health


Great Ormond Street Institute of Child Health


The genetic basis of epilepsy in children with intellectual disabilities

Supervisors: Professor David Skuse, Professor Helen Cross

In England, there are over a million people with learning disabilities, a quarter of whom are children of school age. Most moderate to severe intellectual disability (ID) has a genetic cause. To identify those genetic risks, the NHS is now routinely screening the DNA of children who have significant developmental delays. The IMAGINE-ID programme of research has recruited a national cohort of 3,402 UK families whose child has ID due to a genetic cause, the largest cohort of its type in the world. It includes ~2400 children with pathogenic copy number variants (CNV) and ~1000 with single nucleotide variants (SNV). Using a combination of online interviews, questionnaires, and face-to-face meetings with families, we have built up a comprehensive picture of those children's strengths and weaknesses, and secured MRC-UK funding for a longitudinal follow up (2020-2024). Cohort participants have a range of behavioural difficulties and co-morbidities for which standardized measures have been obtained. Over 50% have co-occurring mental health disorders, nearly half have neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). 18% have had seizures. Intellectual disability, epilepsy and neurodevelopmental disorders are frequently co-morbid (Lee et al., 2015), but the behavioural phenotypes associated with rare genetic disorders and epilepsy in childhood have not been comprehensively documented and the generalizability of findings is questionable because of ascertainment bias. The IMAGINE-ID cohort is unique because, in virtually all cases, the reason for genetic testing was developmental delay rather than seizures (contrast Niestroj et al, 2020) and the diversity of CNV and SNV found to be associated with seizures is substantial (not limited to a few candidate genes or CNVs known to be associated with high susceptibility).

First, to describe the natural history, co-morbidities, response to treatment, behavioural phenotypes and educational attainment of IMAGINE-ID cohort children with epilepsy. We propose taking a genetics-first approach, comparing the behavioural phenotypes of subgroups with and without a history of seizures, but who share the same genetic condition (CNV/SNV), in order to identify phenotypic commonalities that could have arisen in those with epilepsy (Allen et al, 2013). Second, to identify risk and resilience factors that could influence behavioural outcomes in terms of psycho-social adjustment and mental health. Finally, to identify from medical histories, those syndrome-specific treatments that have led to optimal outcomes; we know from existing data that there is great diversity in UK management by region. The IMAGINE-ID dataset will be linked to UK Hospital Episode Statistics and to the National Pupil Database.  
The candidate will initially undertake a systematic review of extant research on CNV and SNV that are associated with epilepsy, then identify from the IMAGINE-ID database participants with a history of seizures and classify these by neurodevelopmental characteristics and the associated genetic anomaly. A pattern of phenotypic development over time (including behavioural adjustment and educational progress) can be identified from data obtained during the longitudinal follow-up study. Further information on medical histories and management will be obtained from HES data-linkage, and from direct enquiry of participating families where appropriate. There will be the opportunity to describe ultra-rare genetic associations with seizures and potential further projects based upon these findings that could explore phenotypic characteristics in depth (e.g. EEG/neuroimaging). 


Lee, B. H., Smith, T., & Paciorkowski, A. R. (2015). Autism spectrum disorder and epilepsy: disorders with a shared biology. Epilepsy & Behavior, 47, 191-201.

Allen AS, Berkovic SF, Cossette P, Delanty N, Dlugos D, Eichler EE, Epstein MP, Glauser T, Goldstein DB, Han Y, Heinzen EL. De novo mutations in epileptic encephalopathies. Nature. 2013 Sep;501(7466):217.

Niestroj, L. M., Howrigan, D. P., Perez-Palma, E., Saarentaus, E., Nürnberg, P., Stevelink, R., ... & Collaborative, E. (2019). Evaluation of copy number burden in specific epilepsy types from a genome-wide study of 18,564 subjects. BioRxiv, 651299.