Diagnostic gene sequencing in adults with epilepsy and intellectual disability

MCT Research Talks – 20th February 2017

Sinead Heavin reports

Sinead Heavin, PhD Post-Doctoral Researcher

Epilepsy is a common neurological disorder that affects ~40,000 people in Ireland. There are many different types of seizures which are caused by uncontrolled electrical impulses in the brain. Anti-epileptic drugs control seizures for ~50% of people with epilepsy but up to ~30% of patients remain uncontrolled despite treatment with multiple drugs. Epilepsy is caused by a number of factors include stroke, trauma and infections. However, more recently we have learned that epilepsy can be caused by genetic mutations. Some epilepsies are heritable while others arise de-novo. Many patients with an intellectual disability (ID) also have epilepsy. Many of these patients lack a specific diagnosis due to limited testing and available investigations. We sequenced a cohort of 99 adult patients with epilepsy and ID on a custom gene panel of ~150 genes. A likely pathogenic variant was identified in 20 patients in 19 different genes, including SCN1A, DCX and DEPDC5, well-known epilepsy genes. Furthermore, we identified copy number variants in two patients which are likely causative. Further work is needed to investigate the phenotype-genotype correlations identified in this study and any potential treatment options that may arise.

A pharmacogenomic exploration of adverse drug reactions in epilepsy (PGXOME)

For most people with epilepsy, long term treatment with anti-epileptic drugs (AEDs) are necessary to prevent the seizure, and 40% do not respond to the first line of AED, leading to an often lifelong odyssey of trial and error towards effective treatment that is often not found. Epilepsy is primarily treated using AEDs, but these are associated with a considerable risk for adverse drug reactions (ADRs), some of which have been shown to have a genetic predisposition. For example, the genetic variant HLA-A*3101 is a common risk factor for rash and severe blistering skin reactions with the drug carbamazepine (Tegretol) in Europeans. However there are few other predictors of some more common ADRs.

Dr. Mark McCormack

The EpiPGX Consortium was established to identify genetic biomarkers of epilepsy treatment response from patient centres across Europe. The EpiPGX Consortium has generated genetic profiles on over 8000 patients with matching detailed drug response and medical histories. In order to investigate the links between genetic profiles and ADRs in epilepsy, Dr. Mark McCormack will travel to UMC Utrecht, the Netherlands for one year on a  Marie-Skłodowska-Curie Fellowship from the European Commission.

The aim of this fellowship is to identify clinically useful genetic variants to predict adverse reactions to AEDs. This will help optimize personalized treatment, limit the trial and error approach of AED choice, and thus improve medication safety and quality of life in epilepsy.