Uncovering the genetic causes of Epilepsy and the associated comorbidities

(PI: Professor Leanne Dibbens)

Epilepsy is one of the most common and serious neurological disorders. People with epilepsy experience recurrent and unprovoked seizures and it affects more than 2% of the worldwide population. The epilepsies are actually a diverse family of more than 30 different disorders which can be difficult to clinically diagnose and treat without knowing the underlying cause, and there is increasing recognition that genetic causes are important.

Recently we have successfully employed whole exome sequencing to identify new genes: KCNT1, DEPDC5, NPRL2 and NPRL3. Our identification and characterisation of these new genes has initiated trials of two existing pharmaceuticals for ‘off-label’ use as targeted therapies.

Despite these successes, of all mutations in the genes identified to date, collectively they account for less than 10% of focal epilepsy cases. Thus, the causes of the vast majority of cases of epilepsy are yet to be identified.

With our expertise in genetics, molecular biology, next generation sequencing, bioinformatics and the investigation of mouse and Drosophila models of human disorders, we identify and characterise new epilepsy genes. We apply state of the art genomic sequencing technologies and novel bioinformatics to analyse our cohort of patients which include multigenerational families with multiple affected individuals.

Once we identify these genes we examine their expression in the brain. Once we have confirmed the causative role of the new genes, we will use CRISPR/Cas9 genome editing technology to generate gene knockout models in mice or Drosophila. These are investigated for seizure phenotypes and underlying pathobiology for the development and evaluation of new therapeutic interventions. This project will provide much needed improvements in accuracy of diagnosis and the selection of treatment regimes for people with epilepsy.

(PIs: Professor Leanne Dibbens)

Neuromuscular disorders (NMDs) are a collection of different disorders affecting the nervous system and musculature that are often characterised by progressive muscle weakness and wasting. NMDs can be extremely debilitating, placing a significant burden on individuals, families and the healthcare system. Cases may be sporadic, where there is no family history of the disease, or familial where individuals are affected by an inherited mutation. Currently, treatments for patients with NMDs are extremely limited and there are no cures, highlighting the need for new drugs and improved treatments. Genetic mutations are a major cause of neuromuscular disorders and a number of genes associated with the disease have been identified. However, the genetic cause in approximately 40% of patients with an NMD have not yet been identified. It is important that patients know the genetic cause of their NMD so that they and their families can benefit from genetic counselling and receive optimised personalized care.

We use the latest genetic and genomic technologies such as Whole Exome and Whole Genome Sequencing to study patients and their families to identify new genetic and epigenetic causes of neuromuscular disorders. Once we have identified a potential candidate gene for NMD, we create cell and animal models of NMD in order to identify what biological processes go wrong in patients. Human disease-causing mutations identified are introduced into the models using the latest gene editing technologies and the model organisms are studied using a range of methodologies. Once we have developed these animal models for our novel NMD genes, we use these to carry out drug screening to identify potential new drugs and therapies to treat patients with NMD.