The Genetics of Epilepsy

We are delighted to invite you to our exclusive and free webinar series on Complex Diseases, which has been extended to January 2021. Our fourth speaker is Associate Professor Michael Hildebrand with his talk entitled “Somatic Mutation: The Hidden Genetics of Epilepsy.” Register for this webinar here.

Date: Thursday, January 28th, 2021
Time: 2:00pm - 3:00pm (AEDT)

I am a neurogeneticist with international research experience and collaborations, and I completed my PhD in late 2006 (University of Melbourne). I head the Translational Neurogenetics Laboratory in the Epilepsy Research Centre at the Melbourne Brain Centre, Austin Hospital, and am currently supported by with the supported of by a NHMRC Centre of Research Excellence in Speech and Language Neurobiology (APP1116976), and NHMRC Project Grants on detection of somatic mutations in sporadic epilepsy (APP1129054) and improving diagnosis, prognosis, and clinical care in childhood speech disorders (APP1127144).

The focus of my research is to understand the basic neurobiology of human epilepsy and speech disorders and translate this knowledge into improved treatments for patients. 

Abstract 

Epilepsy is a common disorder with a ~3-4% lifetime risk. In about 20-30% of cases there is a clear acquired cause (e.g., head trauma or stroke), but in the remaining group, genetic factors often play a role. The most common group, focal epilepsies (FEs), account for ~ 60% of all epilepsies. Some FEs, such as those caused by brain malformations, are amenable to resective surgery, allowing privileged access to brain tissue. Genetic analysis of epileptogenic brain malformations has revealed both inherited and de novo variants in genes of the mTOR and other pathways in a growing number of cases. Within these brain abnormalities (lesions) the pathogenic variants are present in only a fraction of the cells (mosaicism), yet this is sufficient to disrupt neuronal development and lead to FE. 

The first step towards rational precision medicine treatments for FE, targeting the underlying neurobiological basis of seizures, is precision diagnosis for individual patients. The overall contribution of mosaic variants, and their associated developmental pathways, to FE is not known, and is limited by the current need for brain tissue to identify most mosaic FE-related variants. Novel, minimally invasive approaches are required to detect mosaic variants in patients with FE using alternate sources of DNA, particularly for patients with ‘non-lesional’ FE (i.e. without neuroimaging evidence of a lesion) and no brain tissue available for analysis.