Exploring mosaic brain variants that cause focal epilepsies

Research Opportunity
PhD students
Department / Centre
Medicine
Location
Austin Health
Primary Supervisor Email Number Webpage
Associate Professor Michael Hildebrand michael.hildebrand@unimelb.edu.au +61390357143 Personal web page
Co-supervisor Email Number Webpage
Professor Samuel Berkovic s.berkovic@unimelb.edu.au 9035 7121 Personal web page
Professor Ingrid Scheffer i.scheffer@unimelb.edu.au 90357120

Summary This project will explore pathogenic variants present in only a fraction of brain cells (mosaicism) of patients with focal epilepsies. These mosaic variants are sufficient to disrupt neuronal development and lead to focal epilepsy. To better understand the genetics of focal epilepsies the student will take advantage of existing resected brain tissue from patients undergoing epilepsy surgery. The candidate will implement novel, minimally invasive sampling approaches to identify brain mosaicism in the absence of resected tissue. These methods are significant because most patients with focal epilepsies are not candidates for epilepsy surgery. This project will have the funding support of 2021 MRFF Genomics Health Futures Mission and NHMRC Investigator grants.

Project Details

Epilepsy is a common disorder with a ~3-4% lifetime risk. The most common group, the focal epilepsies, account for ~ 60% of all epilepsies and involve recurring seizures arising from a specific region or regions of the brain. In about 20-30% of cases there is a clear acquired cause (e.g., head trauma or stroke); of the remaining group, genetic factors are often thought to underlie the condition. Genetic factors are increasingly recognized in focal epilepsies and better understanding may pave the way to novel personalized therapies. Only a small proportion of patients currently have a genetic cause identified in blood derived DNA; this applies to two groups – those will normal brain MRI, and those with a brain malformation. There is increasing interest in brain mosaicism causing malformations associated with epilepsy. However, only < 5% of patients with focal epilepsies, typically those caused by brain lesions, are amenable to resective surgery, meaning that access to brain tissue for genetic studies is extremely limited.

In this project the PhD candidate will explore pathogenic variants present in only a fraction of brain cells (mosaicism) of patients with focal epilepsies. These mosaic variants are sufficient to disrupt neuronal development and lead to focal epilepsy. To better understand the genetics of focal epilepsies the student will take advantage of existing resected brain tissue from patients undergoing epilepsy surgery. The candidate will implement novel, minimally invasive sampling approaches to identify brain mosaicism in the absence of resected tissue. These methods are significant because most patients with focal epilepsies are not candidates for epilepsy surgery. This project will have the funding support of 2021 MRFF Genomics Health Futures Mission and NHMRC Investigator grants.

Aims :

  1. To analyse existing high depth exome sequencing data from brain tissue of unsolved patients in a epilepsy surgery cohort for mosaic variant detection and gene discovery.
  2. To optimise cerebrospinal fluid (CSF) liquid biopsy for clinical implementation to detect mosaic variants and provide genetic diagnosis.
  3. To explore new methods for amplifying mosaic variants in trace brain tissue from Stereo-electroencephalography (Stereo-EEG) depth electrodes of patients with focal epilepsies.
  4. To develop the first clinical recommendations for interpretating mosaic variants in focal epilepsies with potential relevance to other neurological disorders.

Methodology :

Application of a variety of current and novel genomic testing technologies to patients with brain tissue, CSF and depth electrodes available to test for causative mosaic variants.

This project provides the exceptional opportunity to work in an a large multidisciplinary clinical and laboratory research team with extensive clinical research and discovery science expertise. In addition to clinical understanding and laboratory techniques, the development of project management, sample coordination and communication skills will be fostered.



Faculty Research Themes

School Research Themes

Neuroscience & Psychiatry



Research Opportunities

PhD students
Students who are interested in joining this project will need to consider their elegibility as well as other requirements before contacting the supervisor of this research

Graduate Research application

Honours application

Key Contact

For further information about this research, please contact a supervisor.

Department / Centre

Medicine

Research Node

Austin Health

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