The genomic and epigenomic landscapes of epilepsy

About

There are two visions of our team, led by Associate Professor Lata Vadlamudi.

  1. Deepen understanding of the complex genomic and epigenomic landscapes of epilepsy; and
  2. Integrate genomics into clinical practice to improve patient management.

Our research is focused on answering two of the most difficult clinical questions that neurologists struggle to answer in the epilepsy clinic – “What is the cause of my epilepsy” and “How can my epilepsy be treated?”.

Epilepsy is one of the most common neurological disorders affecting over 50 million people worldwide and is characterised by occurrence of seizures. One in 26 people will develop epilepsy during their lifetime. Despite more than 20 anti-epileptic medications, more than 30% of patients are not able to control their seizures with anti-epileptic medications. Refractory epilepsy is the failure of two anti-epileptic medications to control seizures.

With the rapid increase in gene discovery in epilepsy, functional genomics are required to understand the role of complex genomic landscapes within individual patients and provide patients with a cause for their epilepsy. The future lies in then developing bespoke treatments, based on the functional genomics outcomes, to ultimately cure this debilitating disorder.

A/Prof Lata Vadlamudi has been a researcher in the field of epilepsy for over 15 years and has been a neurologist in clinical practice for almost 20 years.

Our team collaborates with Prof Ernst Wolvetang, an international leader in the field of pluripotent stem cell biology and functional genomics for almost 20 years.  He is the senior group leader of the Stem Cell Engineering Group at The University of Queensland’s Australian Institute for Bioengineering and Nanotechnology (AIBN) and Co-director of the Centre for stem cell ageing and regenerative engineering (stemCARE).

Our team also collaborates with A/Prof Jeffrey Craig from the Deakin University in Victoria, who is an epigeneticist and twin researcher with over 20 years’ experience. He is the Deputy Director of Twins Research Australia.

Funding for this research has been from the following sources: Queensland Genomics, University of Queensland Mayne Bequest Funding, Queensland Health Research Fellowship, Royal Brisbane and Women’s Hospital Research Project Grants, Viertel Charitable Foundation Establishment Grant, Ramaciotti Establishment Grant and RACP Servier Barry Young Fellowship in Neurology.

Contact

+61 7 3346 5034

l.vadlamudi@uq.edu.au

Australian Institute for Bioengineering and Nanotechnology

Professor Ernst WolvetangProfessor Ernst Wolvetang ​

Senior Group Leader, Head of the Stem Cell Engineering Laboratory, University of Queensland

 

Murdoch Childrens Research Institute

Namitha MohandasNamitha Mohandas

PhD Candidate

Email address: namitha.mohandas@mcri.edu.au

Affiliations: 

  • Early Life Epigenetics, Murdoch Childrens Research Institute, Melbourne 
  • Royal Children's Hospital, Melbourne
  • Department of Paediatrics, The University of Melbourne

Jane LokeYuk Jing (Jane) Loke

Research Officer

Email address: jane.loke@mcri.edu.au

Affiliations: 

  • Murdoch Childrens Research Institute, Melbourne

Stephanie HopkinsStephanie Hopkins

Honours Student

Email address: stephanie.hopkins@mcri.edu.au

Affiliations: 

  • Murdoch Childrens Research Institute, Melbourne
  • University of Newcastle, Newcastle

Deakin University

Associate Professor Jeffrey CraigAssociate Professor Jeffrey Craig

Deakin University, Centre for Molecular and Medical Research, School of Medicine, Faculty of Health

Email address: Jeffrey.craig@deakin.edu.au

Affiliations:

  • Murdoch Childrens Research Institute, Melbourne
  • Royal Children’s Hospital, Melbourne
  • Department of Paediatrics, University of Melbourne

Clinical genomics

The goal is to demonstrate that integration of genomics into the clinical care of refractory epilepsy patients will significantly improve their healthcare and show that this can be delivered using available resources effectively and efficiently. This project involves screening for genes, to see if we can identify a cause for the epilepsy.

The mission will be accomplished by creating a diagnostic and management algorithm which incorporates accessible genomic testing for the treating neurologist, a multi-disciplinary approach for report generation, enabling a clinically meaningful report to the neurologists as well as individualised reports to patients.

Functional genomics

The rate of gene discovery however, has outpaced our ability to understand the pathophysiology of gene variants and how they relate to phenotypes. There is an imperative need to develop high-throughput functional analyses, such as induced pluripotent stem cells and cerebral organoids (3D neuronal networks), that are able to model the combinatorial impact of genetic variants observed in patients and their functional impact. A further proof of principle approach would involve introducing some common genetic variants into a control pluripotent cell line, to determine which are of functional significance.

Epigenomics

Epigenetics is the study of changes in gene expression without changes to the DNA sequence. The most studied epigenetic mechanism is DNA methylation. Twins are an ideal paradigm for differentiating between the three major components of phenotypic variation: genetics, shared, and non-shared environment. The discordant monozygotic twin model further provides an elegant study design that controls for shared genetic and environmental factors, enabling focus on the non-shared environment, the largest component of risk variance across all chronic disorders. Twin models are ideal for understanding the epigenetic and genetic landscape in epilepsies.

Improving patient outcomes in neurological disorders: Piloting a neurogenetics service for refractory epilepsy patients

The goal is to demonstrate that this model of care in refractory epilepsy patients will significantly improve their healthcare and show that this can be delivered using available resources effectively and efficiently.

A functional genomics approach to personalise refractory epilepsy management

This project will establish if genomic variants, identified from next generation sequencing, can cause disease. The project then leverages cutting-edge technology to develop a novel drug testing platform, for delivery of optimised and personalised treatment to epilepsy patients. This project is in collaboration with Prof Ernst Wolvetang from The University of Queensland Australian Institute for Bioengineering and Nanotechnology.

Genetic networks in epilepsy; A tissue specific approach

This singleton project utilises brain, buccal and blood derived samples from temporal lobe epilepsy patients to look at genes and genetic pathways where the epigenetic state links with epilepsy. By comparing different samples, we will be able to address the issue of tissue specificity in epigenomic studies. This project is in collaboration with A/Prof Jeff Craig, Centre for Molecular and Medical Research, School of Medicine, Faculty of Health Deakin University.

The epigenetic and genetic landscape of idiopathic epilepsies: the testament of twins

This project provides a novel approach to deepen our understanding of phenotypic expression of idiopathic epilepsies by studying discordant monozygotic twins. The aim of this project is to focus on generating peripheral biomarkers for idiopathic epilepsies to aid in the diagnosis of idiopathic epilepsies and also act as specific markers for idiopathic epilepsy subtypes. The long-term hope of a peripheral biomarker will be the development of disease-modifying treatments. This project is in collaboration with /Prof Jeff Craig, Centre for Molecular and Medical Research, School of Medicine, Faculty of Health Deakin University.

Genetics of epilepsy: A twin approach to complex and non-traditional inheritance patterns

This project builds the resource of an epilepsy twin cohort in Queensland and investigates the role of non-traditional inheritance patterns through monozygotic twin pairs discordant for epilepsy.