Project Title:

Exploring the role of DEPDC5 mutations in childhood brain abnormalities

Discipline:

Genetic Medicine

Chief Investigator:

Associate Professor Leanne Dibbens

Funding Amount:

$70,000

Recipient:

University of South Australia

Overview:

We will determine if mutations in the DEPDC5 gene are responsible for some defects in child brain development. We recently discovered DEPDC5 mutations cause familial focal epilepsy (inherited). Some patients with earlier age of seizure onset (1-7yrs) have visible brain malformations and intellectual disability and/or autism spectrum disorder. Because DEPDC5 negatively regulates cell growth and metabolism these brain lesions may be due to abnormal growth and metabolism of brain cells. If we can establish this is the case, drugs exist that could treat these children and may prevent some symptoms.

Research Outcomes:

Researchers:

Leanne Dibbens

Research Completed:

2018

Research Findings:

Epilepsy is a common, serious neurologica l disorder affecting more than 5 million people worldwide. Most cases of epilepsy begin in childhood and most begin in the first year of life. It can be very difficult to treat epilepsy associated with a brain malformation in children. Some children have surgery to remove the brain malformation to try to stop their seizures. Recently we discovered that mutations in DEPDCS can cause brain-malformation associated epilepsy. In this project we collected brain samples from epilepsy surgeries and made DNA from the samples. We developed a new test for detecting DEPDCS mutations and tested 60 surgical samples. We identified 3 mutations in DEPDCS. These findings are important as they show that mutations in DEPDCS may account for around 5% children with focal epilepsy associated with a brain malformation. These findings will provide a new diagnostic test for children with severe epilepsies and will help to guide clinical treatment by highlighting the importance of brain imaging in children with epilepsy, which may lead to surgical treatment for more children.

Key Outcomes:

Epilepsy is a chronic neurological condition characterised by recurrent and unprovoked seizures. Epileptic seizures of focal origin are the most common accounting for approximately 60% of cases. Focal seizures are often localised to one brain region, and in most cases are caused by structural brain lesions. These cases are believed to be of genetic aetiology as 70% of epilepsy cases are determined by genetic factors. Indeed we have recently published the finding that mutations in DEPDC5 contribute to focal epilepsy with brain malformations. In this study we sought to identify mutations in DEPDC5 in children with difficult to treat focal epilepsy who have had brain tissue removed by surgery to treat their epilepsy.

This grant allowed us to employ a part-time technical and research assistant to work with other members in the research team. We generated genomic DNA from tissue excised from 60 children who have undergone surgical treatment for their severe epilepsy. We designed a custom-targeted high throughput assay in order to detect gene mutations. We analysed the samples for the presence of mutations in DEPDC5 and then compared this to see if the same mutation was present in patient-matched blood-derived genomic DNA. Sequenced variants detected were validated and segregation analysis of available family members was carried out by direct Sanger sequencing. All changes considered as potentially pathogenic were compared with a range of publicly available SNP/mutation databases and analysed using in silico pathogenic prediction programs.

We identified 3 mutations in DEPDC5 in the cohort of 60 children with sporadic focal epilepsy associated with a brain malformation. We showed that two of the mutations occurred de novo in the children, while one was inherited from an affected parent. These findings are important as they show that mutations in DEPDC5 may account for around 5% children with focal epilepsy associated with a brain malformation. These findings will provide a new diagnostic test for children with severe epilepsies and will help to guide clinical treatment by highlighting the importance of brain imaging in children with epilepsy, which may lead to surgical treatment for more children.

Research Papers:

Manuscript in preparation

Related Publications:

Future Outcomes:

Remarks:

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