Project title:

Understanding the genetics of childhood diseases with Next Generation Sequencing

Chief Investigator:

Associate Professor Leanne Dibbens

Funding Amount:

$70,000

Recipient:

University of South Australia

Overview:

The majority of childhood diseases do not receive a specific molecular diagnosis. By utilizing the latest in Next Generation DNA Sequencing technologies we can change this. We can now relatively rapidly sequence affected children as well as their affected /unaffected parents and relatives to hunt down the gene(s) causing the disease. This can now be achieved in a few months instead of many years. We will study difficult to solve childhood patients with Neurological disorders referred to us by the Women’s and Children’s Hospital in Adelaide.

Research outcomes:

Researchers:

Leanne Dibbens

Research Completed:

2016

Research Findings:

In this project we studied ten Australian families with one or more children affected with a neurological disorder who do not know the cause of their disorder. The children have previously undergone genetic testing with no cause identified. We used recently available technology known as whole exome sequencing to analyse the DNA of the affected children and available family members. We generated genetic data on the family members and used our in-house pipeline to analyse the genetic data. In one family two children were affected with profound developmental delay in early infancy and had drug resistant seizures with beginning at 4 months of age. The children were born to unaffected parents who were not known to be related to one another. We identified gene mutations in a new gene not previously associated with these clinical features. Both affected children have a mutation in this gene while their parents do not. This has provided a cause of the disorder for the family and the finding is being used to guide clinical care. These findings will be reported in a manuscript in preparation. A second family had one child affected with severe seizures and cognitive impairment. In the analysis of this family we have identified a strong candidate causative gene. We are currently analysing other patients with similar clinical features to identify further mutations in this gene to validate this finding before preparing a manuscript to report this finding. We are continuing to investigate the genomic data generated for the other families to identify and validate the causative genes. We have also begun collaborations to investigate the effects of the identified mutations in animal models.

Key Outcomes:

Genetics makes an important contribution to the aetiology of childhood diseases including neurological disorders. The disorders may be sporadic where an affected child has no family history of the disease or it may be inherited where the disease is passed on from the parents. Many children in South Australia and around the world do not know the cause of their genetic disorder. Genetic testing is only available to a small percentage of affected children and relies on genes being academically discovered to cause a disorder. In the absence of a genetic cause, it can be difficult to know how to best treat the disorder and the risks of other family members having the disorder are unknown. It is therefore to identify the genetic cause of neurological disorders. In this project we studied ten Australian families with one or more children affected with a neurological disorder. The children had undergone previous genetic testing with no cause identified. We undertook whole exome sequencing of the affected children and available family members and used our in-house bioinformatics pipeline to analyse the genetic variants. In one family two children were affected with profound developmental delay in early infancy and drug resistant seizures with onset at 4 months. The children were born to unaffected, unrelated parents. We identified pathogenic mutations in a new gene not previously associated with these clinical features. Both affected children have a mutation in this gene while their parents do not. This has provided a cause of the disorder for the family and the finding is being used to guide clinical care. These findings will be reported in a manuscript in preparation. A second family had one child affected with severe seizures and cognitive impairment. In the analysis of this family we have identified a strong candidate causative gene. We are currently analysing other patients with similar clinical features to identify further mutations in this gene to validate this finding before preparing a manuscript to report this finding. We are continuing to investigate the genomic data generated for the other families to identify and validate the causative genes. We have also begun collaborations to investigate the effects of the identified mutations in animal models.

Research Papers:

This project was presented at:
Clinical and Molecular Medicine seminar series, Flinders University, Adelaide
The importance of genetics in epilepsy and its comorbidities.

Health Development Adelaide, Research & Innovation Cluster in South Australia
Public Lecture: The genetics of childhood epilepsy.

Paediatric Seminar Series, Flinders Medical Centre, Adelaide
The genetics of childhood disorders.

International Fellows Symposium: Neurogenomics, Sydney, Australia

Related Publications:

Future Outcomes:

Patenting and licensing of new gene findings will be pursued.

Remarks:

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