Understanding the utility and yield of Next generation sequencing gene panels for the diagnosis of genetic movement disorders in children

Summary

Movement disorders are common in children, and include tics, dystonia, chorea, myoclonus and tremor. Other than tics, these disorders often have a genetic basis, which is ‘monogenic', meaning highly pathogenic variations in single genes. There are many monogenic causes of genetic movement disorders (~200 genes to date associated with movement disorders in children, and the suspected yield is only ~25% but steadily increasing). 

At the Children's hospital at Westmead, we have an established program of research with integrated clinical and laboratory input for the diagnosis of genetic movement disorders. We are the referral site for all children with suspected genetic movement disorders in NSW. Likewise, our laboratory has established a genetic movement disorder panel and ‘tiered' approach to the genomic investigation of children with movement disorders. This clinical and research environment is therefore excellent to examine the utility of this approach in the diagnosis of children with suspected genetic movement disorders to understand and improve utility and be part of the process of new gene discovery in genetic movement disorders.

Supervisor(s)

Dr Shekeeb Mohammad

Research Location

Westmead - Childrens Hospital at Westmead Clinical School

Program Type

Masters/PHD

Synopsis



Aim:
1. To examine the yield of NGS in the investigation of children with suspected genetic movement disorders.
2. To form a live database/website of genetic movement disorders responsive to deep brain stimulation.
3. Using odds ratios, determine clinical and investigation variables that associate with a positive genetic finding. Examine the increasing overlap of genes that cause epilepsy and movement disorders. Examine the yield of this approach in the diagnosis of highly treatable conditions.
4. In prospective testing, examine the time (and therefore cost) of the different genomic approaches in the determination of the cause of genetic movement disorders. 

Methodology:
This will be mixed methodology and include retrospective and prospective patients who have been recruited with suspected genetic movement disorders and had NGS (gene panel, exome or genome, singleton or trio) performed at the molecular genetics laboratory (CHW) or research laboratory institute of Child Health London since 2012 and ongoing.

Skills that will be acquired:
This project is of interest to a clinician wishing to perform clinical and genomic research, or alternatively an emerging scientist who wishes to interface more with clinical research and translation.
The skills that will be acquired:
1. Understanding of the clinical features of genetic movement disorders. This will include engagement with patents in the clinical movement disorder service (observation only unless clinical training allows more involvement in patient care). Understand the consent process and ethics of genomic testing.
2. Involve with clinical phenotyping including interpretation of videos, and integration of standarised videos of children with movement disorders.
3. Formation of a clinical database to record clinical and investigation variables and genomic findings.
4. Engagement with clinicians and laboratory staff involved in the NGS approach and interpretation of data. Observe the genomic technology in the laboratory, although this will not be a laboratory project so this will be mostly observational.
5. Be involved in the bioinformatic filtering and interpretation, and correlations by the laboratory and clinical staff.
6. Perform rigorous classification of variants for analysis, and perform analysis of the yield of NGS technology, and clinical features that associate with pathogenic genomic variants in this population (odds ratios). Provide data analysis on the proportion of pathogenic variants that result in a specific therapeutic intervention such as a specific medical or invasive treatment (eg carbamazepine of paroxysmal kinesigenic dyskinesia, deep brain stimulation for KMT2B).
7. Perform economic analysis of how much the different approaches cost in consumables and time of the clinicians and laboratory staff.

Outcomes:
This study will provide key information in the yield of a currently provided and evolving technology and its application to a specific group of patients. This will result in improved learning, and modification of the approach, and add to the literature on the clinical and economic utility and applicability of NGS technology in genetic movement disorders.

Additional Information

• Use of research technique / methodology / technology
• Potential topics of interest for the research opportunity
• Current PHD and/or Masters topics
• Eligibility criteria / candidate profile
• Scholarship(s) / funding available

Want to find out more?

Contact us to find out what’s involved in applying for a PhD. Domestic students and International students

Contact Research Expert to find out more about participating in this opportunity.

Browse for other opportunities within the Westmead - Childrens Hospital at Westmead Clinical School .

Keywords

Genetics, Movement disorders, genomics, NGS, neurology, Child neurology, dystonia

Opportunity ID

The opportunity ID for this research opportunity is: 2651