Raising Money for
2014 MRF Research Grantee
FINAL REPORT: Use of Next Generation Sequencing Technology to Identify Novel Hemiplegic Migraine and Migraine Related Mutations
Published in BioMed Central (2016).
The aim of this project was to develop and optimize a targeted Next Generation Sequencing (NGS) approach to identify novel genetic mutations associated with familial hemiplegic migraine (FHM) and migraine-related phenotypes. In addition, this study aimed to utilise this methodology to identify and validate novel mutations, confirmed with Sanger sequencing and bioinformatic interrogation, for severe migraine-related disorders.
Hypothesis v. Findings
We hypothesized that using a targeted multi-gene NGS panel would enable a faster, cost-effective and more comprehensive analysis approach, involving the simultaneous interrogation of currently implicated and related genes. Upon screening 120 undiagnosed FHM cases using the targeted NGS panel, 24 known and novel mutations were identified in 26 cases of the screened FHM cases (21.6%).
This NGS approach has increased the rate of mutation detection over iterative testing by Sanger sequencing by around four-fold and is thus much more effective at detecting mutations in these targeted disease-causing genes. This strongly indicates that multiple gene screening could be a clinically valuable approach.
Our findings show that the targeted multi-gene panel was capable of identifying new and known mutations in FHM sufferers. However, around 78% of the cases still had no definitive diagnosis, with these results indicating that there are other FHM causative genes yet to be identified. To identify novel FHM genes, we believe that a whole exome sequencing approach would be suitable to help in identifying new causative genes involved in FHM conditions. Hence, although this research has provided a very useful, cost-effective approach to identify mutations in known FHM genes, this research has also shown that there are currently unidentified genes involved in this disorder. We are planning to continue our research to identify novel FHM genes to enable more comprehensive diagnosis of all FHM cases.
What this Research Means to You
These findings show the benefit of NGS for neurogenetic diagnostics and have added considerably to the field of molecular genetics. Since there is symptom overlap in relation to migraine disorders, it is often hard for the clinician to choose which genes to investigate in terms of diagnostic testing, further driving up patient costs. Therefore, the targeted NGS panel will be of enormous aid in diagnosing the FHM sub-types of migraine to enable effective treatment choice.