Abstract
Malformations of cortical development (MCD) are a heterogenous group of brain malformations, which represent a significant burden for health care and society. Affected individuals suffer from drug-resistant epilepsy and varying degrees of intellectual and motor disability. Using current molecular techniques including SNP-array and whole exome sequencing (WES), over half of MCD cases remain unsolved.
Factors contributing to the "unsolved" MCD cases include coding variants of unknown significance (VUS) in known MCD genes, non-coding variants in the known genes influencing splicing or gene expression as well as more complex mutation types (e.g., structural variants, copy number variants), urging the use of whole genome sequencing (WGS) for MCD genetic testing. However, this approach will inevitably lead to the identification of more rare variants of unknown significance (VUS) in known MCD genes. Finally, novel disease genes not previously linked to MCD are still to be discovered.
In this project, we aim to establish of a gene-specific disease signature based on RNA-sequencing data that pinpoints the disease gene or pathway on which WGS-based variant analysis should be focused. The selected genes affect either the PI3K-AKT-mTOR pathway or microtubule dynamics, two major pathways involved in brain development.
Furthermore, we aim to increase the diagnostic yield in MCD patients by integrating transcriptomics and WGS data of currently "unsolved" MCD cases, allowing the identification of additional variants of interest.
Finally, we use the identified disease signatures in the validation of novel MCD candidate genes with similar pathophysiological mechanisms.
The results of this project will guide the implementation of transcriptome analysis as another tool in the genetic diagnostic toolbox for MCD and hereby improve patient management and appropriate counseling of families.
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