Research Anna Jansen

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.

Researcher(s)

• Promoter: Jansen Anna
• Co-promoter: Meuwissen Marije
• Fellow: Rosenblum Jessica

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Dravet syndrome (DS) is a genetically caused severe neurodevelopmental disease with drug-resistant epilepsy, cognitive impairment and a strongly increased risk of premature death already at young ages. The occurrence of sudden death is most probably facilitated by sustained susceptibility to cardiorespiratory dysfunction. Our primary hypothesis is that the alterations of autonomic functions observed in DS result from the interplay between the genetically-based neurodevelopmental disorder and effects of recurrent seizures. Epilepsy might thus progressively aggravate the autonomic abnormalities and risk of sudden death related to the underlying genetic disease, through an effect on central control of vegetative functions, a direct effect on cardiac functioning or both. Here, we will: (i) analyze in a DS animal model and in DS patients the temporal relationship between evolution of epilepsy and alteration of autonomic cardiorespiratory functions; (ii) distinguish in rodents the relation between these evolutions of the alterations of the central regulation, the cardiac functioning, and the risk of sudden death; and (iii) evaluate in rodents and in DS patients if the evolution of autonomic dysfunction can be monitored with functional imaging targeting the serotonin pathway. The anticipated findings will be used to stratify DS patients at very high risk of sudden death and may allow novel approaches for pharmacological modulation of the risk of sudden death in DS.

Researcher(s)

• Promoter: Verhulst Stijn
• Co-promoter: Ceulemans Berten
• Co-promoter: Jansen Anna

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project