Unravelling Mendelian epilepsy disorders with Next Generation Sequencing technologies
15 April 2015
Promotiezaal (UAntwerp, Campus Drie Eiken, Building Q) - Universiteitsplein 1 - 2610 Wilrijk (Antwerp)
4:00 PM - 6:00 PM
Prof Peter De Jonghe
PhD defence Katia Hardies - Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Department of Biomedical Sciences
Epilepsy is one of the most common neurological disorders and is characterized by recurrent and spontaneous seizures. The clinical manifestation of epilepsy phenotypes differs greatly in onset age, seizure type(s) and frequency, drug-response, and additional features affecting the cognitive, physical, psychological, and social wellbeing of the patient. Despite the existence of different symptomatic treatments, multiple therapy is often needed to gain seizure control. Side-effects are also frequent, and 30% of the patients remain refractory. New insights in the precise underlying pathomechanism of brain hyperexcitability are required to elucidate the true basis of epileptogenesis and locate potential novel therapeutic targets.
In 70% of the epilepsy patients genetic factors are thought to play a role. Gene-identification studies using traditional genetic approaches have led to the association of a dozen epilepsy causing genes and many more associated loci. The last decade, next generation sequencing (NGS) technologies have introduced a less biased and wider applicable gene-identification approach. Despite the increasing amount of disease associated gene defects and partially because of unexpected geno-phenotype relationships, many patients remain without a molecular diagnosis. Gene identification studies remain thus important to establish a framework for better diagnostic strategies. They also lay the groundwork for studying disease mechanisms and provide input for generating disease models.
As a starting point for the conducted molecular genetic studies, this thesis focused on patients and families exhibiting a Mendelian inheritance pattern. By applying different NGS strategies in large scale investigations I aimed to further broaden our understanding on heritable epilepsy syndromes. A general overview of the currently used research methods are described. Application of these led to the results described in chapter 2.1 to 3.3. I further discuss my work and experiences in a broader context of contemporary challenges in epilepsy research, the role of molecular genetic studies in the research field, and the implications of NGS on gene-identification studies in general.