Unusual mutational mechanisms in the epileptic encephalopathies: highlighting the dark side of the genome
19 September 2018
UAntwerp, Campus Drie Eiken, Building Q, Promotiezaal - Universiteitsplein 1 - 2610 Wilrijk (Antwerp) (route: UAntwerpen, Campus Drie Eiken
4:00 PM - 6:00 PM
Peter De Jonghe, Jurgen Del-Favero, Sarah Weckhuysen
Phd defence Jolien Roovers - Department of Biomedical Sciences
Epilepsy is one of the most common neurological disorders, characterized by recurrent and spontaneous epileptic seizures, which are the clinical manifestations of abnormal excessive or synchronous neuronal activity of the brain. In this thesis, I will focus on the Developmental and Epileptic Encephalopathies (DEE), a subgroup of the severe epilepsies, in which the abundant epileptiform activity is thought to interfere with development, causing cognitive delay and behavioral impairments in an individual with (in theory) pre-existing normal development. Many of these DEE are believed to have a genetic cause. In the majority of patients the pathogenic variant occurred de novo, which means that the variant arose in the parental gametes or during early embryogenesis, and consequently is absent in both parents. With the rise of massive parallel sequencing technologies many genes have been identified that can cause DEE when mutated. Nonetheless, still about 50-60% of DEE patients are currently genetically undiagnosed, highlighting the need for novel strategies to solve the missing heritability.
Through this thesis I focus on unusual mutational mechanisms (e.g. other variants besides variants in the exome or copy number variants). Only 2% of the genome is thoroughly studied nowadays and I believe that focusing on the remaining non-coding parts with a regulatory function will solve a substantial portion of the missing genetic diagnoses and will advance the diagnostic yield. In this thesis, I show that de novo variants in newly identified exons of SCN1A cause Dravet syndrome, a well-defined DEE syndrome. I furthermore investigated variants in brain-expressed microRNAs, a class of small non-coding regulatory genes, and identified a de novo variant in hsa-mir-124-1, the most abundant microRNA in neuronal cells. This variant has an effect on the processing of hsa-mir-124-1 and on the gene expression of genes involved in pathways relevant to the DEE phenotype of the patient. Another explanation for the missing heritability are classical mutations in well-known genes that still remain to be found in small subsets of DEE patients as illustrated by our study that identified de novo missense variants in the FZR1 gene. In the last chapter I review the therapeutic potential of RNA regulation in neurological disorders, which highlights the importance of a correct molecular diagnosis for the development of emerging therapeutic strategies.
Overall, my results contribute to a better understanding of the genetic etiology of DEE, and support the need for further investigation of the non-coding part of the genome.