The goal of our lab is to determine the genetic causes of epilepsy, as well as study how mutations in these genes affect how the brain develops and functions, and ultimately find ways to intervene.
Genetic causes of epilepsy
The next generation sequencing era has led to an explosion in the number of genes implicated in epilepsy, and there are now mutations in over 100 genes that can cause this disorder. Despite these progresses 30-70% of severe early onset pediatric epilepsies remain of unknown etiology. Our work focuses on finding new genes in the undiagnosed pediatric patients. We are also interested in using our knowledge of the genetic architecture of pediatric patients to understand the role of genetics in adult patients with epilepsy.
Gene discovery in epilepsy Pathogenic variants in CHRNA4 were first identified in patients with focal epilepsies in 1994, for the next 19 years, the majority of new genes were identified either using linkage mapping in familial epilepsies, in specific syndromes or on the X chromosome. Since the introduction of next generation sequencing in 2013, the number of new epilepsy genes has rapidly risen; over half of the known genes have been identified in just the last four years. Dr. Carvill and colleagues have identified or expanded the phenotypic spectrum of all genes in red.
In addition to hunting for new genes for epilepsy, we are also interested in the ‘other 99% of the genome’. Only about 1% of our genome contains DNA sequences that contain the code to make proteins – the other 99% is known as non-coding DNA. One of the functions of these regions of DNA is to control the expression of other genes. In the lab we use a range of epigenetic and next-generation sequencing techniques to identify regions in the genome that control the expression of genes involved in the development and functioning of the brain, as well as whether these regions are mutated in patients with epilepsy.
Epigenetic mechanisms in epilepsy
We have noted that many of these genes that can cause epilepsy control the expression of other genes. In other words, they are responsible for switching certain genes ‘on’ or ‘off’ during the development and/or functioning of the brain. This switching is dependent on the 3D structure of DNA – called the epigenome. A class of genes - the chromatin remodelers, alter this 3D structure, while another class of genes - transcription factors, bind the DNA regions that are now accessible and can promote the expression of the target genes. In the lab we are using gene-editing technologies (CRISPR-Cas9) and reprograming of patient cells to make stem cell models of genetic epilepsy. We then differentiate these cells to a neuronal lineage and study how these mutations change the epigenome structure, as well as the genes and pathways that are disrupted. These studies will provide new targets for therapeutic development and testing.
Epigenetic mechanisms in epilepsy Pathogenic variants in various genes that control the epigenetic machinery are implicated in epilepsy, our lab is focusing on the chromatin remodeler, CHD2 and the transcription factor CUX2 to understand how alteration of these genes affect neuronal development and function.