Diving into gene discovery to determine the genetic and biological basis of pediatric epilepsies
Seizure disorders that begin in the first weeks to years of a child’s life can be difficult to treat. They are associated with poor developmental outcomes, developmental delays, intellectual disability, and autism spectrum disorder. Our laboratory investigates the genetic basis of rare forms of epilepsy and related neurodevelopmental disorders. Our goal is to identify novel mutations and determine their biological implications to help inform precision therapeutic development.
The overarching goal of the research in our laboratory aims to understand the genetic basis of neurologic and neurodevelopmental diseases, particularly severe forms of epilepsy. We have identified some of the first recurrent deletions associated with an increased risk of epilepsy and applied sequencing techniques to identify genetic variants in large cohorts of patients with epileptic encephalopathies. We have explored several non-traditional mechanisms of disease to identify disease-associated variants in epilepsy and several other developmental disorders. Our research strives to understand the underlying biology so we can ultimately identify potential treatment targets.
Because approximately 50% of severe pediatric epilepsy cases have an unknown etiology, a large part of our research focuses on discovery efforts to identify novel genetic and epigenetic drivers of pediatric epilepsy. Standard sequencing and historical clinical testing approaches are limited in scope, interrogating changes to the exome only. We use short-read and long-read genome sequencing to identify potentially pathogenic variants including non-coding variants, copy number changes, and repeat expansions. We are also using patient-derived cells to create organoid systems that facilitate transcriptome analysis. Recognizing that methylation represents a major class of epigenetic variation that drives disease, we are performing genome-wide methylation array analysis to identifier outlier differentially methylated regions of the genome. Identifying epigenetic causes of disease may have treatment implications, as there are several available drugs that target related processes.
Armed with this genetic information, our laboratory then works to define the clinical phenotype and natural history associated with our genetic discoveries, both of which are particularly important for affected families and treating physicians. An emerging area of research in our laboratory focuses on the molecular and functional implications of the genetic mutations we identify. We are developing cell lines from patient families to characterize and determine pathways disrupted in disease. These approaches are foundational to informing precision therapies – whether customized by patient, by gene, or by disorder.