Discovery and functional characterization of somatic variation in intractable focal epilepsy

PROJECT ABSTRACT
Focal epilepsy is the most common form of refractory epilepsy. Focal seizures are often associated with
malformations of cortical development (MCD) but can also occur in the absence of a radiographically-detected
lesion. Patients will often require surgical resection of the epileptogenic lesion to control their seizures, as many
patients develop a drug resistance to the numerous antiepileptic drugs available. The availability of resected
tissue has allowed for the study of the role of somatic variation in focal epilepsy. Somatic variation arising during
embryonic brain development is increasingly recognized as a major contributor to genetic risk of focal epilepsy.
Somatic variants localized to the brain have been readily identified in hemimegalencephaly and focal cortical
dysplasia (FCD) type II; furthermore, evidence suggests that somatic variants also contribute to FCD type I and
radiographically nonlesional focal epilepsy. While there has been substantial progress in our understanding of
the genetic architecture underlying focal epilepsy, more work is needed to characterize the remaining cases
lacking a genetic cause. Continued work to identify novel genes and the types of variants involved in focal
epilepsy is essential to further advance understanding of the underlying mechanisms of disease and fuel the
development of novel therapeutic approaches. The overall goal of my dissertation and postdoctoral research is
to advance novel gene discovery in focal epilepsy and identify pathways that cause focal seizures to better inform
drug discovery strategies and widen the scope of treatment. I have demonstrated my ability to identify putative
pathogenic somatic variation affecting known epilepsy genes, as shown in my preliminary data in Aim 1. I have
also identified a disease-causing variant in genes not yet associated with focal epilepsy. In Aim 1, I propose
using deep exome and targeted sequencing approaches to identify novel genes and variants contributing to
intractable focal epilepsy. Additionally, I propose using duplex sequencing to detect low abundance somatic
variants that may have been missed by exome and panel sequencing. In the K00 Phase, I plan to expand these
studies to in vivo models to probe the functional consequence of pathogenic somatic variation in the zebrafish
model system. The proposed research provides opportunities for developing technical expertise in gene
discovery, functional characterization of disease-causing somatic variation and drug discovery. I will rely heavily
on the support of my sponsors to contribute to the development of my skillset in experimental design, scientific
communication, and grantsmanship; as well as advancing my search for a postdoctoral training environment that
is aligned with my research interests and career goals. The training plan outlined in this proposal integrates
scientific and professional development that will put me on a trajectory to emerge as a well-rounded and
independent investigator.

Grant Number: 5F99NS139548-02
NIH Institute/Center: NIH
Principal Investigator: Ana Berglind