Towards a Better Understanding of the Genetic Contributions to Epilepsy Restricted; Files & ToC

Mattison, Kari (Spring 2022)

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Epilepsy, characterized by recurrent and unprovoked seizures, is a common neurological disorder affecting more than 3 million individuals in the United States. Use of next-generation sequencing in genetic testing of epilepsy patients has led to the identification of over 200 known and evidence-based epilepsy genes, representing diverse biological functions. The goal of this dissertation was to gain a better understanding of the genetic contributions to epilepsy. We utilized three approaches for the identification of candidate disease variants. The first approach was to analyze gene panel data consisting of approximately 4,800 evidence-based disease genes from 460 patients with epilepsy. We identified 8 variants in SLC6A1 from this data set which was a similar to the diagnostic yield of established epilepsy genes, SCN2A and CDKL5. We showed, for the first time, through functional assays that SLC6A1 variants identified in epilepsy patients result in decreased GABA re-uptake. In the second approach, we analyzed whole exome sequencing data from 218 patients with epilepsy. From this we identified a single de novo, heterozygous variant in ATP6V0C (p.A138P). Using GeneMatcher and other publicly available datasets, we subsequently identified 25 additional patients with ATP6V0C variants. To confirm pathogenicity of the identified variants, we developed functional assays using Saccharomyces cerevisiae which demonstrated that the ATP6V0C variants result in loss of vacuolar ATPase function. Our work resulted in the largest cohort to-date of patients with ATP6V0C variants and provides strong support for ATP6V0C as an epilepsy gene. Lastly, we performed whole genome sequencing in two brothers with epilepsy from a consanguineous family to identify variants within shared regions of homozygosity. We identified a homozygous variant, p.G228R, in CNTNAP2 and subsequently found co-segregation of the same variant in an unrelated family with overlapping clinical presentations. Taken together, three epilepsy genes were identified, each with a unique disease mechanism and function related to neuronal signaling. The knowledge gained from the identification and functional analysis of variants can provide insight into treatment options and/or development of precision therapies for patients.

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