Epilepsy affects approximately one percent of the population and one in 200 children. Epilepsy syndromes with proven or likely genetic cause contribute substantially to the causes of epilepsy, especially in children. Over the last half century, there has been increasing recognition that genetic factors play an important role in predisposing individuals to epilepsy. The traditional approach of linkage analysis in families with well-defined epilepsy syndromes has been successful in identifying the genes responsible for some of these syndromes. To date, most of these genes encode ion channel subunits and provide an explanation for only a small proportion of epilepsy. We hypothesize that by studying familial forms of epilepsy with both dominant and recessive inheritance, we will discover novel genes and novel processes that set the stage for epilepsy in the developing brain. Such discovery will deepen our understanding of the developmental processes and pathways important in epilepsy and may also identify novel approaches to rational pharmacological treatment for patients with epilepsy. We will first perform rigorous phenotyping methods to classify individuals in families with individual diagnoses and familial epilepsy syndromes. We will use genome-wide markers of genetic variability (short tandem repeat polymorphisms and single nucleotide polymorphisms) to perform analyses of linkage between disease status and genomic loci, and we will further analyze the regions with evidence of linkage with positional cloning and high-throughput sequencing to identify specific genetic mutations in these families. Once this is achieved, we will screen other families and sporadic individuals with the same epilepsy phenotypes for mutations in these genes. The candidate is a board-certified child neurologist with additional clinical neurophysiology/pediatric EEG training. She will perform this research at Children's Hospital Boston under the supervision of Dr. Christopher Walsh, a renowned expert in the field of neurogenetics with extensive clinical and research experience in the genetics of brain malformations, with co-mentorship from Dr. Ruth Ottman, a pioneer in the field of epilepsy genetics who has developed the phenotyping methodologies now accepted as standard for epilepsy genetics research. In addition to the combined training under these mentors, the candidate will also participate in the Epilepsy Phenome Genome Project and receive additional training from a renowned group of national experts in epilepsy genetics. The experience and skills she will garner during this training period will set the stage for an independent career in clinical neuroscience research.

Public Health Relevance

Epilepsy is a common condition, affecting approximately one in one hundred people. While the causes of epilepsy are varied, genetics play an important role in the development of epilepsy in many individuals and may affect several individuals in a family. The goal of this project is to gain deeper insight into the fundamental causes of epilepsy by studying the genetics of familial forms of epilepsy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Mentored Patient-Oriented Research Career Development Award (K23)
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NST-2 Subcommittee (NST)
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Whittemore, Vicky R
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Children's Hospital Boston
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Ottman, Ruth; Freyer, Catharine; Mefford, Heather C et al. (2018) Return of individual results in epilepsy genomic research: A view from the field. Epilepsia 59:1635-1642
D'Gama, Alissa M; Woodworth, Mollie B; Hossain, Amer A et al. (2017) Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias. Cell Rep 21:3754-3766
Olson, Heather E; Kelly, McKenna; LaCoursiere, Christopher M et al. (2017) Genetics and genotype-phenotype correlations in early onset epileptic encephalopathy with burst suppression. Ann Neurol 81:419-429
Smith, Lacey A; Ullmann, Jeremy F P; Olson, Heather E et al. (2017) A Model Program for Translational Medicine in Epilepsy Genetics. J Child Neurol 32:429-436
Meyer, Michaela; Dhamne, Sameer C; LaCoursiere, Christopher M et al. (2016) Microarray Noninvasive Neuronal Seizure Recordings from Intact Larval Zebrafish. PLoS One 11:e0156498
EpiPM Consortium (2015) A roadmap for precision medicine in the epilepsies. Lancet Neurol 14:1219-28
Fallil, Zianka; Pardoe, Heath; Bachman, Robert et al. (2015) Phenotypic and imaging features of FLNA-negative patients with bilateral periventricular nodular heterotopia and epilepsy. Epilepsy Behav 51:321-7
Nakayama, Tojo; Al-Maawali, Almundher; El-Quessny, Malak et al. (2015) Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination. Am J Hum Genet 96:709-19
Stödberg, Tommy; McTague, Amy; Ruiz, Arnaud J et al. (2015) Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures. Nat Commun 6:8038
D'Gama, Alissa M; Geng, Ying; Couto, Javier A et al. (2015) Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia. Ann Neurol 77:720-5

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