Molecular Genetic Mechanisms of Infantile Epilepsies and the Impact of Genetic Diagnosis

PROJECT SUMMARY/ABSTRACT Epilepsies with onset in the first year of life are common, affecting 1 in 1000 infants, and are associated with significant morbidity, notably drug-resistant seizures and impaired developmental outcomes, and increased mortality. Although most infantile epilepsies have presumed molecular genetic etiologies, most cases remain genetically “unsolved” and the full molecular genetic landscape is unknown, which limits our ability to develop effective precision therapies. Further, the impact of genetic diagnosis in infantile epilepsies is largely unknown, which limits our ability to broadly implement genetic testing for this population. This proposal will address these knowledge gaps by identifying novel molecular genetic etiologies (genetic diagnoses) and evaluating their impact in a prospectively enrolled, longitudinally followed cohort of infants with unexplained epilepsy. Aim 1 will apply cutting-edge, comprehensive genomic analyses to identify novel genetic etiologies of infantile epilepsies, using short-read and long-read genome sequencing to identify pathogenic germline variants (Aim 1a) and deep sequencing to identify pathogenic mosaic variants (Aim 1b). Aim 2 will evaluate the multidimensional impact of genetic diagnosis (or lack thereof), using a validated measure of clinical utility and follow up of developmental progress and seizure frequency to assess impact on infants (Aim 2a) and a validated measure of parent-perceived utility and interviews with parents to assess impact on families (Aim 2b). The insights from this proposal will advance scientific knowledge and clinical care, with immediate diagnostic and therapeutic implications for infants with epilepsy, with the ultimate goal of advancing precision medicine and improving outcomes for this vulnerable population. Dr. D’Gama is a neonatologist with prior experience in basic neurogenetics research whose career goal is to become an independent physician-scientist at an academic medical center with a translational research program focused on precision medicine for infantile epilepsies and related neurogenetic disorders. Through the proposed K23 training program, Dr. D’Gama will gain new knowledge and skills in patient-oriented clinical and translational research, including advanced genomic sequencing and analyses, neonatal and infantile epilepsy phenotyping, epidemiology and biostatistics, qualitative analyses, and human subjects and clinical trials research, which will position her to successfully transition to independence. Dr. D’Gama’s mentor, Dr. Annapurna Poduri, is a leader in pediatric epilepsy and epilepsy genetics research, and her co-mentor, Dr. Margaret Parker, is a leader in neonatology and health services research. Both Drs. Poduri and Parker have extensive mentorship track records and Dr. D’Gama has also assembled a Scientific Advisory Committee and collaborators with complementary expertise. The institutional resources and intellectual community available through Boston Children’s Hospital and Harvard Medical School are world-class and will provide an ideal environment for Dr. D’Gama’s career development as a physician-scientist.