Mapping Genetic Pathways Associated With Neurodevelopmental Variability after Fetal Anti-Seizure Medication Exposure

Stanford University, Stanford CA

Investigators

Abstract

PROJECT SUMMARY The mechanisms underlying the variability of cognitive outcomes seen in children born to women with epilepsy (WWE) remain poorly understood, and our ability to predict individual outcomes is limited. As discontinuation of anti-seizure medications (ASMs) during pregnancy is often not an option, current practice focuses on optimizing medical management prior to and during pregnancy for WWE, knowing that a variable degree of teratogenicity could be seen in patients treated with ASMs. However, we cannot effectively counsel WWE on how to mitigate the risk to their children beyond avoiding specific ASMs or polypharmacy. Genetic factors account for up to 50% of cognitive variation, but the susceptible genotypes that interact with ASM exposure in WWE and their children remain unknown. Hence, there is a compelling need for properly controlled studies in WWE during pregnancy to investigate factors affecting children's long-term outcomes. This proposal aims to investigate the impact of genetic variants and pathways in WWE and their children on the children's long-term cognitive status after fetal ASM exposure. My pilot study showed that genetic variants in WWE that are known to affect ASM transport and metabolism were associated with their children's cognitive outcome at 3 years of age, indicating the genetic background of WWE could potentially impact the children's cognitive outcome following ASM exposure. My hypothesis is that genetic variants in either or both WWE and their children are associated with the variance of cognitive outcomes seen in children after fetal ASM exposure. Further, combining clinical/external factors and genetic/intrinsic biomarkers of WWE and their children will create a better predictive model of neurocognitive outcomes in children of WWE. These findings could pave the way for the development of preventive strategies to optimize care for WWE and advance our understanding of the underlying mechanisms driving heterogeneity in children's neurodevelopmental outcomes despite similar ASM exposures. Aim 1: Determine the correlation between genetic variants and pathways related to ASM transport and metabolism in WWE and their children, and the children’s neurodevelopmental outcomes following fetal ASM exposure, using a targeted approach. Aim 2: Identify novel candidate genetic variants and pathways in WWE and their children associated with neurodevelopmental outcomes following fetal ASM exposure, using a machine learning approach. To achieve my objectives, I will have direct guidance from an internationally renowned team with expertise in cognitive neurology, epilepsy, genetics and bioinformatics. This mentorship will help me develop my own expertise in interfacing with these areas. The generated data will bridge existing gaps in our management of WWE to optimize their children's outcomes and lay the groundwork for future diagnostic approaches utilizing innovative precision medicine methods.