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Cognitive Outcomes at 2 Years Old in Children of Women with Epilepsy Are Associated with Fetal Alcohol Syndrome Risk Genes: MONEAD Study

Conference Paper

Li, Y.; Zhang, S.; Pennell, P.; Cohen, M.; Loring, D.; Matthews, A.; Robalino, C.; Finnell, R.; Snyde, M.; Meador, K.

AES Annual Meeting 2022

Nashville, TN


This abstract is a recipient of the Kimford J. Meador Research in Women with Epilepsy Award This abstract has been invited to present during the Clinical Research platform session Rationale: Fetal antiseizure medication (ASMs) exposure has potential behavioral teratogenicity resulting in cognitive impairments. Children's cognitive development is substantially mediated by genetic factors; it is known that teratogens act on a susceptible genotype, but little is known about the gene variants impacting this inter-individual variability seen in children of women with epilepsy (WWE). Current findings signify that fetal ASM associated behavioral teratogenicity and fetal alcohol syndrome (FAS) share similarities in many cognitive and behavioral domains, e.g., impaired intellectual function, autistic traits, social adaptive skills. Emerging evidence has also shown that they may share common pathogenic processes including but not limited to apoptosis, mitochondrial toxicity and oxidative stress. We hypothesize that maternal genetic variations in FAS risk genes could help predict the inter-individual variability of cognitive outcome seen in children of WWE. Methods: WWE in this cohort were enrolled in the prospective Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study. Their children were assessed at 2 yo via the Bayley Scales of Infant and Toddler Development-3 (BSID-III); the language domain score was used as the primary outcome. Samples underwent whole exome sequencing (WES) with collaboration of Epi25 at the Broad Institute on the Illumina HiSeq X platform. To guarantee high quality of the sequencing data, several quality control procedures were performed. Genes associated with FAS were extracted from existing literature (n=16). Rare variants in genes of interest were identified with occurrence < 1% in gnomAD v2. Only rare exonic variants, which were indicated to have potential biological effect such as loss of function or missense or splicing based on ANNOVOR, were extracted for final analysis. The impact of these rare genetic variants in WWE on their children’s cognitive outcome were evaluated via a linear regression model. Results: A total of 190 pregnant WWE were included in this analysis. Total rare variant counts in FAS risk genes were significantly associated with language (r2 = -0.17, p= 0.02) domains of the BSID-III. Clinical characteristics were also assessed and variables with statistical significance were incorporated into the regression analysis. In adjusted analysis including WWE’s IQ and education background, child's gender, exposure of alcohol and post-birth average anxiety score, the rare genetic variant counts in the FAS risk genes remained as an independent factor to predict the poorer language (95% CIs = -3.97, -1.16, p< 0.001) in BSID-III (Table 1). Clinical Epilepsy

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