Abstracts

Transcription Factor Binding and Genetic Risk for Valproic Acid Teratogenicity

Abstract number : 2.281
Submission category : 7. Anti-seizure Medications / 7D. Drug Side Effects
Year : 2023
Submission ID : 365
Source : www.aesnet.org
Presentation date : 12/3/2023 12:00:00 AM
Published date :

Authors :
Presenting Author: Alison Anderson, PhD – Monash University

Dina Battino, MD – IRCCS Neurological Institute; Samuel Berkovic, MD, FRS – University of Melbourne; Ellen Campbell, MD – 13. Belfast Health and Social Care Trust; Maria Canevini, MD, PhD – San Paolo Hospital; John Craig, MD – 13. Belfast Health and Social Care Trust; David Goldstein, PhD – Columbia University; Janet Graham, RN – Royal Melbourne Hospital; Alison Hitchcock, RN – Royal Melbourne Hospital; Dana Jazayeri, PhD – University of Melbourne; Bobby Koeleman, PhD – University Medical Center Utrecht; Patrick Kwan, FRACP, PhD – Monash University; Lieven Lagae, MD, PhD – University Hospitals Leuven; Meritxell Martinez Ferri, MD – Hospital Mútua de Terrassa; Terence O’Brien, MD – Monash University; Emilio Perucca, MD, PhD – Monash University; Piero Perucca, MD, PhD – University of Melbourne; Slavé Petrovski, PhD – University of Melbourne; Anne Rochtus, MD, PhD – University Hospitals Leuven; Ingrid Scheffer, MBBS, PhD – University of Melbourne; Sanjay Sisodiya, FRCP, PhD – University College London; Marian Todaro, PhD – Monash University; Torbjörn Tomson, MD – Karolinska Institute; Frank Vajda, MD – University of Melbourne; Elena Zambrelli, MD – San Paolo Hospital

Rationale: The teratogenic effects of valproic acid are well established and limit its use in women of childbearing potential who could therapeutically benefit from it, in particular those with generalized epilepsies and bipolar disorder. Not all exposed children are affected, and among those that are there is a wide range of birth defects and adverse neurodevelopmental outcomes. Genetic variation is thought to modify risk but identifying genetic biomarkers has remained elusive. Transcription factors (TFs) bind to DNA and form multi-protein complexes which act as “master regulators” and play a critical role in orchestrating the precise expression of genes during embryogenesis. We hypothesised that genetic variation that impacts on the binding of TFs to DNA might account for both variance in inter-individual risk and birth defect types.

Methods: Whole-exome data was obtained from women recruited through an international collaboration. We reasoned that genetic risk would be highly heterogeneous among mothers with affected infants and involve multiple variants that impact on common TF complexes but confer tissue-specific consequence. To elucidate variant impact shared across birth defect types, we constructed a network representing genes implicated in one or more structural birth defects (n=29) that were also associated with birth defects in our cohort (affected pregnancies N=22, unaffected N=93, SKAT test P < 0.05). The functional impact of variants across the network was determined using DeepBind, an AI tool to predict impact on TF binding,
Anti-seizure Medications