Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load

Abstract

Objective: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism that we investigated. Methods: Whole exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and de novo copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in children exposed prenatally to AEDs (AED-exposed children) versus children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs versus those without BDs, adjusting for confounders. Fisher exact test was used to compare categorical data. Results: Sixty-seven child-parent trios were included: 10 with AED-exposed children with BDs, 46 with AED-exposed unaffected children, and 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children (median dnSNV/indel number/child [range] = 3 [0-7] vs 3 [1-5], p = 0.50). Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9 of 67 (13%) children, none of whom had BDs. The proportion of cases harboring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed View this article online at wileyonlinelibrary.com.Additional supporting information can be found in the online version of this article.

Rare Genetic Variation and Outcome of Surgery for Mesial Temporal Lobe Epilepsy

“…This case-control study was carried out within the EPIGEN Consortium, an international collaborative framework that has the goal of unraveling genomic contributions to epilepsy and its treatment outcomes. [23][24][25] Cases. DNA samples were collected from patients of European ancestry (given the paucity of knowledge of genetic variants in non-European populations) who underwent epilepsy surgery for drug-resistant unilateral MTLE at one of 9 centers across Europe, North America, and Australasia (Table S1).…”

Autoimmune encephalitis during pregnancy: A diagnostic and therapeutic challenge—A systematic review with individual patients' analysis and clinical recommendations

“…trimester, the use of antiseizure medications (ASMs) such as valproate and phenobarbital, 8 immunomodulatory drugs (i.e., cyclophosphamide and rituximab), 9 or radiological examinations (e.g., computer tomography [CT] or magnetic resonance image [MRI] scans with contrast agents) 10 are associated with increased rates of intra-uterine death, congenital malformations (like spina bifida or cardiac anomalies), and newborn distress. This systematic review aims to reassume and analyze the available data on the diagnostic and therapeutic approach to AE during pregnancy highlighting the associated maternal and fetal clinical outcomes.…”

“…AE diagnosis and treatment during pregnancy are challenging due to the possible teratogenic effects of certain diagnostic procedures and therapeutic approaches. Especially in the first trimester, the use of antiseizure medications (ASMs) such as valproate and phenobarbital, 8 immunomodulatory drugs (i.e., cyclophosphamide and rituximab), 9 or radiological examinations (e.g., computer tomography [CT] or magnetic resonance image [MRI] scans with contrast agents) 10 are associated with increased rates of intra‐uterine death, congenital malformations (like spina bifida or cardiac anomalies), and newborn distress.…”

Preventing Teratogenicity in Women with Epilepsy

“…Some studies have attempted to better define the individual risks for ASMs and adverse fetal/infant outcomes, such as the risks for recurrence and pharmacogenetic influences. 81,82 There do appear to be some individual susceptibilities to such outcomes, but results to date have not provided any insight. Clearly, there is still much to be learned.…”