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Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load

  • Perucca, Piero;
  • Anderson, Alison;
  • Jazayeri, Dana;
  • Hitchcock, Alison;
  • Graham, Janet;
  • Todaro, Marian;
  • Tomson, Torbjorn;
  • Battino, Dina;
  • Perucca, Emilio;
  • Ferri, Meritxell Martinez;
  • Rochtus, Anne; 87045;
  • Lagae, Lieven; 18472;
  • Canevini, Maria Paola;
  • Zambrelli, Elena;
  • Campbell, Ellen;
  • Koeleman, Bobby PC;
  • Scheffer, Ingrid E;
  • Berkovic, Samuel F;
  • Kwan, Patrick;
  • Sisodiya, Sanjay M;
  • And 5 more
Publication Date
Apr 15, 2020
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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 and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome. INTERPRETATION: Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counseling. ANN NEUROL 2020;87:897-906. / status: published

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