Medicine (Austin & Northern Health) - Research Publications

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Author: Berkovic, Samuel × Author: Kwan, Patrick × Author: Vajda, Frank × Start date: 2020 ×

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    Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load
    Perucca, P ; Anderson, A ; Jazayeri, D ; Hitchcock, A ; Graham, J ; Todaro, M ; Tomson, T ; Battino, D ; Perucca, E ; Ferri, MM ; Rochtus, A ; Lagae, L ; Canevini, MP ; Zambrelli, E ; Campbell, E ; Koeleman, BPC ; Scheffer, IE ; Berkovic, SF ; Kwan, P ; Sisodiya, SM ; Goldstein, DB ; Petrovski, S ; Craig, J ; Vajda, FJE ; O'Brien, TJ (WILEY, 2020-06)
    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.