Published 2020
| Version v1
Publication
Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load
Creators
- Perucca P.
- Anderson A.
- Jazayeri D.
- Hitchcock A.
- Graham J.
- Todaro M.
- Tomson T.
- Battino D.
- Perucca E.
- Ferri M. M.
- Rochtus A.
- Lagae L.
- Canevini M. P.
- Zambrelli E.
- Campbell E.
- Koeleman B. P. C.
- Scheffer I. E.
- Berkovic S. F.
- Kwan P.
- Sisodiya S. M.
- Goldstein D. B.
- Petrovski S.
- Craig J.
- Vajda F. J. E.
- O'Brien T. J.
- Leu C.
- Wolking S.
- Peter S.
- Weber Y. G.
- Weckhuysen S.
- Moller R. S.
- Nikanorova M.
- Muhle H.
- Avbersek A.
- Heggeli K.
- Striano P.
- Gambardella A.
- Langley S. R.
- Krenn M.
- Klein K. M.
- McCormack M.
- Borghei M.
- Willis J.
- Berghuis B.
- Jorgensen A.
- Auce P.
- Francis B.
- Srivastava P.
- Sonsma A. C. M.
- Sander JW.
- Zimprich F.
- Depondt C.
- Johnson M. M.
- Marson A. G.
- Sills G. J.
- Kunz W. S.
- Cavalleri G. L.
- Delanty N.
- Zara F.
- Krause R.
- Lerche H.
- Andrade D.
- Sen A.
- Bazil C. W.
- Boland M.
- Cavalleri G.
- Choi H.
- Colombo S.
- Costello D.
- Delanty N.
- Depondt C.
- Devinsky O.
- Doherty C. P.
- Dugan P.
- Frankel W.
- Heinzen E.
- Johnson M.
- Marson T.
- McCormack M.
- Mikati M.
- Ottman R.
- Pandolfo M.
- Radtke R.
- Rees M.
- Sadoway T.
- Valley N.
- Walley N.
- Wood N.
- Zuberi S.
Contributors
Others:
- Perucca, P.
- Anderson, A.
- Jazayeri, D.
- Hitchcock, A.
- Graham, J.
- Todaro, M.
- Tomson, T.
- Battino, D.
- Perucca, E.
- Ferri, M. M.
- Rochtus, A.
- Lagae, L.
- Canevini, M. P.
- Zambrelli, E.
- Campbell, E.
- Koeleman, B. P. C.
- Scheffer, I. E.
- Berkovic, S. F.
- Kwan, P.
- Sisodiya, S. M.
- Goldstein, D. B.
- Petrovski, S.
- Craig, J.
- Vajda, F. J. E.
- O'Brien, T. J.
- Leu, C.
- Wolking, S.
- Peter, S.
- Weber, Y. G.
- Weckhuysen, S.
- Moller, R. S.
- Nikanorova, M.
- Muhle, H.
- Avbersek, A.
- Heggeli, K.
- Striano, P.
- Gambardella, A.
- Langley, S. R.
- Krenn, M.
- Klein, K. M.
- Mccormack, M.
- Borghei, M.
- Willis, J.
- Berghuis, B.
- Jorgensen, A.
- Auce, P.
- Francis, B.
- Srivastava, P.
- Sonsma, A. C. M.
- Sander, Jw.
- Zimprich, F.
- Depondt, C.
- Johnson, M. M.
- Marson, A. G.
- Sills, G. J.
- Kunz, W. S.
- Cavalleri, G. L.
- Delanty, N.
- Zara, F.
- Krause, R.
- Lerche, H.
- Andrade, D.
- Sen, A.
- Bazil, C. W.
- Boland, M.
- Cavalleri, G.
- Choi, H.
- Colombo, S.
- Costello, D.
- Delanty, N.
- Depondt, C.
- Devinsky, O.
- Doherty, C. P.
- Dugan, P.
- Frankel, W.
- Heinzen, E.
- Johnson, M.
- Marson, T.
- Mccormack, M.
- Mikati, M.
- Ottman, R.
- Pandolfo, M.
- Radtke, R.
- Rees, M.
- Sadoway, T.
- Valley, N.
- Walley, N.
- Wood, N.
- Zuberi, S.
Description
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.
Additional details
Identifiers
- URL
- http://hdl.handle.net/11567/1021849
- URN
- urn:oai:iris.unige.it:11567/1021849
Origin repository
- Origin repository
- UNIGE