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dc.contributor.authorPerucca, Piero-
dc.contributor.authorAnderson, Alison-
dc.contributor.authorJazayeri, Dana-
dc.contributor.authorHitchcock, Alison-
dc.contributor.authorGraham, Janet-
dc.contributor.authorTodaro, Marian-
dc.contributor.authorTomson, Torbjörn-
dc.contributor.authorBattino, Dina-
dc.contributor.authorPerucca, Emilio-
dc.contributor.authorMartinez Ferri, Meritxell-
dc.contributor.authorRochtus, Anne-
dc.contributor.authorLagae, Lieven-
dc.contributor.authorCanevini, Maria Paola-
dc.contributor.authorZambrelli, Elena-
dc.contributor.authorCampbell, Ellen-
dc.contributor.authorKoeleman, Bobby P C-
dc.contributor.authorScheffer, Ingrid E-
dc.contributor.authorBerkovic, Samuel F-
dc.contributor.authorKwan, Patrick-
dc.contributor.authorSisodiya, Sanjay M-
dc.contributor.authorGoldstein, David B-
dc.contributor.authorPetrovski, Slavé-
dc.contributor.authorCraig, John-
dc.contributor.authorVajda, Frank J E-
dc.contributor.authorO'Brien, Terence J-
dc.identifier.citationAnnals of neurology 2020; online first: 25 March-
dc.description.abstractThe 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 which we investigated. Whole-exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in: children exposed prenatally to AEDs (AED-exposed children) vs children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs vs those without BDs, adjusting for confounders. Fisher's exact test was used to compare categorical data. 67 child-parent trios were included: 10 with AED-exposed children with BDs; 46 with AED-exposed unaffected children; 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 9/67 (13%) children, none of whom had BDs. The proportion of cases harbouring 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. 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 counselling. This article is protected by copyright. All rights reserved.-
dc.titleAntiepileptic drug teratogenicity and de novo genetic variation load.-
dc.typeJournal Article-
dc.identifier.journaltitleAnnals of neurology-
dc.identifier.affiliationInstitute of Genomic Medicine, Columbia University, New York, USAen
dc.identifier.affiliationBelfast Health and Social Care Trust, Belfast, UKen
dc.identifier.affiliationChalfont Centre for Epilepsy, Chalfont-St-Peter, UKen
dc.identifier.affiliationCentre for Genomic Research, AstraZeneca, Cambridge, UKen
dc.identifier.affiliationDepartment of Neuroscience, Central Clinical School, Monash Universityen
dc.identifier.affiliationDepartment of Health Sciences, University of Milan, Italyen
dc.identifier.affiliationEpilepsy Center, Department of Neurophysiology and Experimental Epileptology, I.R.C.C.S. Neurological Institute "Carlo Besta" Foundation, Milan, Italyen
dc.identifier.affiliationDepartment of Internal Medicine and Therapeutics, University of Pavia, and Clinical Trial Center, IRCCS Mondino Foundation, Pavia, Italyen
dc.identifier.affiliationChild Neuropsychiatry Unit-Epilepsy Center, San Paolo Hospital, Milan, Italyen
dc.identifier.affiliationDepartments of Medicine and Neurology, The University of Melbourne, The Royal Melbourne Hospital, Melbourne, Australiaen
dc.identifier.affiliationDepartment of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UKen
dc.identifier.affiliationEpilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australiaen
dc.identifier.affiliationChild Neuropsychiatry Unit-Epilepsy Center, San Paolo Hospital, Milan, Italyen
dc.identifier.affiliationDepartment of Paediatrics, The University of Melbourne, Royal Children's Hospital, Florey and Murdoch Children's Research Institutes, Melbourne, Australiaen
dc.identifier.affiliationDepartment of Neurology, Alfred Health, Melbourne, Australiaen
dc.identifier.affiliationDepartment of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden..-
dc.identifier.affiliationServicio de Neurología, Hospital Mútua de Terrassa, Barcelona, Spain..-
dc.identifier.affiliationDepartment of Development and Regeneration, Section of Pediatric Neurology, University Hospitals Leuven, Leuven, Belgium..-
dc.identifier.affiliationDepartment of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, The Netherlands..-
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