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Title: Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load.
Austin Authors: Perucca, Piero ;Anderson, Alison;Jazayeri, Dana;Hitchcock, Alison;Graham, Janet;Todaro, Marian;Tomson, Torbjörn;Battino, Dina;Perucca, Emilio;Ferri, Meritxell Martinez;Rochtus, Anne;Lagae, Lieven;Canevini, Maria Paola;Zambrelli, Elena;Campbell, Ellen;Koeleman, Bobby P C;Scheffer, Ingrid E ;Berkovic, Samuel F ;Kwan, Patrick;Sisodiya, Sanjay M;Goldstein, David B;Petrovski, Slavé;Craig, John;Vajda, Frank J E;O'Brien, Terence J
Affiliation: Child Neuropsychiatry Unit-Epilepsy Center, San Paolo Hospital, Milan, Italy
Epilepsy Research Centre
Centre for Genomic Research, AstraZeneca, Cambridge, United Kingdom
Departments of Medicine and Neurology, University of Melbourne, Royal Melbourne Hospital, Melbourne, Victoria, Australia
Chalfont Centre for Epilepsy, Chalfont-St-Peter, United Kingdom
Department of Clinical and Experimental Epilepsy, University College London Queen Square Institute of Neurology, London, United Kingdom
Department of Neurology, Alfred Health, Melbourne, Victoria, Australia
Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
Department of Health Sciences, University of Milan, Milan, Italy
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Florey and Murdoch Children's Research Institutes, Melbourne, Victoria, Australia
Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
Epilepsy Center, Department of Neurophysiology and Experimental Epileptology, IRCCS Neurological Institute "Carlo Besta" Foundation, Milan, Italy
Department of Internal Medicine and Therapeutics, University of Pavia, and Clinical Trial Center, IRCCS Mondino Foundation, Pavia, Italy
Neurology Service, Hospital Mútua de Terrassa, Barcelona, Spain
Department of Development and Regeneration, Section of Pediatric Neurology, University Hospitals Leuven, Leuven, Belgium
Child Neuropsychiatry Unit-Epilepsy Center, San Paolo Hospital, Milan, Italy
Belfast Health and Social Care Trust, Belfast, United Kingdom
Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
Institute of Genomic Medicine, Columbia University, New York, NY, USA
Belfast Health and Social Care Trust, Belfast, United Kingdom
Issue Date: Jun-2020 2020-04-15
Publication information: Annals of Neurology 2020; 87(6): 897-906
Abstract: 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. 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. 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. 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.
DOI: 10.1002/ana.25724
ORCID: 0000-0002-7855-7066
PubMed URL: 32215971
Type: Journal Article
Appears in Collections:Journal articles

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