Piero Perucca1,2,3, Alison Anderson1,2, Dana Jazayeri2, Alison Hitchcock2, Janet Graham2, Marian Todaro2, Torbjörn Tomson4, Dina Battino5, Emilio Perucca6, Meritxell Martinez Ferri7, Anne Rochtus8, Lieven Lagae8, Maria Paola Canevini9,10, Elena Zambrelli9, Ellen Campbell11, Bobby P C Koeleman12, Ingrid E Scheffer13,14, Samuel F Berkovic13, Patrick Kwan1,2,3, Sanjay M Sisodiya15,16, David B Goldstein17, Slavé Petrovski2,18, John Craig11, Frank J E Vajda1,2, Terence J O'Brien1,2,3. 1. Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia. 2. Departments of Medicine and Neurology, University of Melbourne, Royal Melbourne Hospital, Melbourne, Victoria, Australia. 3. Department of Neurology, Alfred Health, Melbourne, Victoria, Australia. 4. Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden. 5. Epilepsy Center, Department of Neurophysiology and Experimental Epileptology, IRCCS Neurological Institute "Carlo Besta" Foundation, Milan, Italy. 6. Department of Internal Medicine and Therapeutics, University of Pavia, and Clinical Trial Center, IRCCS Mondino Foundation, Pavia, Italy. 7. Neurology Service, Hospital Mútua de Terrassa, Barcelona, Spain. 8. Department of Development and Regeneration, Section of Pediatric Neurology, University Hospitals Leuven, Leuven, Belgium. 9. Child Neuropsychiatry Unit-Epilepsy Center, San Paolo Hospital, Milan, Italy. 10. Department of Health Sciences, University of Milan, Milan, Italy. 11. Belfast Health and Social Care Trust, Belfast, United Kingdom. 12. Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands. 13. Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Melbourne, Victoria, Australia. 14. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Florey and Murdoch Children's Research Institutes, Melbourne, Victoria, Australia. 15. Department of Clinical and Experimental Epilepsy, University College London Queen Square Institute of Neurology, London, United Kingdom. 16. Chalfont Centre for Epilepsy, Chalfont-St-Peter, United Kingdom. 17. Institute of Genomic Medicine, Columbia University, New York, NY, USA. 18. Centre for Genomic Research, AstraZeneca, Cambridge, United Kingdom.
Abstract
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.
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.