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Original research
Exome sequencing in patients with antiepileptic drug exposure and complex phenotypes
  1. Adam Jackson1,
  2. Heather Ward2,
  3. Rebecca Louise Bromley3,4,
  4. Charulata Deshpande5,
  5. Pradeep Vasudevan6,
  6. Ingrid Scurr7,
  7. John Dean8,
  8. Nora Shannon9,
  9. Jonathon Berg10,
  10. Susan Holder11,
  11. Diana Baralle12,
  12. Jill Clayton-Smith13
  13. DDD Study
  1. 1 Blackpool Teaching Hospitals NHS Trust, Blackpool, UK
  2. 2 Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester, UK
  3. 3 Division of Evolution and Genomic Science, University of Manchester, Manchester, UK
  4. 4 Paediatric Psychosocial Department, Royal Manchester Children's Hospital, Manchester, UK
  5. 5 Clinical Genetics Department, Guy’s and St Thomas’ NHS Foundation Trust, Guy’s Hospital, London, UK
  6. 6 Department of Clinical Genetics, University Hospitals Leicester NHS Trust, Leicester, UK
  7. 7 Department of Clinical Genetics, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
  8. 8 Clinical Genetics Centre, University of Aberdeen College of Life Sciences and Medicine, Aberdeen, UK
  9. 9 Clinical Genetics Service, Nottingham City Hospital, Nottingham, UK
  10. 10 Department of Clinical Genetics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
  11. 11 North West Thames Regional Genetics Service, Northwick Park and St Mark’s Hospitals, London, UK
  12. 12 Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
  13. 13 Genetic Medicine, Central Manchester University Hospitals Foundation Trust, Manchester, UK
  1. Correspondence to Dr Adam Jackson, Blackpool Teaching Hospitals NHS Trust, Blackpool FY3 8NR, UK; adam.jackson{at}


Introduction Fetal anticonvulsant syndrome (FACS) describes the pattern of physical and developmental problems seen in those children exposed to certain antiepileptic drugs (AEDs) in utero. The diagnosis of FACS is a clinical one and so excluding alternative diagnoses such as genetic disorders is essential.

Methods We reviewed the pathogenicity of reported variants identified on exome sequencing in the Deciphering Developmental Disorders (DDD) Study in 42 children exposed to AEDs in utero, but where a diagnosis other than FACS was suspected. In addition, we analysed chromosome microarray data from 10 patients with FACS seen in a Regional Genetics Service.

Results Seven children (17%) from the DDD Study had a copy number variant or pathogenic variant in a developmental disorder gene which was considered to explain or partially explain their phenotype. Across the AED exposure types, variants were found in 2/15 (13%) valproate exposed cases and 3/14 (21%) carbamazepine exposed cases. No pathogenic copy number variants were identified in our local sample (n=10).

Conclusions This study is the first of its kind to analyse the exomes of children with developmental disorders who were exposed to AEDs in utero. Though we acknowledge that the results are subject to bias, a significant number of children were identified with alternate diagnoses which had an impact on counselling and management. We suggest that consideration is given to performing whole exome sequencing as part of the diagnostic work-up for children exposed to AEDs in utero.

  • anticonvulsant
  • fetal
  • valproate
  • sequencing
  • genetics

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  • Collaborators DDD Study Group Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

  • Contributors AJ wrote the article and performed data searches and analysis. RB and JC-S supervised the project and helped conceive the idea for the study. HW performed analysis of CMA variants. CD, PV, IS, JD, NS, JB, SH, DB all provided phenotypic data on their patients and constructive comments for the manuscript. The DDD study provided exome data.

  • Funding The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC).

  • Disclaimer The views expressed in this publication are those of the authors and not necessarily those of Wellcome or the Department of Health.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Ethical approval was obtained for the study from the relevant bodies (REC 16/NW/0788).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request.