Exome Sequencing in Patients With Antiepileptic Drug Exposure And Complex Phenotypes

Deciphering Developmental Disorders (DDD) Study, Adam Jackson (Lead / Corresponding author), Heather Ward, Rebecca Bromley, Charu Deshpande, Pradeep C. Vasudevan, Ingrid Scurr, John Dean, Nora Shannon, Jonathan Berg, Susan Holder, Diana Baralle, Jill Clayton-Smith

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Abstract

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.

Original languageEnglish
Pages (from-to)384-389
Number of pages6
JournalArchives of Disease in Childhood
Volume105
Issue number4
Early online date3 Sep 2019
DOIs
Publication statusPublished - 19 Mar 2020

Keywords

  • Anticonvulsant
  • Fetal
  • Genetics
  • Sequencing
  • Valproate

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    Deciphering Developmental Disorders (DDD) Study, Jackson, A., Ward, H., Bromley, R., Deshpande, C., Vasudevan, P. C., Scurr, I., Dean, J., Shannon, N., Berg, J., Holder, S., Baralle, D., & Clayton-Smith, J. (2020). Exome Sequencing in Patients With Antiepileptic Drug Exposure And Complex Phenotypes. Archives of Disease in Childhood, 105(4), 384-389. https://doi.org/10.1136/archdischild-2018-316547