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Exome sequencing in patients with antiepileptic drug exposure and complex phenotypes

Exome sequencing in patients with antiepileptic drug exposure and complex phenotypes
Exome sequencing in patients with antiepileptic drug exposure and complex phenotypes
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, genetics, sequencing, valproate
0003-9888
384-389
Jackson, Adam
e676126a-4743-4456-b023-deafc8b8a427
Ward, Heather
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Bromley, Rebecca
1bf37e5c-c697-49ce-949a-ef9370d18b12
Deshpande, Charu
048e996c-5f8b-4140-ad9c-261da16fb85f
Vasudevan, Pradeep
60a989b7-5b4f-4a99-80fd-2236404603a9
Scurr, Ingrid
324303ec-81d0-4be8-a9cd-7899e4e0c6be
Dean, John
febc468e-8d31-4470-8a55-0dce898c2d68
Shannon, Nora
7438aa4f-7ff8-44cf-acfe-1a47fa444b10
Berg, Jonathan
b05b030d-b9e1-4c89-b3da-57c6c67c772f
Holder, Susan
60178065-9c2e-473b-8ce1-354964ba3ec1
Baralle, Diana
faac16e5-7928-4801-9811-8b3a9ea4bb91
Clayton-Smith, Jill
df8946ac-9da9-4ef2-b180-f468a5424844
DDD Study
Jackson, Adam
e676126a-4743-4456-b023-deafc8b8a427
Ward, Heather
0654e0d8-38cd-4c35-84d6-a030b7fbc50a
Bromley, Rebecca
1bf37e5c-c697-49ce-949a-ef9370d18b12
Deshpande, Charu
048e996c-5f8b-4140-ad9c-261da16fb85f
Vasudevan, Pradeep
60a989b7-5b4f-4a99-80fd-2236404603a9
Scurr, Ingrid
324303ec-81d0-4be8-a9cd-7899e4e0c6be
Dean, John
febc468e-8d31-4470-8a55-0dce898c2d68
Shannon, Nora
7438aa4f-7ff8-44cf-acfe-1a47fa444b10
Berg, Jonathan
b05b030d-b9e1-4c89-b3da-57c6c67c772f
Holder, Susan
60178065-9c2e-473b-8ce1-354964ba3ec1
Baralle, Diana
faac16e5-7928-4801-9811-8b3a9ea4bb91
Clayton-Smith, Jill
df8946ac-9da9-4ef2-b180-f468a5424844

Jackson, Adam, Ward, Heather, Bromley, Rebecca, Deshpande, Charu, Vasudevan, Pradeep, Scurr, Ingrid, Dean, John, Shannon, Nora, Berg, Jonathan, Holder, Susan, Baralle, Diana and Clayton-Smith, Jill , DDD Study (2020) Exome sequencing in patients with antiepileptic drug exposure and complex phenotypes. Archives of Disease in Childhood, 105 (4), 384-389. (doi:10.1136/archdischild-2018-316547).

Record type: Article

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.

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More information

Accepted/In Press date: 21 August 2019
e-pub ahead of print date: 3 September 2019
Published date: 1 April 2020
Keywords: anticonvulsant, fetal, genetics, sequencing, valproate

Identifiers

Local EPrints ID: 433684
URI: http://eprints.soton.ac.uk/id/eprint/433684
ISSN: 0003-9888
PURE UUID: 403a054f-c666-441a-a6f8-9f18d2251032
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833

Catalogue record

Date deposited: 30 Aug 2019 16:30
Last modified: 26 Nov 2021 06:53

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Contributors

Author: Adam Jackson
Author: Heather Ward
Author: Rebecca Bromley
Author: Charu Deshpande
Author: Pradeep Vasudevan
Author: Ingrid Scurr
Author: John Dean
Author: Nora Shannon
Author: Jonathan Berg
Author: Susan Holder
Author: Diana Baralle ORCID iD
Author: Jill Clayton-Smith
Corporate Author: DDD Study

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