Antiepileptic drug teratogenicity and de novo genetic variation load

Piero Perucca; Alison Anderson; Dana Jazayeri; Alison Hitchcock; Janet Graham; Marian Todaro; Torbjörn Tomson; Dina Battino; Emilio Perucca; Meritxell Martinez Ferri; Anne Rochtus; Lieven Lagae; Maria Paola Canevini; Elena Zambrelli; Ellen Campbell; Bobby P C Koeleman; Ingrid E Scheffer; Samuel F Berkovic; Patrick Kwan; Sanjay M Sisodiya; David B Goldstein; Slavé Petrovski; John Craig; Frank J E Vajda; Terence J O'Brien

doi:10.1002/ana.25724

Antiepileptic drug teratogenicity and de novo genetic variation load

Piero Perucca, Alison Anderson, Dana Jazayeri, Alison Hitchcock, Janet Graham, Marian Todaro, Torbjörn Tomson, Dina Battino, Emilio Perucca, Meritxell Martinez Ferri, Anne Rochtus, Lieven Lagae, Maria Paola Canevini, Elena Zambrelli, Ellen Campbell, Bobby P C Koeleman, Ingrid E Scheffer, Samuel F Berkovic, Patrick Kwan, Sanjay M SisodiyaDavid B Goldstein, Slavé Petrovski, John Craig, Frank J E Vajda, Terence J O'Brien

Research output: Contribution to journal › Article › peer-review

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 which we investigated.

METHODS: Whole-exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in: children exposed prenatally to AEDs (AED-exposed children) vs children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs vs those without BDs, adjusting for confounders. Fisher's exact test was used to compare categorical data.

RESULTS: 67 child-parent trios were included: 10 with AED-exposed children with BDs; 46 with AED-exposed unaffected children; 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 9/67 (13%) children, none of whom had BDs. The proportion of cases harbouring 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 counselling. This article is protected by copyright. All rights reserved.

Original language	English
Pages (from-to)	897–906
Number of pages	9
Journal	Annals of Neurology
Volume	87
Early online date	2020
DOIs	https://doi.org/10.1002/ana.25724
Publication status	Published - Mar 25 2020

Access to Document

10.1002/ana.25724

Fingerprint Dive into the research topics of 'Antiepileptic drug teratogenicity and de novo genetic variation load'. Together they form a unique fingerprint.

Cite this

Perucca, P., Anderson, A., Jazayeri, D., Hitchcock, A., Graham, J., Todaro, M., Tomson, T., Battino, D., Perucca, E., Martinez Ferri, M., Rochtus, A., Lagae, L., Canevini, M. P., Zambrelli, E., Campbell, E., Koeleman, B. P. C., Scheffer, I. E., Berkovic, S. F., Kwan, P., ... O'Brien, T. J. (2020). Antiepileptic drug teratogenicity and de novo genetic variation load. Annals of Neurology, 87, 897–906. https://doi.org/10.1002/ana.25724

Antiepileptic drug teratogenicity and de novo genetic variation load. / Perucca, Piero; Anderson, Alison; Jazayeri, Dana; Hitchcock, Alison; Graham, Janet; Todaro, Marian; Tomson, Torbjörn; Battino, Dina ; Perucca, Emilio; Martinez Ferri, Meritxell; 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.

In: Annals of Neurology, Vol. 87, 25.03.2020, p. 897–906.

Research output: Contribution to journal › Article › peer-review

Perucca, P, Anderson, A, Jazayeri, D, Hitchcock, A, Graham, J, Todaro, M, Tomson, T, Battino, D , Perucca, E, Martinez Ferri, M, Rochtus, A, Lagae, L, Canevini, MP, Zambrelli, E, Campbell, E, Koeleman, BPC, Scheffer, IE, Berkovic, SF, Kwan, P, Sisodiya, SM, Goldstein, DB, Petrovski, S, Craig, J, Vajda, FJE & O'Brien, TJ 2020, 'Antiepileptic drug teratogenicity and de novo genetic variation load', Annals of Neurology, vol. 87, pp. 897–906. https://doi.org/10.1002/ana.25724

Perucca, Piero ; Anderson, Alison ; Jazayeri, Dana ; Hitchcock, Alison ; Graham, Janet ; Todaro, Marian ; Tomson, Torbjörn ; Battino, Dina ; Perucca, Emilio ; Martinez Ferri, Meritxell ; 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. / Antiepileptic drug teratogenicity and de novo genetic variation load. In: Annals of Neurology. 2020 ; Vol. 87. pp. 897–906.

@article{d5eaaf80034c4d54a1b2e2f781fbff3b,

title = "Antiepileptic drug teratogenicity and de novo genetic variation load",

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 which we investigated.METHODS: Whole-exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in: children exposed prenatally to AEDs (AED-exposed children) vs children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs vs those without BDs, adjusting for confounders. Fisher's exact test was used to compare categorical data.RESULTS: 67 child-parent trios were included: 10 with AED-exposed children with BDs; 46 with AED-exposed unaffected children; 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 9/67 (13%) children, none of whom had BDs. The proportion of cases harbouring 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 counselling. This article is protected by copyright. All rights reserved.",

author = "Piero Perucca and Alison Anderson and Dana Jazayeri and Alison Hitchcock and Janet Graham and Marian Todaro and Torbj{\"o}rn Tomson and Dina Battino and Emilio Perucca and {Martinez Ferri}, Meritxell and Anne Rochtus and Lieven Lagae and Canevini, {Maria Paola} and Elena Zambrelli and Ellen Campbell and Koeleman, {Bobby P C} and Scheffer, {Ingrid E} and Berkovic, {Samuel F} and Patrick Kwan and Sisodiya, {Sanjay M} and Goldstein, {David B} and Slav{\'e} Petrovski and John Craig and Vajda, {Frank J E} and O'Brien, {Terence J}",

year = "2020",

month = mar,

day = "25",

doi = "10.1002/ana.25724",

language = "English",

volume = "87",

pages = "897–906",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John Wiley and Sons Inc.",

}

TY - JOUR

T1 - Antiepileptic drug teratogenicity and de novo genetic variation load

AU - Perucca, Piero

AU - Anderson, Alison

AU - Jazayeri, Dana

AU - Hitchcock, Alison

AU - Graham, Janet

AU - Todaro, Marian

AU - Tomson, Torbjörn

AU - Battino, Dina

AU - Perucca, Emilio

AU - Martinez Ferri, Meritxell

AU - Rochtus, Anne

AU - Lagae, Lieven

AU - Canevini, Maria Paola

AU - Zambrelli, Elena

AU - Campbell, Ellen

AU - Koeleman, Bobby P C

AU - Scheffer, Ingrid E

AU - Berkovic, Samuel F

AU - Kwan, Patrick

AU - Sisodiya, Sanjay M

AU - Goldstein, David B

AU - Petrovski, Slavé

AU - Craig, John

AU - Vajda, Frank J E

AU - O'Brien, Terence J

PY - 2020/3/25

Y1 - 2020/3/25

N2 - 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 which we investigated.METHODS: Whole-exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in: children exposed prenatally to AEDs (AED-exposed children) vs children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs vs those without BDs, adjusting for confounders. Fisher's exact test was used to compare categorical data.RESULTS: 67 child-parent trios were included: 10 with AED-exposed children with BDs; 46 with AED-exposed unaffected children; 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 9/67 (13%) children, none of whom had BDs. The proportion of cases harbouring 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 counselling. This article is protected by copyright. All rights reserved.

AB - 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 which we investigated.METHODS: Whole-exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in: children exposed prenatally to AEDs (AED-exposed children) vs children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs vs those without BDs, adjusting for confounders. Fisher's exact test was used to compare categorical data.RESULTS: 67 child-parent trios were included: 10 with AED-exposed children with BDs; 46 with AED-exposed unaffected children; 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 9/67 (13%) children, none of whom had BDs. The proportion of cases harbouring 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 counselling. This article is protected by copyright. All rights reserved.

U2 - 10.1002/ana.25724

DO - 10.1002/ana.25724

M3 - Article

C2 - 32215971

VL - 87

SP - 897

EP - 906

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

ER -