Discovery of DNA methylation signature in the peripheral blood of individuals with history of antenatal exposure to valproic acid

Sadegheh Haghshenas; Audrey Putoux; Jack Reilly; Michael A Levy; Raissa Relator; Sourav Ghosh; Jennifer Kerkhof; Haley McConkey; Patrick Edery; Gaetan Lesca; Alicia Besson; Christine Coubes; Marjolaine Willems; Nathalie Ruiz-Pallares; Mouna Barat-Houari; Eduardo F Tizzano; Irene Valenzuela; Quentin Sabbagh; Jill Clayton-Smith; Adam Jackson; James O'Sullivan; Rebecca Bromley; Siddharth Banka; David Genevieve; Bekim Sadikovic

doi:10.1016/j.gim.2024.101226

Discovery of DNA methylation signature in the peripheral blood of individuals with history of antenatal exposure to valproic acid

Sadegheh Haghshenas, Audrey Putoux, Jack Reilly, Michael A Levy, Raissa Relator, Sourav Ghosh, Jennifer Kerkhof, Haley McConkey, Patrick Edery, Gaetan Lesca, Alicia Besson, Christine Coubes, Marjolaine Willems, Nathalie Ruiz-Pallares, Mouna Barat-Houari, Eduardo F Tizzano, Irene Valenzuela, Quentin Sabbagh, Jill Clayton-Smith, Adam JacksonJames O'Sullivan, Rebecca Bromley, Siddharth Banka, David Genevieve, Bekim Sadikovic

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

Abstract

PURPOSE: Valproic acid or valproate is an effective antiepileptic drug; however, embryonic exposure to valproate can result in a teratogenic disorder referred to as fetal valproate syndrome (FVS, OMIM #609442). Currently there are no diagnostic biomarkers for the condition. This study aims to define an episignature biomarker for teratogenic antenatal exposure to valproate.

METHODS: DNA extracted from peripheral blood of individuals with teratogenic antenatal exposure to valproate was processed using DNA methylation microarrays. Subsequently, methylation profiling and construction of support vector machine classifiers were performed in R.

RESULTS: Genomic DNA methylation analysis was applied, and a distinct DNA methylation profile was identified in the majority of affected individuals. This profile was used to develop a diagnostic episignature classifier. The valproate exposure episignature exhibited high sensitivity and specificity relative to a large reference dataset of unaffected controls and individuals with a wide spectrum of syndromic disorders with episignatures. Gene set enrichment analysis demonstrated an enrichment for terms associated with cell adhesion, including significant overrepresentation of the cadherin superfamily.

CONCLUSION: This study provides evidence of a robust peripheral blood-based diagnostic epigenetic biomarker for a prenatal teratogenic disorder.

Original language	English
Pages (from-to)	101226
Journal	Genetics in medicine : official journal of the American College of Medical Genetics
Early online date	29 Jul 2024
DOIs	https://doi.org/10.1016/j.gim.2024.101226
Publication status	E-pub ahead of print - 29 Jul 2024

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Haghshenas, S., Putoux, A., Reilly, J., Levy, M. A., Relator, R., Ghosh, S., Kerkhof, J., McConkey, H., Edery, P., Lesca, G., Besson, A., Coubes, C., Willems, M., Ruiz-Pallares, N., Barat-Houari, M., Tizzano, E. F., Valenzuela, I., Sabbagh, Q., Clayton-Smith, J., ... Sadikovic, B. (2024). Discovery of DNA methylation signature in the peripheral blood of individuals with history of antenatal exposure to valproic acid. Genetics in medicine : official journal of the American College of Medical Genetics, 101226. Advance online publication. https://doi.org/10.1016/j.gim.2024.101226

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title = "Discovery of DNA methylation signature in the peripheral blood of individuals with history of antenatal exposure to valproic acid",

abstract = "PURPOSE: Valproic acid or valproate is an effective antiepileptic drug; however, embryonic exposure to valproate can result in a teratogenic disorder referred to as fetal valproate syndrome (FVS, OMIM #609442). Currently there are no diagnostic biomarkers for the condition. This study aims to define an episignature biomarker for teratogenic antenatal exposure to valproate.METHODS: DNA extracted from peripheral blood of individuals with teratogenic antenatal exposure to valproate was processed using DNA methylation microarrays. Subsequently, methylation profiling and construction of support vector machine classifiers were performed in R.RESULTS: Genomic DNA methylation analysis was applied, and a distinct DNA methylation profile was identified in the majority of affected individuals. This profile was used to develop a diagnostic episignature classifier. The valproate exposure episignature exhibited high sensitivity and specificity relative to a large reference dataset of unaffected controls and individuals with a wide spectrum of syndromic disorders with episignatures. Gene set enrichment analysis demonstrated an enrichment for terms associated with cell adhesion, including significant overrepresentation of the cadherin superfamily.CONCLUSION: This study provides evidence of a robust peripheral blood-based diagnostic epigenetic biomarker for a prenatal teratogenic disorder.",

author = "Sadegheh Haghshenas and Audrey Putoux and Jack Reilly and Levy, {Michael A} and Raissa Relator and Sourav Ghosh and Jennifer Kerkhof and Haley McConkey and Patrick Edery and Gaetan Lesca and Alicia Besson and Christine Coubes and Marjolaine Willems and Nathalie Ruiz-Pallares and Mouna Barat-Houari and Tizzano, {Eduardo F} and Irene Valenzuela and Quentin Sabbagh and Jill Clayton-Smith and Adam Jackson and James O'Sullivan and Rebecca Bromley and Siddharth Banka and David Genevieve and Bekim Sadikovic",

note = "Copyright {\textcopyright} 2024. Published by Elsevier Inc.",

year = "2024",

month = jul,

day = "29",

doi = "10.1016/j.gim.2024.101226",

language = "English",

pages = "101226",

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Haghshenas, S, Putoux, A, Reilly, J, Levy, MA, Relator, R, Ghosh, S, Kerkhof, J, McConkey, H, Edery, P, Lesca, G, Besson, A, Coubes, C, Willems, M, Ruiz-Pallares, N, Barat-Houari, M, Tizzano, EF, Valenzuela, I, Sabbagh, Q, Clayton-Smith, J, Jackson, A, O'Sullivan, J , Bromley, R , Banka, S, Genevieve, D & Sadikovic, B 2024, 'Discovery of DNA methylation signature in the peripheral blood of individuals with history of antenatal exposure to valproic acid', Genetics in medicine : official journal of the American College of Medical Genetics, pp. 101226. https://doi.org/10.1016/j.gim.2024.101226

Discovery of DNA methylation signature in the peripheral blood of individuals with history of antenatal exposure to valproic acid. / Haghshenas, Sadegheh; Putoux, Audrey; Reilly, Jack et al.
In: Genetics in medicine : official journal of the American College of Medical Genetics, 29.07.2024, p. 101226.

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

TY - JOUR

T1 - Discovery of DNA methylation signature in the peripheral blood of individuals with history of antenatal exposure to valproic acid

AU - Haghshenas, Sadegheh

AU - Putoux, Audrey

AU - Reilly, Jack

AU - Levy, Michael A

AU - Relator, Raissa

AU - Ghosh, Sourav

AU - Kerkhof, Jennifer

AU - McConkey, Haley

AU - Edery, Patrick

AU - Lesca, Gaetan

AU - Besson, Alicia

AU - Coubes, Christine

AU - Willems, Marjolaine

AU - Ruiz-Pallares, Nathalie

AU - Barat-Houari, Mouna

AU - Tizzano, Eduardo F

AU - Valenzuela, Irene

AU - Sabbagh, Quentin

AU - Clayton-Smith, Jill

AU - Jackson, Adam

AU - O'Sullivan, James

AU - Bromley, Rebecca

AU - Banka, Siddharth

AU - Genevieve, David

AU - Sadikovic, Bekim

PY - 2024/7/29

Y1 - 2024/7/29

N2 - PURPOSE: Valproic acid or valproate is an effective antiepileptic drug; however, embryonic exposure to valproate can result in a teratogenic disorder referred to as fetal valproate syndrome (FVS, OMIM #609442). Currently there are no diagnostic biomarkers for the condition. This study aims to define an episignature biomarker for teratogenic antenatal exposure to valproate.METHODS: DNA extracted from peripheral blood of individuals with teratogenic antenatal exposure to valproate was processed using DNA methylation microarrays. Subsequently, methylation profiling and construction of support vector machine classifiers were performed in R.RESULTS: Genomic DNA methylation analysis was applied, and a distinct DNA methylation profile was identified in the majority of affected individuals. This profile was used to develop a diagnostic episignature classifier. The valproate exposure episignature exhibited high sensitivity and specificity relative to a large reference dataset of unaffected controls and individuals with a wide spectrum of syndromic disorders with episignatures. Gene set enrichment analysis demonstrated an enrichment for terms associated with cell adhesion, including significant overrepresentation of the cadherin superfamily.CONCLUSION: This study provides evidence of a robust peripheral blood-based diagnostic epigenetic biomarker for a prenatal teratogenic disorder.

AB - PURPOSE: Valproic acid or valproate is an effective antiepileptic drug; however, embryonic exposure to valproate can result in a teratogenic disorder referred to as fetal valproate syndrome (FVS, OMIM #609442). Currently there are no diagnostic biomarkers for the condition. This study aims to define an episignature biomarker for teratogenic antenatal exposure to valproate.METHODS: DNA extracted from peripheral blood of individuals with teratogenic antenatal exposure to valproate was processed using DNA methylation microarrays. Subsequently, methylation profiling and construction of support vector machine classifiers were performed in R.RESULTS: Genomic DNA methylation analysis was applied, and a distinct DNA methylation profile was identified in the majority of affected individuals. This profile was used to develop a diagnostic episignature classifier. The valproate exposure episignature exhibited high sensitivity and specificity relative to a large reference dataset of unaffected controls and individuals with a wide spectrum of syndromic disorders with episignatures. Gene set enrichment analysis demonstrated an enrichment for terms associated with cell adhesion, including significant overrepresentation of the cadherin superfamily.CONCLUSION: This study provides evidence of a robust peripheral blood-based diagnostic epigenetic biomarker for a prenatal teratogenic disorder.

U2 - 10.1016/j.gim.2024.101226

DO - 10.1016/j.gim.2024.101226

M3 - Article

C2 - 39097820

SN - 1098-3600

SP - 101226

JO - Genetics in medicine : official journal of the American College of Medical Genetics

JF - Genetics in medicine : official journal of the American College of Medical Genetics

ER -

Discovery of DNA methylation signature in the peripheral blood of individuals with history of antenatal exposure to valproic acid

Abstract

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