DNA Methylation at Birth Predicts Intellectual Functioning and Autism Features in Children with Fragile X Syndrome

Claudine M. Kraan; Emma K. Baker; Marta Arpone; Minh Bui; Ling Ling; Dinusha Gamage; Lesley Bretherton; Carolyn Rogers; Michael J. Field; Tiffany L. Wotton; David Francis; Matt F. Hunter; Jonathan Cohen; David J. Amor; David E. Godler

doi:10.3390/ijms21207735

DNA Methylation at Birth Predicts Intellectual Functioning and Autism Features in Children with Fragile X Syndrome

Claudine M. Kraan, Emma K. Baker, Marta Arpone, Minh Bui, Ling Ling, Dinusha Gamage, Lesley Bretherton, Carolyn Rogers, Michael J. Field, Tiffany L. Wotton, David Francis, Matt F. Hunter, Jonathan Cohen, David J. Amor, David E. Godler

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14 Citations (Scopus)

Abstract

Fragile X syndrome (FXS) is a leading single-gene cause of intellectual disability (ID) with autism features. This study analysed diagnostic and prognostic utility of the Fragile X-Related Epigenetic Element 2 DNA methylation (FREE2m) assessed by Methylation Specific-Quantitative Melt Analysis and the EpiTYPER system, in retrospectively retrieved newborn blood spots (NBS) and newly created dried blood spots (DBS) from 65 children with FXS (~2–17 years). A further 168 NBS from infants from the general population were used to establish control reference ranges, in both sexes. FREE2m analysis showed sensitivity and specificity approaching 100%. In FXS males, NBS FREE2m strongly correlated with intellectual functioning and autism features, however associations were not as strong for FXS females. Fragile X mental retardation 1 gene (FMR1) mRNA levels in blood were correlated with FREE2m in both NBS and DBS, for both sexes. In females, DNAm was significantly increased at birth with a decrease in childhood. The findings support the use of FREE2m analysis in newborns for screening, diagnostic and prognostic testing in FXS.

Original language	English
Article number	7735
Number of pages	18
Journal	International Journal of Molecular Sciences
Volume	21
Issue number	20
DOIs	https://doi.org/10.3390/ijms21207735
Publication status	Published - 2 Oct 2020
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Autism spectrum disorder (ASD)
DNA methylation (DNAm)
Fragile X mental retardation 1 gene (FMR1 gene)
Fragile X syndrome (FXS)
Intellectual disability (ID)
Newborn screening

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Kraan, C. M., Baker, E. K., Arpone, M., Bui, M., Ling, L., Gamage, D., Bretherton, L., Rogers, C., Field, M. J., Wotton, T. L., Francis, D., Hunter, M. F., Cohen, J., Amor, D. J., & Godler, D. E. (2020). DNA Methylation at Birth Predicts Intellectual Functioning and Autism Features in Children with Fragile X Syndrome. International Journal of Molecular Sciences, 21(20), Article 7735. https://doi.org/10.3390/ijms21207735

@article{7f540953406042cf9882e77a9e0537fd,

title = "DNA Methylation at Birth Predicts Intellectual Functioning and Autism Features in Children with Fragile X Syndrome",

abstract = "Fragile X syndrome (FXS) is a leading single-gene cause of intellectual disability (ID) with autism features. This study analysed diagnostic and prognostic utility of the Fragile X-Related Epigenetic Element 2 DNA methylation (FREE2m) assessed by Methylation Specific-Quantitative Melt Analysis and the EpiTYPER system, in retrospectively retrieved newborn blood spots (NBS) and newly created dried blood spots (DBS) from 65 children with FXS (~2–17 years). A further 168 NBS from infants from the general population were used to establish control reference ranges, in both sexes. FREE2m analysis showed sensitivity and specificity approaching 100%. In FXS males, NBS FREE2m strongly correlated with intellectual functioning and autism features, however associations were not as strong for FXS females. Fragile X mental retardation 1 gene (FMR1) mRNA levels in blood were correlated with FREE2m in both NBS and DBS, for both sexes. In females, DNAm was significantly increased at birth with a decrease in childhood. The findings support the use of FREE2m analysis in newborns for screening, diagnostic and prognostic testing in FXS.",

keywords = "Autism spectrum disorder (ASD), DNA methylation (DNAm), Fragile X mental retardation 1 gene (FMR1 gene), Fragile X syndrome (FXS), Intellectual disability (ID), Newborn screening",

author = "Kraan, {Claudine M.} and Baker, {Emma K.} and Marta Arpone and Minh Bui and Ling Ling and Dinusha Gamage and Lesley Bretherton and Carolyn Rogers and Field, {Michael J.} and Wotton, {Tiffany L.} and David Francis and Hunter, {Matt F.} and Jonathan Cohen and Amor, {David J.} and Godler, {David E.}",

note = "Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2020",

month = oct,

day = "2",

doi = "10.3390/ijms21207735",

language = "English",

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Kraan, CM, Baker, EK, Arpone, M, Bui, M, Ling, L, Gamage, D, Bretherton, L, Rogers, C, Field, MJ, Wotton, TL, Francis, D, Hunter, MF, Cohen, J, Amor, DJ & Godler, DE 2020, 'DNA Methylation at Birth Predicts Intellectual Functioning and Autism Features in Children with Fragile X Syndrome', International Journal of Molecular Sciences, vol. 21, no. 20, 7735. https://doi.org/10.3390/ijms21207735

TY - JOUR

T1 - DNA Methylation at Birth Predicts Intellectual Functioning and Autism Features in Children with Fragile X Syndrome

AU - Kraan, Claudine M.

AU - Baker, Emma K.

AU - Arpone, Marta

AU - Bui, Minh

AU - Ling, Ling

AU - Gamage, Dinusha

AU - Bretherton, Lesley

AU - Rogers, Carolyn

AU - Field, Michael J.

AU - Wotton, Tiffany L.

AU - Francis, David

AU - Hunter, Matt F.

AU - Cohen, Jonathan

AU - Amor, David J.

AU - Godler, David E.

PY - 2020/10/2

Y1 - 2020/10/2

N2 - Fragile X syndrome (FXS) is a leading single-gene cause of intellectual disability (ID) with autism features. This study analysed diagnostic and prognostic utility of the Fragile X-Related Epigenetic Element 2 DNA methylation (FREE2m) assessed by Methylation Specific-Quantitative Melt Analysis and the EpiTYPER system, in retrospectively retrieved newborn blood spots (NBS) and newly created dried blood spots (DBS) from 65 children with FXS (~2–17 years). A further 168 NBS from infants from the general population were used to establish control reference ranges, in both sexes. FREE2m analysis showed sensitivity and specificity approaching 100%. In FXS males, NBS FREE2m strongly correlated with intellectual functioning and autism features, however associations were not as strong for FXS females. Fragile X mental retardation 1 gene (FMR1) mRNA levels in blood were correlated with FREE2m in both NBS and DBS, for both sexes. In females, DNAm was significantly increased at birth with a decrease in childhood. The findings support the use of FREE2m analysis in newborns for screening, diagnostic and prognostic testing in FXS.

AB - Fragile X syndrome (FXS) is a leading single-gene cause of intellectual disability (ID) with autism features. This study analysed diagnostic and prognostic utility of the Fragile X-Related Epigenetic Element 2 DNA methylation (FREE2m) assessed by Methylation Specific-Quantitative Melt Analysis and the EpiTYPER system, in retrospectively retrieved newborn blood spots (NBS) and newly created dried blood spots (DBS) from 65 children with FXS (~2–17 years). A further 168 NBS from infants from the general population were used to establish control reference ranges, in both sexes. FREE2m analysis showed sensitivity and specificity approaching 100%. In FXS males, NBS FREE2m strongly correlated with intellectual functioning and autism features, however associations were not as strong for FXS females. Fragile X mental retardation 1 gene (FMR1) mRNA levels in blood were correlated with FREE2m in both NBS and DBS, for both sexes. In females, DNAm was significantly increased at birth with a decrease in childhood. The findings support the use of FREE2m analysis in newborns for screening, diagnostic and prognostic testing in FXS.

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KW - DNA methylation (DNAm)

KW - Fragile X mental retardation 1 gene (FMR1 gene)

KW - Fragile X syndrome (FXS)

KW - Intellectual disability (ID)

KW - Newborn screening

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U2 - 10.3390/ijms21207735

DO - 10.3390/ijms21207735

M3 - Article

C2 - 33086711

AN - SCOPUS:85092932025

SN - 1661-6596

VL - 21

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

IS - 20

M1 - 7735

ER -

DNA Methylation at Birth Predicts Intellectual Functioning and Autism Features in Children with Fragile X Syndrome

Abstract

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Keywords

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