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DNA methylation at birth predicts intellectual functioning and autism features in children with fragile x syndrome

journal contribution
posted on 15.12.2020, 01:53 authored by CM Kraan, Emma BakerEmma Baker, M Arpone, M Bui, L Ling, D Gamage, L Bretherton, C Rogers, MJ Field, TL Wotton, D Francis, MF Hunter, J Cohen, DJ Amor, DE Godler
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. 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.


This research was funded by The Victorian Government's Operational Infrastructure Support Program, Murdoch Children's Research Institute, Royal Children's Hospital Foundation, Martin and E.H. Flack Trust, Pierce Armstrong Trust, Financial Markets Foundation for Children (Australia) (FMFC; grant number: 2017-361), the National Health and Medical Research Council (NHMRC project grant numbers: 1049299 and 1103389 to D.E.G.; NHMRC Early Career fellowship project grant numbers. 1120561 to C.M.K.). D.E.G. salary was supported by the Next Generation Clinical Researchers Program-Career Development Fellowship Funded by the Medical Research Future Fund (grant number 1141334). Genetics of Learning Disability (GOLD) Service (M.J.F.). M.A. was supported by an Australian Postgraduate Award, the International Postgraduate Research Scholarships (IPRS) and the Research Training Program Fee offset scholarship funded by the Australian Government and awarded by the University of Melbourne, and in part by the Diagnosis and Development group of the Murdoch Children's Research Institute.


Publication Date



International Journal of Molecular Sciences





Article Number

ARTN 7735







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