220823_Arpone,M_2018.pdf (1.41 MB)
Intragenic DNA methylation in buccal epithelial cells and intellectual functioning in a paediatric cohort of males with fragile X
journal contributionposted on 2022-03-29, 22:40 authored by Marta Arpone, Emma BakerEmma Baker, Lesley Bretherton, Minh Bui, Xin Li, Simon Whitaker, Cheryl DissanayakeCheryl Dissanayake, Jonathan Cohen, Chriselle Hickerton, Carolyn Rogers, Mike Field, Justine Elliott, Solange M Aliaga, Ling Ling, David Francis, Stephen JC Hearps, Matthew F Hunter, David J Amor, David E Godler
Increased intragenic DNA methylation of the Fragile X Related Epigenetic Element 2 (FREE2) in blood has been correlated with lower intellectual functioning in females with fragile X syndrome (FXS). This study explored these relationships in a paediatric cohort of males with FXS using Buccal Epithelial Cells (BEC). BEC were collected from 25 males with FXS, aged 3 to 17 years and 19 age-matched male controls without FXS. Methylation of 9 CpG sites within the FREE2 region was examined using the EpiTYPER approach. Full Scale IQ (FSIQ) scores of males with FXS were corrected for floor effect using the Whitaker and Gordon (WG) extrapolation method. Compared to controls, children with FXS had significant higher methylation levels for all CpG sites examined (p < 3.3 × 10-7), and within the FXS group, lower FSIQ (WG corrected) was associated with higher levels of DNA methylation, with the strongest relationship found for CpG sites within FMR1 intron 1 (p < 5.6 × 10-5). Applying the WG method to the FXS cohort unmasked significant epi-genotype-phenotype relationships. These results extend previous evidence in blood to BEC and demonstrate FREE2 DNA methylation to be a sensitive epigenetic biomarker significantly associated with the variability in intellectual functioning in FXS.
This work was funded by The Victorian Government's Operational Infrastructure Support Program, Murdoch Children's Research Institute, Royal Children's Hospital Foundation, Martin & 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: 1017263, 104299 and 1103389). D.E. Godler was supported by the NHMRC development grant number 1017263, NHMRC project grant number 104299 and the Next Generation Clinical Researchers Program - Career Development Fellowship Funded from the Medical Research Future Fund (grant number 1141334). M. Arpone was supported by 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 Cyto-molecular Diagnostics Research group of the Murdoch Children's Research Institute. S.M. Aliaga was funded by the CONICYT and Chile's National Commission for Scientific and Technological Research. We sincerely thank all participants and their families for their contribution. We also thank Dr Cherie Green, Annabel May Marsh and Dr Nusrat Ahmed for assisting with participants' assessments.
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Science & TechnologyMultidisciplinary SciencesScience & Technology - Other TopicsINTRON 1 METHYLATIONFMRP EXPRESSIONFEMALE CARRIERSCHILDRENBLOODIQMUTATIONALLELESMARKERSDISABILITIESAdolescentChildChild, PreschoolCpG IslandsDNA MethylationEpigenesis, GeneticEpithelial CellsFragile X Mental Retardation ProteinHumansIntronsMale