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Tissue mosaicism, FMR1 expression and intellectual functioning in males with fragile X syndrome

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posted on 2023-07-03, 02:20 authored by Emma BakerEmma Baker, M Arpone, M Bui, CM Kraan, L Ling, D Francis, MF Hunter, C Rogers, MJ Field, L Santa María, V Faundes, B Curotto, P Morales, C Trigo, I Salas, AM Alliende, DJ Amor, DE Godler
Fragile X syndrome (FXS) is caused by hypermethylation of the FMR1 promoter due to the full mutation expansion (full mutation [FM]: CGG ≥ 200 repeats) and silencing of FMR1. Assessment of mosaicism for active-unmethylated alleles has prognostic utility. This study examined relationships between FMR1 methylation in different tissues with FMR1 messenger ribonucleic acid (mRNA) and intellectual functioning in 87 males with FXS (1.89–43.17 years of age). Methylation sensitive Southern blot (mSB) and Methylation Specific-Quantitative Melt Aanalysis (MS-QMA) were used to examine FMR1 methylation. FMR1 mRNA levels in blood showed strong relationships with FMR1 methylation assessed using MS-QMA in blood (n = 68; R2 = 0.597; p = 1.4 × 10−10) and buccal epithelial cells (BEC) (n = 62; R2 = 0.24; p = 0.003), with these measures also showing relationships with intellectual functioning scores (p < 0.01). However, these relationships were not as strong for mSB, with ~40% of males with only FM alleles that were 100% methylated and non-mosaic by mSB, showing methylation mosaicism by MS-QMA. This was confirmed through presence of detectable levels of FMR1 mRNA in blood. In summary, FMR1 methylation levels in blood and BEC examined by MS-QMA were significantly associated with FMR1 mRNA levels and intellectual functioning in males with FXS. These relationships were not as strong for mSB, which underestimated prevalence of mosaicism.


Chile's National Commission for Scientific and Technological Research; Comision Nacional de Investigacion Cientifica Y Tecnologica; Financial Markets Foundation for Children, Grant/Award Number: 2017-361; International Postgraduate Research Scholarship; Martin & E.H. Flack Trust; Medical Research Future Fund, Grant/Award Number: 1141334; Murdoch Children's Research Institute; National Health and Medical Research Council, Grant/Award Numbers: 1103389, 1049299; Pierce Armstrong Trust; Research Training Program Scholarship; Royal Children's Hospital Foundation; The Victorian Government's Operational Infrastructure Support Program; NHMRC Early Career Fellowship, Grant/Award Number: 1112934


Publication Date



American Journal of Medical Genetics Part A






13p. (p. 357-369)





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© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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