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Assessment of mosaicism for active\u2010unmethylated alleles has prognostic utility. This study examined relationships between <jats:italic>FMR1<\/jats:italic> methylation in different tissues with <jats:italic>FMR1<\/jats:italic> messenger ribonucleic acid (mRNA) and intellectual functioning in 87 males with FXS (1.89\u201343.17\u2009years of age). Methylation sensitive Southern blot (mSB) and Methylation Specific\u2010Quantitative Melt Aanalysis (MS\u2010QMA) were used to examine <jats:italic>FMR1<\/jats:italic> methylation. <jats:italic>FMR1<\/jats:italic> mRNA levels in blood showed strong relationships with <jats:italic>FMR1<\/jats:italic> methylation assessed using MS\u2010QMA in blood (<jats:italic>n<\/jats:italic>\u00a0=\u00a068; <jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u00a00.597; <jats:italic>p<\/jats:italic>\u00a0=\u00a01.4 \u00d7\u200910<jats:sup>\u221210<\/jats:sup>) and buccal epithelial cells (BEC) (<jats:italic>n<\/jats:italic>\u00a0=\u00a062; <jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u00a00.24; <jats:italic>p<\/jats:italic>\u00a0=\u00a00.003), with these measures also showing relationships with intellectual functioning scores (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). However, these relationships were not as strong for mSB, with ~40% of males with only FM alleles that were 100% methylated and non\u2010mosaic by mSB, showing methylation mosaicism by MS\u2010QMA. This was confirmed through presence of detectable levels of <jats:italic>FMR1<\/jats:italic> mRNA in blood. In summary, <jats:italic>FMR1<\/jats:italic> methylation levels in blood and BEC examined by MS\u2010QMA were significantly associated with <jats:italic>FMR1<\/jats:italic> mRNA levels and intellectual functioning in males with FXS. These relationships were not as strong for mSB, which underestimated prevalence of mosaicism.<\/jats:p>","DOI":"10.1002\/ajmg.a.63027","type":"journal-article","created":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T07:25:13Z","timestamp":1667978713000},"page":"357-369","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Tissue mosaicism, <scp><i>FMR1<\/i><\/scp> expression and intellectual functioning in males with fragile X syndrome"],"prefix":"10.1002","volume":"191","author":[{"given":"Emma K.","family":"Baker","sequence":"first","affiliation":[{"name":"Diagnosis and Development, Murdoch Children's Research Institute Royal Children's Hospital  Melbourne Victoria Australia"},{"name":"Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences University of Melbourne  Parkville Victoria Australia"},{"name":"School of Psychology and Public Health La Trobe University  Bundoora Victoria 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