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Mosaicism for FMR1 premutation (PM: 55-199 CGG)/full mutation (FM: >200 CGG) alleles or the presence of unmethylated FM (UFM) have been associated with a less severe fragile X syndrome (FXS) phenotype and fragile X associated tremor/ataxia syndrome (FXTAS)--a late onset neurodegenerative disorder. We describe a 38 year old male carrying a 100% methylated FM detected with Southern blot (SB), which is consistent with complete silencing of FMR1 and a diagnosis of fragile X syndrome. However, his formal cognitive scores were not at the most severe end of the FXS phenotype and he displayed tremor and ataxic gait. With the association of UFM with FXTAS, we speculated that his ataxia might be related to an undetected proportion of UFM alleles. Such UFM alleles were confirmed by more sensitive PCR based methylation testing showing FM methylation between 60% and 70% in blood, buccal, and saliva samples and real-time PCR analysis showing incomplete silencing of FMR1. While he did not meet diagnostic criteria for FXTAS based on MRI findings, the underlying cause of his ataxia may be related to UFM alleles not detected by SB, and follow-up clinical and molecular assessment are justified if his symptoms worsen. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Although fragile X syndrome (FXS) is caused by a hypermethylated full mutation (FM) expansion with ≥200 cytosine-guanine-guanine (CGG) repeats, and a decrease in FMR1 mRNA and its protein (FMRP), incomplete silencing has been associated with more severe autism features in FXS males. This study reports on brothers (B1 and B2), aged 5 and 2 years, with autistic features and language delay, but a higher non-verbal IQ in comparison to typical FXS. CGG sizing using AmplideX PCR only identified premutation (PM: 55–199 CGGs) alleles in blood. Similarly, follow-up in B1 only revealed PM alleles in saliva and skin fibroblasts; whereas, an FM expansion was detected in both saliva and buccal DNA of B2. While Southern blot analysis of blood detected an unmethylated FM, methylation analysis with a more sensitive methodology showed that B1 had partially methylated PM alleles in blood and fibroblasts, which were completely unmethylated in buccal and saliva cells. In contrast, B2 was partially methylated in all tested tissues. Moreover, both brothers had FMR1 mRNA ~5 fold higher values than those of controls, FXS and PM cohorts. In conclusion, the presence of unmethylated FM and/or PM in both brothers may lead to an overexpression of toxic expanded mRNA in some cells, which may contribute to neurodevelopmental problems, including elevated autism features. [ABSTRACT FROM AUTHOR]

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