Dataset Information

Fragile X syndrome in a male with methylated premutation alleles and no detectable methylated full mutation alleles.

ABSTRACT: Most cases of fragile X syndrome (FXS) result from aberrant methylation of the FMR1 gene. Methylation occurs when the number of tandemly arranged cytosine guanine guanine (CGG)-repeats in the 5' end of the transcriptional unit of FMR1 exceeds a certain critical threshold, thought to be between 200 and 400 repeats. Such alleles are referred to as full mutation (FM) alleles. Premutation (PM) alleles, alleles with 55-200 repeats, are generally not aberrantly methylated and in fact may have hyperexpression of the FMR1 mRNA. We describe here a male who meets the diagnostic criteria for FXS, who is highly mosaic with a mixture of multiple PM and FM alleles and 50% methylation. However, the methylated alleles are limited to two alleles in the PM range, ~165 and ~175 repeats respectively, with the FM alleles being unmethylated. This finding has implications for FXS diagnosis as well as for efforts to delete the repeat in individuals with FXS using a CRISPR-Cas9 approach.

SUBMITTER: Hayward B

PROVIDER: S-EPMC9423038 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Fragile X syndrome in a male with methylated premutation alleles and no detectable methylated full mutation alleles.

Hayward Bruce B Loutaev Inna I Ding Xiaohua X Nolin Sarah L SL Thurm Audrey A Usdin Karen K Smith Carolyn B CB

American journal of medical genetics. Part A 20190729 10

Most cases of fragile X syndrome (FXS) result from aberrant methylation of the FMR1 gene. Methylation occurs when the number of tandemly arranged cytosine guanine guanine (CGG)-repeats in the 5' end of the transcriptional unit of FMR1 exceeds a certain critical threshold, thought to be between 200 and 400 repeats. Such alleles are referred to as full mutation (FM) alleles. Premutation (PM) alleles, alleles with 55-200 repeats, are generally not aberrantly methylated and in fact may have hyperexp ...[more]

PMID: 31356000

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Project description:BackgroundFragile X syndrome (FXS) is a common monogenic cause of intellectual disability with autism features. While it is caused by loss of the FMR1 product (FMRP), mosaicism for active and inactive FMR1 alleles, including alleles termed premutation (PM: 55-199 CGGs), is not uncommon. Importantly, both PM and active full mutation (FM: ≥ 200 CGGs) alleles often express elevated levels of mRNA that are thought to be toxic. This study determined if complete FMR1 mRNA silencing from FM alleles and/or levels of FMR1 mRNA (if present) in blood are associated with intellectual functioning and autism features in FXS.MethodsThe study cohort included 98 participants (70.4% male) with FXS (FM-only and PM/FM mosaic) aged 1-43 years. A control group of 14 females were used to establish control FMR1 mRNA reference range. Intellectual functioning and autism features were assessed using the Mullen Scales of Early Learning or an age-appropriate Wechsler Scale and the Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2), respectively. FMR1 mRNA was analysed in venous blood collected at the time of assessments, using the real-time PCR relative standard curve method.ResultsFemales with FXS had significantly higher levels of FMR1 mRNA (p < 0.001) than males. FMR1 mRNA levels were positively associated with age (p < 0.001), but not with intellectual functioning and autistic features in females. FM-only males (aged < 19 years) expressing FM FMR1 mRNA had significantly higher ADOS calibrated severity scores compared to FM-only males with completely silenced FMR1 (p = 0.011). However, there were no significant differences between these subgroups on intellectual functioning. In contrast, decreased levels of FMR1 mRNA were associated with decreased intellectual functioning in FXS males (p = 0.029), but not autism features, when combined with the PM/FM mosaic group.ConclusionIncomplete silencing of toxic FM RNA may be associated with autistic features, but not intellectual functioning in FXS males. While decreased levels of mRNA may be more predictive of intellectual functioning than autism features. If confirmed in future studies, these findings may have implications for patient stratification, outcome measure development, and design of clinical and pre-clinical trials in FXS.

Dataset Information

Fragile X syndrome in a male with methylated premutation alleles and no detectable methylated full mutation alleles.

Publications

Fragile X syndrome in a male with methylated premutation alleles and no detectable methylated full mutation alleles.

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