Abstract
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.
Highlights
Fragile X syndrome (FXS) is a common monogenic cause of intellectual disability with autism features
Inter-group comparisons of intellectual functioning and autism features Comparisons of phenotypic variables between males and females (FM-only and PM/full mutation (FM) mosaics combined) showed that males had significantly lower intellectual functioning scores on all domains assessed (Table 1 and Additional file 1: Table S1), though the two groups did not differ on Autism Diagnostic Observation Schedule (ADOS) scores, after controlling for corrected full scale IQ (cFSIQ) (Table 1)
Incomplete silencing of FMR1 was associated with elevated autistic features as measured by Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2) calibrated severity scores (CSS), with 21% more of the 18 and under full mutation alleles only (FM-only) group expressing FM FMR1 mRNA meeting the ADOS-2 criteria for autism spectrum disorder (ASD) (CSS ≥ 4), as compared to FM-only males with completely silenced FMR1
Summary
Fragile 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. Fragile X Syndrome (FXS) is a common monogenic syndrome associated with intellectual disability (ID) and autism features, caused by a trinucleotide CGG expansion (≥ 200 repeats), termed full mutation (FM) [1]. FMR1 alleles with smaller size CGG expansion (55– 199 repeats) have been termed premutation (PM) These PM alleles have been reported to have an unmethylated FMR1 promoter and abnormally increased levels of FMR1 mRNA [4, 5]. Other potential pathogenic mechanisms described in PM-related disorders include marginally decreased FMRP, expanded repeat associated non-AUG translation, as well as increased transcription of ASFMR1/FMR4 originating from the same locus as FMR1, but in the anti-sense direction (reviewed in [2])
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