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Mol Autism. 2019 May 3;10:21. doi: 10.1186/s13229-019-0271-7. eCollection 2019.

Incomplete silencing of full mutation alleles in males with fragile X syndrome is associated with autistic features.

Author information

1Diagnosis and Development, Murdoch Children's Research Institute, Royal Children's Hospital, 50 Flemington Rd, Parkville, VIC 3052 Australia.
2Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia.
Brain and Mind, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia.
4Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Carlton, Australia.
5Victorian Clinical Genetics Services and Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC Australia.
6Monash Genetics, Monash Health, Melbourne, VIC Australia.
7Department of Paediatrics, Monash University, Clayton, VIC Australia.
Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW Australia.
9Fragile X Alliance Inc, North Caulfield, VIC and Center for Developmental Disability Health Victoria, Monash University, Clayton, Australia.
10Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Clayton, VIC Australia.
11Molecular and Cytogenetics Laboratory, INTA, University of Chile, Santiago, Chile.
Neurodisability and Rehabilitation, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia.
Contributed equally



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. 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.


The 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.


Females 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.


Incomplete 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.


Autism; FMR1 mRNA; Fragile X syndrome; Intellectual disability; Mosaicism

Conflict of interest statement

All procedures were approved by The Royal Children’s Hospital and INTA Human Research Ethics Committees (HREC #33066 and #15, respectively). All parents/caregivers provided written informed consent and those who were deemed cognitively able also provided written informed consent.D. Godler is an inventor of the following patents: PCT/AU2010/001134; filing No. AU2010/903595; filing No. AU2011/902500; and filing No. 2013/900227, related to the technology described in this publication. All other authors have no conflicts of interest to declare.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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