FMR1 mRNA in Blood As a Predictor of Intellectual Functioning and Autism Severity in Fragile X Syndrome: Is There a Difference between Sexes?

Poster Presentation
Friday, May 11, 2018: 5:30 PM-7:00 PM
Hall Grote Zaal (de Doelen ICC Rotterdam)
E. K. Baker1, M. Arpone2, S. Aliaga2, L. Bretherton1, M. Bui3, C. Kraan1, A. Alliende4, V. Faundes5, L. Santa Maria5, C. Rogers6, M. Field7, D. Amor8 and D. E. Godler9, (1)Murdoch Children's Research Institute, Melbourne, Australia, (2)University of Melbourne, Melbourne, Australia, (3)Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Australia, (4)Molecular and Cytogenetics Laboratory, INTA University of Chile, Santiago, Chile, (5)Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile, (6)Hunter Genetics, GOLD Service, Newcastle, Australia, (7)Hunter Genetics, Newcastle, Australia, (8)Victorian Clinical Genetics Service, Melbourne, Australia, (9)Genetics, Murdoch Children's Research Institute, Melbourne, Australia
Background: Fragile X Syndrome (FXS) is a common single gene cause of intellectual disability and co-morbid autism spectrum disorder (ASD). FXS is caused by a large trinucleotide CGG expansion (>200 repeats), termed full mutation (FM), within the FMR1 gene located on the X chromosome. FM alleles are associated with epigenetic changes that result in decreased production of FMR1 mRNA and loss of the FMR1 protein FMRP, which is essential for normal neurodevelopment. While males with FXS typically present with a more severe phenotype compared to females, the molecular mechanisms that underlie differences in cognitive functioning and severity of ASD presentation in both sexes have not been defined.

Objectives: This study aimed to characterise gender differences in the relationships between levels of FMR1 mRNA in blood and FXS phenotypes, including symptoms of ASD and intellectual functioning in males and females with FXS.

Methods: This study used a large international FXS cohort recruited through genetic testing centres and family support organisations in Australia and Chile. 128 individuals (28.1% female) with FXS aged between 1 and 43 years participated in the study. The Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2) was used to assess symptoms associated with ASD while intellectual functioning (Verbal IQ [VIQ], Performance IQ [PIQ] and Full Scale IQ [FSIQ]) was assessed with the Mullen Scales of Early Learning for those < 3 years, and an age appropriate Wechsler scale for those aged ≥ 3 years. FMR1 mRNA was analysed using the real-time PCR relative standard curve method in blood samples collected at the time of assessment.

Results: FXS females performed better than males on all cognitive domains (p < .001; Table 1). Similarly, only 16 (45.7%) FXS females met the cut-off for ASD on the ADOS-2 compared to 77 (82.8%) males (p < 0.001). Genotype-phenotype analyses showed that FMR1 mRNA levels in blood were strongly associated with FSIQ (p = 8.1×10-11; n = 41), VIQ (p = .0002; n = 50) and PIQ (p = 9.8×10-9; n = 50) in males, but not in females (FSIQ: p =.394, n = 24; VIQ: p = .170; n = 25; PIQ: p = .438; n = 25). In contrast, FMR1 mRNA levels were strongly correlated with total (rs = -.651, p = .001), Social Affect (SA; r = -.565, p = .008) and Repetitive and Restricted Behaviours (RRB; rs = -.633, p = .002) Calibrated Severity Scores in females, but not males (Total: rs = -.081, p =.537; SA: rs = -.175, p = .178; RRB: rs = -.002, p =.987.

Conclusions: This study shows that FMR1 mRNA levels in blood are associated with symptoms of ASD in females with FXS, but not with intellectual functioning. In contrast, in males with FXS FMR1 mRNA levels in blood are associated with intellectual functioning, but not symptoms of ASD. This dissociation by gender in the relationships between FMR1 expression with type and severity of cognitive and behavioural phenotypes (e.g., intellectual deficits versus ASD symptoms) warrants further study.

See more of: Genetics
See more of: Genetics