Intellectual functioning and behavioural features associated with mosaicism in fragile X syndrome

Emma K Baker,Jonathan Cohen,David Francis,Alexandra Ure,Ling Ling,Claudine Kraan ,David J Amor,Solange Aliaga Vera,Patricio Morales ,Bianca Curotto,Michael Field ,Justine Elliott,Carolyn Rogers,Matthew Hunter ,Víctor Faundes ,Minh Bui,César Trigo ,Angelica M Alliende,Lesley Bretherton,Marta Arpone,Isabel Salas,Lorena Santa María ,David E Godler

doi:10.1186/s11689-019-9288-7

Abstract

BackgroundFragile X syndrome (FXS) is a common cause of intellectual disability and autism spectrum disorder (ASD) usually associated with a CGG expansion, termed full mutation (FM: CGG ≥ 200), increased DNA methylation of the FMR1 promoter and silencing of the gene. Mosaicism for presence of cells with either methylated FM or smaller unmethylated pre-mutation (PM: CGG 55–199) alleles in the same individual have been associated with better cognitive functioning. This study compares age- and sex-matched FM-only and PM/FM mosaic individuals on intellectual functioning, ASD features and maladaptive behaviours.MethodsThis study comprised a large international cohort of 126 male and female participants with FXS (aged 1.15 to 43.17 years) separated into FM-only and PM/FM mosaic groups (90 males, 77.8% FM-only; 36 females, 77.8% FM-only). Intellectual functioning was assessed with age appropriate developmental or intelligence tests. The Autism Diagnostic Observation Schedule-2nd Edition was used to examine ASD features while the Aberrant Behavior Checklist-Community assessed maladaptive behaviours.ResultsComparing males and females (FM-only + PM/FM mosaic), males had poorer intellectual functioning on all domains (p < 0.0001). Although females had less ASD features and less parent-reported maladaptive behaviours, these differences were no longer significant after controlling for intellectual functioning. Participants with PM/FM mosaicism, regardless of sex, presented with better intellectual functioning and less maladaptive behaviours compared with their age- and sex-matched FM-only counterparts (p < 0.05). ASD features were similar between FM-only and PM/FM mosaics within each sex, after controlling for overall intellectual functioning.ConclusionsMales with FXS had significantly lower intellectual functioning than females with FXS. However, there were no significant differences in ASD features and maladaptive behaviours, after controlling for intellectual functioning, independent of the presence or absence of mosaicism. This suggests that interventions that primarily target cognitive abilities may in turn reduce the severity of maladaptive behaviours including ASD features in FXS.

Highlights

Fragile X syndrome (FXS) is a common cause of intellectual disability and autism spectrum disorder (ASD) usually associated with a CGG expansion, termed full mutation (FM: CGG ≥ 200), increased DNA methylation of the fragile X mental retardation 1 (FMR1) promoter and silencing of the gene
This study contributes to the field by providing a neurodevelopmental characterisation (ID, ASD and maladaptive behaviours) in individuals with FXS, stratified by sex and presence/absence of mosaicism
This study contributes to the field by providing a neurodevelopmental characterisation (ID, ASD and maladaptive behaviours) in individuals with FXS stratified by sex and presence/absence of mosaicism

Summary

Introduction

Fragile X syndrome (FXS) is a common cause of intellectual disability and autism spectrum disorder (ASD) usually associated with a CGG expansion, termed full mutation (FM: CGG ≥ 200), increased DNA methylation of the FMR1 promoter and silencing of the gene. Mosaicism for presence of cells with either methylated FM or smaller unmethylated pre-mutation (PM: CGG 55–199) alleles in the same individual have been associated with better cognitive functioning. Fragile X syndrome (FXS) is a common single-gene cause of inherited intellectual disability (ID) and autism spectrum disorder (ASD), with current prevalence estimates of 1:4000 and 1:8000 males and females, respectively [1]. The primary cause of FXS is a large trinucleotide CGG expansion (≥ 200 repeats), termed full mutation (FM), in the promoter region of the fragile X mental retardation 1 (FMR1) gene [2]. The contribution of genotype mosaicism on psychological functioning, within and between sexes, may shed light on the underlying biology that contributes towards the cognitive, emotional and behavioural phenotype in males and females with FXS

Methods

Results

Discussion

Conclusion