A developmental, longitudinal investigation of autism phenotypic profiles in fragile X syndrome

Michelle Lee, Gary E. Martin, Elizabeth Berry-Kravis, Molly Losh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


Background: Targeting overlapping behavioral phenotypes in neurogenetic disorders can help elucidate gene-behavior relationships. Fragile X syndrome (FXS) and autism spectrum disorder (ASD) have been studied as a model for this approach, and important areas of phenotypic overlap and divergence have been documented. However, few studies have examined how the manifestation of ASD-related phenotypes in FXS may change over development, a question which has important implications for conceptualizing shared etiologies of these disorders and their constituent phenotypes. The goal of this study was to characterize ASD phenotypes in boys and girls with FXS across development, as well as to compare individual component phenotypes among boys with FXS and boys with idiopathic ASD (ASD-O) over time. Methods: Sixty-five boys and girls with FXS and 19 boys with ASD-O completed a battery of diagnostic, cognitive, and language assessments at two time points (mean 2.5 years apart). Nonparametric tests assessed changes in diagnostic classification in FXS over time, and hierarchical linear modeling and repeated measures assessed changes in individual ASD symptoms in FXS over time. Additionally, ANCOVAs compared ASD symptom severity and component phenotypes in boys with FXS-O, FXS-ASD, and ASD-O at both time points. Results: Overall, ASD symptom manifestation for children with FXS significantly increased over time, and developmental predictors varied based on the domain of symptoms assessed. The greatest degree of overlap was observed between boys with FXS-ASD and ASD-O in the domain of reciprocal social communication across time points, whereas boys with ASD-O demonstrated greater impairment in restricted and repetitive behaviors at the later time point. Conclusions: ASD symptoms increased in FXS with age, and social language impairment emerged as a potential core shared feature of FXS and ASD that may help elucidate underlying molecular genetic variation related to phenotypic variance, and aid intervention planning for subgroups of children showing distinct phenotypes. Results highlight the value of a developmental perspective, and longitudinal data in particular, in evaluating shared behavioral phenotypes across genetic conditions, lending insight into underlying cognitive, neural, and genetic mechanisms associated with key developmental phenotypes in ASD and FXS.

Original languageEnglish (US)
Article number47
JournalJournal of neurodevelopmental disorders
Issue number1
StatePublished - Dec 30 2016


  • Autism spectrum disorder
  • Endophenotype
  • FMR1 gene
  • Fragile X syndrome
  • Language
  • Longitudinal
  • Pragmatics
  • Social behavior

ASJC Scopus subject areas

  • Clinical Neurology
  • Cognitive Neuroscience
  • Pediatrics, Perinatology, and Child Health
  • Pathology and Forensic Medicine


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