Fragile X syndrome (FXS) is associated with an increased risk of autism, with prevalence rates ranging from 25-50%. This translates to an approximate relative risk of over 100, indicating that FMR1 (the gene causing FXS) confers considerable vulnerability to autism. While efforts to uncover the causal mechanisms in autism are often confounded by multiple unknown etiologies, genetically defined syndromes such as FXS provide the rare opportunity to examine gene-brain-behavior associations in an etiologically homogeneous condition. This project is an attempt to inform the role of FMR1 in autism symptomatology through the study of 1st degree relatives who are at increased genetic liability - relatives of individuals with autism and relatives of individuals with FXS, who are carriers of the FMR1 premutation. This project builds on our prior studies of autism and the broad autism phenotype (BAP), to examine key developmental, clinical, language, and social cognitive phenotypes shown to cosegregate with autism and the BAP. We propose to examine these phenotypes among FXS carriers in comparison to data collected from 1st degree relatives of individuals with autism, to identify potentially overlapping profiles across groups, which may be linked to FMR1. These analyses capitalize on an unprecedented opportunity -- the availability of archival childhood language and cognitive testing records from a large cohort of families of individuals with FXS and autism. Using these highly valuable data, we will characterize longitudinally the language and cognitive development of autism and FXS relatives over the early school-age years, and examine downstream outcomes across clinical, language, and social cognitive domains. Phenotypes will be examined in relation to FMR1 variation and expression of FMRP, the fragile X-mental retardation protein that is deficient in FXS and is believed to cause the cognitive and behavioral impairments in FXS. The proposed project will help to refine current understanding of the role of FMR1 in autism symptomatology, and further characterize the phenotype of the fragile X premutation.

Public Health Relevance

This project aims to identify specific developmental and cognitive-linguistic markers of genetic liability to autism which may be associated with FMR1, the gene that causes fragile X syndrome (FXS), and which is hypothesized to play a role in autism symptomatology. This project will examine novel longitudinal developmental phenotypes in a cross-population comparison of 1st degree relatives who are at increased genetic liability (and in the case of FXS, who are carriers of the FMR1 premutation), to illuminate the overlap of autism and FXS and investigate subclinical features among relatives which could be related to variation in this candidate gene. Research aimed at uncovering the pathogenesis of autism and its overlap with FXS may lead to evidence-based approaches to prevention or treatment.

National Institute of Health (NIH)
Research Project (R01)
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Child Psychopathology and Developmental Disabilities Study Section (CPDD)
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Gilotty, Lisa
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Northwestern University at Chicago
Other Health Professions
Schools of Arts and Sciences
United States
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Klusek, Jessica; Roberts, Jane E; Losh, Molly (2015) Cardiac autonomic regulation in autism and Fragile X syndrome: a review. Psychol Bull 141:141-75
Klusek, Jessica; Martin, Gary E; Losh, Molly (2014) A comparison of pragmatic language in boys with autism and fragile X syndrome. J Speech Lang Hear Res 57:1692-707
Klusek, J; Martin, G E; Losh, M (2014) Consistency between research and clinical diagnoses of autism among boys and girls with fragile X syndrome. J Intellect Disabil Res 58:940-52
Klusek, Jessica; Losh, Molly; Martin, Gary E (2014) Sex differences and within-family associations in the broad autism phenotype. Autism 18:106-16
Martin, Gary E; Losh, Molly; Estigarribia, Bruno et al. (2013) Longitudinal profiles of expressive vocabulary, syntax and pragmatic language in boys with fragile X syndrome or Down syndrome. Int J Lang Commun Disord 48:432-43