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 aim ed 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)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Child Psychopathology and Developmental Disabilities Study Section (CPDD)
Program Officer
Gilotty, Lisa
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Northwestern University at Chicago
Other Health Professions
Schools of Arts and Sciences
United States
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Barstein, Jamie; Martin, Gary E; Lee, Michelle et al. (2018) A Duck Wearing Boots?! Pragmatic Language Strategies for Repairing Communication Breakdowns Across Genetically Based Neurodevelopmental Disabilities. J Speech Lang Hear Res 61:1440-1454
Lee, Michelle; Martin, Gary E; Hogan, Abigail et al. (2018) What's the story? A computational analysis of narrative competence in autism. Autism 22:335-344
Losh, Molly; Martin, Gary E; Lee, Michelle et al. (2017) Developmental Markers of Genetic Liability to Autism in Parents: A Longitudinal, Multigenerational Study. J Autism Dev Disord 47:834-845
Martin, Gary E; Barstein, Jamie; Hornickel, Jane et al. (2017) Signaling of noncomprehension in communication breakdowns in fragile X syndrome, Down syndrome, and autism spectrum disorder. J Commun Disord 65:22-34
Lee, Michelle; Bush, Lauren; Martin, Gary E et al. (2017) A Multi-Method Investigation of Pragmatic Development in Individuals With Down Syndrome. Am J Intellect Dev Disabil 122:289-309
Hall, D; Todorova-Koteva, K; Pandya, S et al. (2016) Neurological and endocrine phenotypes of fragile X carrier women. Clin Genet 89:60-7
Lee, Michelle; Martin, Gary E; Berry-Kravis, Elizabeth et al. (2016) A developmental, longitudinal investigation of autism phenotypic profiles in fragile X syndrome. J Neurodev Disord 8:47
Hall, Deborah A; Robertson, Erin; Shelton, Annie L et al. (2016) Update on the Clinical, Radiographic, and Neurobehavioral Manifestations in FXTAS and FMR1 Premutation Carriers. Cerebellum 15:578-86
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, 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

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