Fragile X syndrome (FXS) is associated with an increased risk of autism spectrum disorder (ASD), with prevalence rates ranging from ~40-74%1-6, suggesting that the FMR1 gene (the gene causing FXS) and its protein product, the Fragile X Mental Retardation Protein (FMRP), constitute a highly important risk for ASD symptomatology. Importantly, ASD-related features (i.e., the broad autism phenotype, or BAP) have also been observed at elevated rates among carriers of the FMR1 premutation (PM carriers), providing further evidence of the role of FMR1-related variation in ASD-related phenotypes. In the original period of funding, this project identified a number of clinical, psycholinguistic, and social-cognitive features that may serve as candidate endophenotypes (i.e., heritable traits associated with a disease and measurable in affected and unaffected individuals) overlapping in ASD and FXS, which were also evident among first-degree relatives at increased genetic liability (and in the case of FXS, PM carriers). In this revised renewal application, we build on these promising findings with deep behavioral and neural phenotyping in the domain of pragmatic language (where we have demonstrated robust overlap in profiles in ASD and FMR1 mutations (PM carriers and FXS). In particular, we apply multi-method assessments of prosody (e.g., intonation, stress, and rhythm of language), which is a critical pragmatic skill that is impaired in ASD (and linked with social impairments), and also impacted in the BAP in unaffected relatives. Analyses include data from three independent cohorts with extensive existing data available for computational and data-driven analyses to identify phenotypically-defined homogeneous subgroups that may cross diagnostic borders and provide clues to biological mechanisms that can inform studies of etiology and treatment. Preliminary data suggest that these pragmatic and prosodic profiles are associated with the neural processing of speech sounds, with robust differences in the neural frequency following response (FFR). The FFR is a precise neural index of spectral and temporal encoding of sound within the midbrain, that serves as a barometer of rapid auditory processing that is linked to expressive and receptive speech and language-related skills throughout the lifespan7-13. FMRP is highly expressed in the auditory midbrain, making our focus on the spectral and temporal encoding of speech within the midbrain a particularly strong candidate as a neural marker linked with FMR1, and relevant to the pathogenesis of language-related features in ASD. In this renewal application, we investigate the FFR together with a multi- context assessment of prosody in PM carriers (leveraging data from three independent cohorts and applying sophisticated computational modeling of prosody across different conversational contexts) to detect key ASD- related pragmatic and neural phenotypes linked with FMR1-related variation that have significant potential to illuminate the pathogenesis of ASD and inform treatment.

Public Health Relevance

This project builds on three extremely rich existing phenotypic datasets from individuals with the FMR1 premutation and their children with FXS, and parallel data collected from ASD families, to identify key pragmatic and prosodic, neural, and molecular-genetic markers in individuals with the premutation and FXS. This study will investigate whether there may be specific pragmatic/prosodic and neural signatures associated with ASD-risk in these individuals, which can be linked to the FMR1 gene. This research takes an important step toward pinpointing different neurobiological and molecular-genetic factors associated with ASD-specific features, and for understanding gene-brain-behavior links to develop targeted interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH091131-07
Application #
10021718
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gilotty, Lisa
Project Start
2012-05-01
Project End
2024-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Other Health Professions
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Chicago
State
IL
Country
United States
Zip Code
60611
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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