New population-based screening indicates that 1 in 151 women have premutation alleles on the Fragile X Mental Retardation-1 (FMR1) gene (Seltzer, Baker, et al., 2012), which highlights research on the clinical phenotype of the FMR1 premutation as a significant public health priority. Emerging evidence suggests that individuals with the FMR1 premutation show deficits in pragmatic language, or the social use of language (Aziz et al., 2003; Losh, Klusek, et al., 2012). Pragmatic language skills are critical for effectie communication, and deficits in this area may lead to ineffective social interchange and difficulty managing social relationships (Bates, 1976). This proposal aims to further delineate the pragmatic language phenotype of women with the FMR1 premutation, including the possible interface between pragmatics and anxiety disorders, which are seen at elevated rates among individuals with the FMR1 premutation (Bailey et al., 2008; Roberts et al., 2009). A comparison group of mothers of children with autism spectrum disorder (ASD) will be included in order to inform disassociation across phenotypes and shed light on the range of pragmatic features that may be attributed to the biochemical effects of FMR1. Specifically, this study aims to: (1) identif specific aspects of the pragmatic language profile of mothers with the FMR1 premutation that are shared or distinct from the profile of mothers of children with ASD, and compared to controls, (2) evaluate the functional impact of pragmatic language deficits on individual and family outcomes, and (3) determine the relationship between pragmatic language and anxiety, and how it differs among mothers with the FMR1 premutation, mothers of children with ASD, and control mothers. By integrating scientific advances in neuroscience to apply a combined behavioral (both standardized and experimental) and biomarker approach, this proposal aims to clarify the nature, underlying mechanisms and functional consequences of pragmatic impairments in the FMR1 premutation. This research will inform the range of features that may be specifically linked to the biochemical effects of FMR1, and has implications for potential prevention and treatment efforts. This research will be implemented within the excellent training environment at the University of South Carolina, within the context of an expert, interdisciplinary mentorship team that has a proven history of successful collaboration. The proposed training plan focuses on: (1) developing a comprehensive understanding of the impact of anxiety on language function, (2) attaining expertise in the use of physiological and neuroendocrine markers of stress, (3) training to use eyetracking methods to index language and related processes, (4) honing skills in pragmatic language assessment and theory, and (5) sharpening professional skills such as grant writing, research ethics, etc. The proposed research and training experiences will provide the fellow with the necessary skills to develop a programmatic line of research focused on identifying profiles and predictors of communication impairments in ASD and FMR1-associated conditions.

Public Health Relevance

Research focused on determining the clinical consequences of the FMR1 premutation is a significant public health priority, given new population-based screening indicating that 1 in 151 women carry this genetic defect (Seltzer et al., 2012). Although it is clear that the FMR1 premutation is associated with a range of debilitating physical and mental health conditions (e.g., premature ovarian insufficiency, fragile X tremor-ataxia syndrome, mood and anxiety disorders), the clinical manifestation of the FMR1 premutation is not yet well- understood. This proposal aims to clarify the nature, underlying mechanisms, and functional consequences of pragmatic (i.e., social language) impairments in the FMR1 premutation, which has implications for potential prevention and treatment efforts, and will inform the range of features that may be attributable to FMR1-related genetic effects.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDC1-SRB-R (36))
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Rivera-Rentas, Alberto L
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University of South Carolina at Columbia
Schools of Arts and Sciences
United States
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Klusek, Jessica; Ruber, Alexis; Roberts, Jane E (2018) Impaired eye contact in the FMR1 premutation is not associated with social anxiety or the broad autism phenotype. Clin Neuropsychol 32:1337-1352
Robinson, Marissa; Klusek, Jessica; Poe, Michele D et al. (2018) The Emergence of Effortful Control in Young Boys With Fragile X Syndrome. Am J Intellect Dev Disabil 123:89-102
Klusek, Jessica; Porter, Anna; Abbeduto, Leonard et al. (2018) Curvilinear Association Between Language Disfluency and FMR1 CGG Repeat Size Across the Normal, Intermediate, and Premutation Range. Front Genet 9:344
Adlof, Suzanne M; Klusek, Jessica; Hoffmann, Anne et al. (2018) Reading in Children With Fragile X Syndrome: Phonological Awareness and Feasibility of Intervention. Am J Intellect Dev Disabil 123:193-211
Klusek, Jessica; Schmidt, Joseph; Fairchild, Amanda J et al. (2017) Altered sensitivity to social gaze in the FMR1 premutation and pragmatic language competence. J Neurodev Disord 9:31
Klusek, Jessica; LaFauci, Giuseppe; Adayev, Tatyana et al. (2017) Reduced vagal tone in women with the FMR1 premutation is associated with FMR1 mRNA but not depression or anxiety. J Neurodev Disord 9:16
Klusek, Jessica; McGrath, Sara E; Abbeduto, Leonard et al. (2016) Pragmatic Language Features of Mothers With the FMR1 Premutation Are Associated With the Language Outcomes of Adolescents and Young Adults With Fragile X Syndrome. J Speech Lang Hear Res 59:49-61
Randel, Allison; Adlof, Suzanne; Klusek, Jessica et al. (2015) Teaching reading to youth with fragile X syndrome: Should phonemic awareness and phonics instruction be used? EBP Briefs 9:47-61
Klusek, Jessica; Roberts, Jane E; Losh, Molly (2015) Cardiac autonomic regulation in autism and Fragile X syndrome: a review. Psychol Bull 141:141-75
Adlof, Suzanne M; Klusek, Jessica; Shinkareva, Svetlana V et al. (2015) Phonological awareness and reading in boys with fragile X syndrome. J Child Psychol Psychiatry 56:30-9

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