The parent R01 for this revision application was intended to inform the role of FMR1-related molecular variation 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. The proposal built 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 are examining these phenotypes among premutation 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-related molecular variation. The original proposal also capitalized 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. The project has proceeded strongly and steadily, while at the same time a number of important findings have emerged from a companion grant focused on identifying genetically meaningful language features in autism and the BAP. We piloted these measures in a production, and potentially related to autonomic arousal. With an expanded team of expert collaborators subgroup of premutation carriers, with exciting results. In this revision application we propose a battery of tools for analyzing discours production, drawing on techniques that have been developed in psycholinguistics and computational linguistics, and which Preliminary Data suggest may capture important language-related profiles in the BAP and the FMR1 premutation. These tools provide quantitative measures of key lexical and semantic features of discourse, as well as using eye tracking to provide new information on how language processing is linked to perception and attention during discourse included, we believe that the addition of these novel measures of language will substantially enhance the value of our existing data, and sharpen our understanding of the role of FMR1, and FMRP more specifically, in autism symptomatology, as well as further characterize the phenotype of the FMR1 premutation.
This project aims to identify specific biomarkers of risk to autism that may be associated with the FMR1 gene that causes fragile X syndrome (FXS). In this revision application we propose to add a battery of novel computational linguistic and psycholinguistic measures which our preliminary data suggest tap core underlying abilities linked to variation in this gene and its protein, FMRP, and therefore may help us better understand the pathogenesis of autism, leading to evidence-based approaches to prevention or treatment.
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