A Unique Visual Attention Profile Associated With the FMR1 Premutation.

Molly Winston,John Sideris,Elizabeth Berry-Kravis,Nell Maltman,Molly Losh,Lili Zhou,Emily Landau,Kritika Nayar,Kevin Sharp

doi:10.3389/fgene.2021.591211

Abstract

Atypical visual attention patterns have been observed among carriers of the fragile X mental retardation gene (FMR1) premutation (PM), with some similarities to visual attention patterns observed in autism spectrum disorder (ASD) and among clinically unaffected relatives of individuals with ASD. Patterns of visual attention could constitute biomarkers that can help to inform the neurocognitive profile of the PM, and that potentially span diagnostic boundaries. This study examined patterns of eye movement across an array of fixation measurements from three distinct eye-tracking tasks in order to investigate potentially overlapping profiles of visual attention among PM carriers, ASD parents, and parent controls. Logistic regression analyses were conducted to examine whether variables constituting a PM-specific looking profile were able to effectively predict group membership. Participants included 65PM female carriers, 188 ASD parents, and 84 parent controls. Analyses of fixations across the eye-tracking tasks, and their corresponding areas of interest, revealed a distinct visual attention pattern in carriers of the FMR1 PM, characterized by increased fixations on the mouth when viewing faces, more intense focus on bodies in socially complex scenes, and decreased fixations on salient characters and faces while narrating a wordless picture book. This set of variables was able to successfully differentiate individuals with the PM from controls (Sensitivity = 0.76, Specificity = 0.85, Accuracy = 0.77) as well as from ASD parents (Sensitivity = 0.70, Specificity = 0.80, Accuracy = 0.72), but did not show a strong distinction between ASD parents and controls (Accuracy = 0.62), indicating that this set of variables comprises a profile that is unique to PM carriers. Regarding predictive power, fixations toward the mouth when viewing faces was able to differentiate PM carriers from both ASD parents and controls, whereas fixations toward other social stimuli did not differentiate PM carriers from ASD parents, highlighting some overlap in visual attention patterns that could point toward shared neurobiological mechanisms. Results demonstrate a profile of visual attention that appears strongly associated with the FMR1 PM in women, and may constitute a meaningful biomarker.

Highlights

A range of clinical and subclinical phenotypes result from mutations in the fragile X mental retardation gene (FMR1) on the X-chromosome involving a cytosine-guanine-guanine (CGG) repeat expansion in the promotor region of the gene (Bagni and Oostra, 2013)
Secondary Analysis of Group Classification Results Using Mann-Whitney U tests to account for unequal sample sizes, we examined whether PM carriers who were misclassified in the logistic regression model as autism spectrum disorder (ASD) parents might display higher rates of ASD-related features that comprise the broad autism phenotype (BAP), and may show differences in FMR1-related molecular-genetic variability
The present study examined patterns of looking across three separate eye tracking tasks in female carriers of the FMR1 PM, parents of individuals with ASD, and controls, using a series t-tests and logistic regression analyses to investigate whether there may exist patterns of visual fixations across eye-tracking tasks, representing a PM-specific profile, that could effectively predict group membership

Summary

Introduction

A range of clinical and subclinical phenotypes result from mutations in the fragile X mental retardation gene (FMR1) on the X-chromosome involving a cytosine-guanine-guanine (CGG) repeat expansion in the promotor region of the gene (Bagni and Oostra, 2013). The FMR1 PM is associated with a range of clinical phenotypes, including higher rates of psychiatric and medical comorbidities (Hagerman and Hagerman, 2002; Bourgeois et al, 2011; Besterman et al, 2014). Manifestation of the PM phenotype is thought to be in part related to moleculargenetic differences including levels of FMRP and CGG repeat length (Wheeler et al, 2014). With respect to this study, some literature suggests that this variation is related to social language (Klusek et al, 2018b) and fixation patterns (Nayar et al, 2019; Winston et al, 2020), evidence is mixed (Cornish et al, 2005; Wheeler et al, 2014; Klusek et al, 2018a)

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