Impaired eye contact in the<i>FMR1</i>premutation is not associated with social anxiety or the broad autism phenotype

Klusek, Jessica; Ruber, Alexis; Roberts, Jane

doi:10.1080/13854046.2017.1384063

Cited by 13 publications

(7 citation statements)

References 84 publications

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“…Thus, filled pauses can serve as pragmatic markers, and some emerging evidence suggest that their occurrence is correlated with measures of autism symptom severity ( Irvine et al, 2016 ). Pragmatic language difficulties and features of the broad autism phenotype have been documented in women with the FMR1 premutation in a number of prior reports ( Losh et al, 2012 ; Schneider et al, 2016 ; Klusek et al, 2017b , c , 2018 ). Follow-up studies are needed to explore the possibility that the filled pause disfluencies observed in the present study marked pragmatic, rather than executive, processes.…”

Section: Discussionmentioning

confidence: 96%

Curvilinear Association Between Language Disfluency and FMR1 CGG Repeat Size Across the Normal, Intermediate, and Premutation Range

et al. 2018

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Historically, investigations of FMR1 have focused almost exclusively on the clinical effects of CGG expansion within the categories of the premutation (55–200 CGG repeats) and fragile X syndrome (>200 CGG repeats). However, emerging evidence suggests that CGG-dependent phenotypes may occur across allele sizes traditionally considered within the “normal” range. This study adopted an individual-differences approach to determine the association between language production ability and CGG repeat length across the full range of normal, intermediate, and premutation alleles. Participants included 61 adult women with CGG repeats within the premutation (n = 37), intermediate (i.e., 41–54 repeats; n = 2), or normal (i.e., 6–40 repeats; n = 22) ranges. All participants were the biological mothers of a child with a developmental disorder, to control for the potential effects of parenting stress. Language samples were collected and the frequency of language disfluencies (i.e., interruptions in the flow of speech) served as an index of language production skills. Verbal inhibition skills, measured with the Hayling Sentence Completion Test, were also measured and examined as a correlate of language disfluency, consistent with theoretical work linking language disfluency with inhibitory deficits (i.e., the Inhibition Deficit Hypothesis). Blood samples were collected to determine FMR1 CGG repeat size. A general linear model tested CGG repeat size of the larger allele (allele-2) as the primary predictor of language disfluency, covarying for education level, IQ, age, and CGG repeats on the other allele. A robust curvilinear association between CGG length and language disfluency was detected, where low-normal (∼ <25 repeats) and mid-premutation alleles (∼90–110 repeats) were linked with higher rates of disfluency. Disfluency was not associated with inhibition deficits, which challenges prior theoretical work and suggests that a primary language deficit could account for elevated language disfluency in FMR1-associated conditions. Findings suggest CGG-dependent variation in language production ability, which was evident across individuals with and without CGG expansions on FMR1.

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Section: Discussionmentioning

confidence: 96%

Curvilinear Association Between Language Disfluency and FMR1 CGG Repeat Size Across the Normal, Intermediate, and Premutation Range

et al. 2018

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“…A variety of social difficulties have been documented as part of the FMR1 premutation phenotype, such as atypical use of eye gaze, elevated broad autism phenotype traits, and ASD occurring in about 5% of females with the premutation (Clifford et al 2007; Klusek et al 2017b, c; Losh et al 2012; Schneider et al 2016). Social deficits in this group extend to the domain of pragmatics.…”

Section: The Fmr1 Premutationmentioning

confidence: 99%

Vagal Tone as a Putative Mechanism for Pragmatic Competence: An Investigation of Carriers of the FMR1 Premutation

Klusek

Fairchild

Roberts

2018

J Autism Dev Disord

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Pragmatic language skills exist across a continuum in typical and clinical populations, and are impaired in many neurodevelopmental disorders, most notably autism. The mechanisms underlying pragmatic impairment are poorly understood, although theory suggests dampened vagal tone plays a role. This study investigated the FMR1 premutation as a genetic model that may lend insight into the relationship between vagal function and pragmatic ability. Participants included 38 women with the FMR1 premutation and 23 controls. Vagal tone accounted for significant variance in pragmatics across both groups and statistically mediated the effect of FMR1 premutation status on pragmatic ability. Results support vagal tone as a biophysiological correlate of pragmatic ability, which informs potential mechanistic underpinnings and could have implications for targeted treatment.

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“…Premutation status is approximately twice as likely to occur in females than males, highlighting the critical importance in better understanding neuropsychiatric features in female PMCs ( Hunter et al, 2014 ). Previous studies have documented both intact and impaired executive function, social processing, and psychiatric features of depression and anxiety in female PMCs without FXTAS relative to age- and sex-matched typically-developing controls (TDCs) ( Bennetto et al, 2001 ; Hessl et al, 2001 ; Loesch et al, 2003 ; Ennis et al, 2006 ; Allen et al, 2007 ; Hunter et al, 2008a , b ; Rodriguez-Revenga et al, 2008 ; Roberts et al, 2009b , 2016 ; Seltzer et al, 2012 ; Yang et al, 2013 ; Kraan et al, 2014 ; Mailick et al, 2014 ; Wheeler et al, 2014 ; Shelton et al, 2016 ; Klusek et al, 2018b ; Nayar et al, 2019 ; Winston et al, 2020 ). Severity of executive dysfunction ( Hunter et al, 2008b ; Goodrich-Hunsaker et al, 2011a , b ; Klusek et al, 2020 ), psychiatric symptoms ( Allen et al, 2007 ; Roberts et al, 2009a ; Seltzer et al, 2012 ), and social-communication differences ( Schneider et al, 2016 ; Klusek et al, 2018a ; Maltman et al, 2021 ) have linear and curvilinear associations with increased CGG repeat count in female PMCs.…”

Section: Introductionmentioning

confidence: 99%

Evidence for Three Subgroups of Female FMR1 Premutation Carriers Defined by Distinct Neuropsychiatric Features: A Pilot Study

Schmitt

Dominick

et al. 2022

Front. Integr. Neurosci.

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Over 200 Cytosine-guanine-guanine (CGG) trinucleotide repeats in the 5′ untranslated region of the Fragile X mental retardation 1 (FMR1) gene results in a “full mutation,” clinically Fragile X Syndrome (FXS), whereas 55 – 200 repeats result in a “premutation.” FMR1 premutation carriers (PMC) are at an increased risk for a range of psychiatric, neurocognitive, and physical conditions. Few studies have examined the variable expression of neuropsychiatric features in female PMCs, and whether heterogeneous presentation among female PMCs may reflect differential presentation of features in unique subgroups. In the current pilot study, we examined 41 female PMCs (ages 17–78 years) and 15 age-, sex-, and IQ-matched typically developing controls (TDC) across a battery of self-report, eye tracking, expressive language, neurocognitive, and resting state EEG measures to determine the feasibility of identifying discrete clusters. Secondly, we sought to identify the key features that distinguished these clusters of female PMCs. We found a three cluster solution using k-means clustering. Cluster 1 represented a psychiatric feature group (27% of our sample); cluster 2 represented a group with executive dysfunction and elevated high frequency neural oscillatory activity (32%); and cluster 3 represented a relatively unaffected group (41%). Our findings indicate the feasibility of using a data-driven approach to identify naturally occurring clusters in female PMCs using a multi-method assessment battery. CGG repeat count and its association with neuropsychiatric features differ across clusters. Together, our findings provide important insight into potential diverging pathophysiological mechanisms and risk factors for each female PMC cluster, which may ultimately help provide novel and individualized targets for treatment options.

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Impaired eye contact in theFMR1premutation is not associated with social anxiety or the broad autism phenotype

Cited by 13 publications

References 84 publications

Curvilinear Association Between Language Disfluency and FMR1 CGG Repeat Size Across the Normal, Intermediate, and Premutation Range

Curvilinear Association Between Language Disfluency and FMR1 CGG Repeat Size Across the Normal, Intermediate, and Premutation Range

Vagal Tone as a Putative Mechanism for Pragmatic Competence: An Investigation of Carriers of the FMR1 Premutation

Evidence for Three Subgroups of Female FMR1 Premutation Carriers Defined by Distinct Neuropsychiatric Features: A Pilot Study

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