No abstract

The FMR1 gene is associated with a wide range of clinical and cognitive phenotypes, ranging from intellectual disability and autism symptoms in fragile X syndrome (caused by the FMR1 full mutation), to a more varied, and still poorly understood range of clinical and cognitive phenotypes among carriers of the gene in its premutation state. Because the FMR1 premutation is relatively common among women (as high as 1 in 150), investigations of its phenotypic impact could have broad implications for understanding gene-behavior relationships underlying complex human traits, with potential clinical implications. This study investigated physiological regulation measured by pupillary responses, along with fixation patterns while viewing facial expressions among women who carry the FMR1 premutation (PM group; n=47), to examine whether the FMR1 gene may relate to physiological regulation, social-emotional functioning, and social language skills (where subclinical differences have been previously reported among PM carriers that resemble those documented in autism-related conditions). Relative to controls (n=25), the PM group demonstrated atypical pupillary responses and fixation patterns, controlling for IQ. In the PM group, pupillary response and fixation patterns were related to social cognition, social language abilities, and FMR1-related variation. Results indicate a pattern of atypical attention allocation among women who carry the FMR1 PM that could reflect different emotion-processing strategies mediated by autonomic dysregulation and the FMR1 gene. These findings lend insight into the FMR1 gene's potential contributions to complex human traits such as social emotional processing, and social language.

The FMR1 gene in its premutation (PM) state has been linked to a range of clinical and subclinical phenotypes among FMR1 PM carriers, including some subclinical traits associated with autism spectrum disorder (ASD). This study attempted to further characterize the phenotypic profile associated with the FMR1 PM by studying a battery of assessments examining clinical-behavioral traits, social-cognitive, and executive abilities in women carrying the FMR1 PM, and associations with FMR1-related variability. Participants included 152 female FMR1 PM carriers and 75 female controls who were similar in age and IQ, and screened for neuromotor impairments or signs of fragile X-associated tremor/ataxia syndrome. The phenotypic battery included assessments of ASD-related personality and language (i.e., pragmatic) traits, symptoms of anxiety and depression, four different social-cognitive tasks that tapped the ability to read internal states and emotions based on different cues (e.g., facial expressions, biological motion, and complex social scenes), and a measure of executive function. Results revealed a complex phenotypic profile among the PM carrier group, where subtle differences were observed in pragmatic language, executive function, and social-cognitive tasks that involved evaluating basic emotions and trustworthiness. The PM carrier group also showed elevated rates of ASD-related personality traits. In contrast, PM carriers performed similarly to controls on social-cognitive tasks that involved reliance on faces and biological motion. The PM group did not differ from controls on self-reported depression or anxiety symptoms. Using latent profile analysis, we observed three distinct subgroups of PM carriers who varied considerably in their performance across tasks. Among PM carriers, CGG repeat length was a significant predictor of pragmatic language violations. Results suggest a nuanced phenotypic profile characterized by subtle differences in select clinical-behavioral, social-cognitive, and executive abilities associated with the FMR1 PM in women.

Background Social attention differences, expressed through gaze patterns, have been documented in autism spectrum disorder (ASD), with subtle differences also reported among first-degree relatives, suggesting a shared genetic link. Findings have mostly been derived from standard eye-tracking methods (total fixation count or total fixation duration). Given the dynamics of visual attention, these standard methods may obscure subtle, yet core, differences in visual attention mechanisms, particularly those presenting sub-clinically. This study applied a constellation of eye-tracking analyses to gaze data from individuals with ASD and their parents. Methods This study included n = 156 participants across groups, including ASD (n = 24) and control (n = 32) groups, and parents of individuals with ASD (n = 61) and control parents (n = 39). A complex scene with social/non-social elements was displayed and gaze tracked via an eye tracker. Eleven analytic methods from the following categories were analyzed: (1) standard variables, (2) temporal dynamics (e.g., gaze over time), (3) fixation patterns (e.g., perseverative or regressive fixations), (4) first fixations, and (5) distribution patterns. MANOVAs, growth curve analyses, and Chi-squared tests were applied to examine group differences. Finally, group differences were examined on component scores derived from a principal component analysis (PCA) that reduced variables to distinct dimensions. Results No group differences emerged among standard, first fixation, and distribution pattern variables. Both the ASD and ASD parent groups demonstrated on average reduced social attention over time and atypical perseverative fixations. Lower social attention factor scores derived from PCA strongly differentiated the ASD and ASD parent groups from controls, with parent findings driven by the subset of parents demonstrating the broad autism phenotype. Limitations To generalize these findings, larger sample sizes, extended viewing contexts (e.g., dynamic stimuli), and even more eye-tracking analytical methods are needed. Conclusions Fixations over time and perseverative fixations differentiated ASD and the ASD parent groups from controls, with the PCA most robustly capturing social attention differences. Findings highlight their methodological utility in studies of the (broad) autism spectrum to capture nuanced visual attention differences that may relate to clinical symptoms in ASD, and reflect genetic liability in clinically unaffected relatives. This proof-of-concept study may inform future studies using eye tracking across populations where social attention is impacted.

Background: Efficient neural encoding of sound plays a critical and widespread role in speech and language, and when impaired, may have reverberating effects on a range of communication skills. Autism spectrum disorder (ASD) is a condition involving impaired communication abilities, including atypical prosody (e.g., intonation modulation, rate, rhythm), in which atypical neural processing of speech has been implicated. Parallel patterns of communication differences have been noted in parents of individuals with ASD, who may exhibit subclinical language-related differences believed to reflect genetic liability to ASD. The present study investigated disruptions to neural processing of temporal and spectral (i.e., frequency/pitch) properties of speech sounds as a potential neurobiological mechanism underlying specific language-related impairments in ASD and related subclinical differences documented among first-degree relatives of individuals with ASD. Methods: Participants included individuals with ASD, their parents, and respective control groups. Group differences in temporal and spectral processing based on the neural FFR were assessed using MANCOVAs controlling for chronological age. Relationships between the FFR, pragmatic language ability, and receptive and expressive prosody skills were assessed using Pearson correlations. Familiality of the FFR in mother-child dyads were also examined using Pearson correlations.Results: Findings revealed inefficiencies in neural encoding of speech sounds in both individuals with ASD and their parents (specifically, increased neural noise and delayed neural processing of speech sounds), as well as a less robust neural representation of spectral properties of speech sounds in individuals with ASD. Associations between neural processing of speech sounds and language-related abilities were detected in both groups, along with evidence of familiality of neural pitch processing in the ASD family groups. Limitations: Additional investigation is necessary to determine whether relationships between FFR and pragmatic language and prosody extend to individuals with more severe language and/or cognitive impairments. Conclusions: Overall, results suggest atypical neural processing of speech sounds may constitute an important, heritable ingredient contributing to the ASD language phenotype and subclinical phenotypic expression of genetic liability in parents.