The Phenotypic Profile Associated With the FMR1 Premutation in Women: An Investigation of Clinical-Behavioral, Social-Cognitive, and Executive Abilities

Abstract

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.

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

“…Cluster 1 represented a psychiatric feature group (27% of our sample); Cluster 2 represented a group with executive dysfunction and elevated high frequency (gamma) neural oscillatory activity (32%); and Cluster 3 represented a relatively unaffected group (41%). These represent three clinicallymeaningful clusters with good clinical face-validity (Hagerman et al, 2018) and considerable overlap with clusters recently identified by Maltman et al (2021). Psychiatric features and executive dysfunction have been welldocumented in female PMCs; however, the majority of previous studies have examined these features independently (for review see Hagerman et al, 2018).…”

“…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 typicallydeveloping 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, 2009bRoberts et al, , 2016Seltzer 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. Although these findings may help account for variability in neuropsychiatric features, few studies have explored whether heterogeneous presentation among female PMCs may reflect differential presentation of these features in unique subgroups.…”

“…For example, Allen et al (2020) reported female PMCs fell into one of eight clusters based on their self-reported medical and/or mental health diagnoses. More recently, Maltman et al (2021) used a battery of clinical-behavioral, social-cognitive, and executive function measures to identify three clusters of female PMCs. Profile 1 whose scores across measures were at mean for PMC group;…”

“…A bottom-up approach to identify naturally occurring clusters of co-occurring neuropsychiatric features in female PMCs may be an important step in further parsing variability within the group, ultimately offering better insight into understanding underlying pathology and developing better screening, diagnostic, and treatment planning for this unique population. The present study aimed to build on Maltman et al (2021) by determining the feasibility of identifying discrete clusters of female PMCs defined by neuropsychiatric features using multimodal data including self-report, eye tracking, expressive language, neurocognitive, and resting state EEG measures. Secondly, we sought to identify the key features that distinguished these clusters of female PMCs.…”

A Longitudinal Study of Parent-Child Interactions and Language Outcomes in Fragile X Syndrome and Other Neurodevelopmental Disorders

“…Together with certain personality styles (e.g., social reticence, rigid personality), pragmatic differences comprise a constellation of traits that mirror the defining characteristics of ASD and are referred to collectively as the Broad Autism Phenotype (BAP) (20,53). Features of the BAP (and pragmatic differences in particular) have also been observed among mothers of individuals with FXS, who are carriers of the FMR1 gene in its premutation state (20,54). Some evidence suggests that parent pragmatic language differences are associated with pragmatic language development in children with ASD and FXS (45,55,56).…”