Clinical and Neuropsychological Overlap in the Broad Autism Phenotype and the FMR1 Premutation

Background: Fragile X syndrome (FXS) is associated with an increased risk of autism, with conservative prevalence rates ranging from ~25-50%, suggesting that mutations in FMR1 (the gene causing FXS) is a highly important risk for autism. While efforts to uncover the etiologic mechanisms in autism are often confounded by multiple unknown etiologies, genetically defined syndromes such as FXS provide an uncommon opportunity to examine gene-brain-behavior associations in a more etiologically homogeneous condition.

Objectives: This study investigated the role of FMR1 in autism symptomatology through the study of 1^st degree relatives who are at increased genetic liability (and in the case of FXS, who are carriers of the FMR1 premutation), along measures of the broad autism phenotype (BAP) and neuropsychological characteristics shown to co-segregate with autism and the BAP. Methods: To address the hypothesis that FMR1 may play a role in the BAP, we administered the Broad Autism Phenotype Questionnaire (BAP-Q; Hurley et al., 2007) to a group of 53 FXS mothers, 24 autism mothers, and 17 control mothers. The BAP-Q is a sensitive and specific self- and informant-report questionnaire, developed for detection of the BAP. We also examined group differences on a battery of social cognitive tests previously shown to distinguish autism parents with the BAP from controls (i.e., the Reading the Mind in the Eyes Test, the Trustworthiness of Faces Task, and the Movie Stills Task; Losh et al., 2009). Parent-child correlations were also assessed for evidence of familiality which could further implicate genetic influence.
Results: Significantly higher rates of the BAP were detected in both FXS and autism parent groups, relative to controls (x² (2) = 8.64, p < .05). FXS and autism parents also performed significantly worse than controls on each of the social cognitive measures (p values < .01). Significant parent-child correlations were also detected among FXS families (child data was not available for the autism or control families). The presence of BAP characteristics in parents was significantly associated with children’s vocabulary measured through the PPVT (r=-.66, p<.05). We found similar relationships between parental social cognitive performance on the Movie Stills and Trustworthiness of Faces Tasks, where impaired performance on these measures was correlated with greater delays in children’s vocabulary (r=-.81, p<.05; r = -.73, p< .05, respectively) and more severe impairments in children’s pragmatic language ability (r=-.71, p<.05); r= -0.60, p = .10, respectively). Finally, analyses revealed that parental activation ratio (an index of cells producing FMRP) positively correlated with children’s expressive and receptive vocabulary skills (r=.55911, p<.05; r=.61169, p=.0602, respectively), so that mothers with more normal X activation (i.e., higher activation ratio) tended to have children with more advanced lexical abilities
Conclusions: Findings demonstrate substantially overlapping phenotypes among autism parents and FXS parents who are carriers of FMR1 in its premutation state. Results support a role of FMR1 in the BAP, and in the social cognitive profiles associated with the BAP. Parent-child correlations in phenotypes and genetic characteristics provide further support for genetic influence and overlap of FXS and autism.