Emergence, stability, and predictors of anxiety in Fragile X syndrome

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PROJECT SUMMARY/ABSTRACT Anxiety is the most common pediatric mental health problem, affecting ~10% of children and adolescents1. Given the substantial prevalence and impact of anxiety, recent interest has focused on characterizing anxiety within high-anxiety-risk clinical subgroups (e.g., neurodevelopmental disorders) to provide critical insight into the specific risk factors, developmental pathways, and consequences of anxiety. Individuals with fragile X syndrome (FXS) constitute one such high-anxiety-risk subgroup, with up to ~80% of adolescents and adults meeting criteria for at least one anxiety disorder16. Work from our initial NIMH-funded R01 demonstrated that anxiety emerges early in childhood in FXS, with 39% of preschoolers diagnosed with at least one anxiety disorder17, and increases in severity across early childhood. The first funding period of this R01 (2016-2023) was highly successful (26 papers to date) in characterizing the emergence, stability, and prevalence of anxiety longitudinally across early childhood (3, 4, and 5-7 years) in children with FXS contrasted to children with idiopathic (i.e., non-syndromic) autism spectrum disorder (nsASD) and neurotypical (NT) children. However, this work has fueled a new set of questions regarding the developmental trajectory of anxiety symptoms and diagnoses from early to middle childhood in FXS which are crucial to identifying the stability and consequences of anxiety in FXS across critical early developmental periods when intervention is known to be most effective. To address these gaps, this competitive renewal application will leverage our existing, rich, multidimensional longitudinal dataset and follow our existing cohort of children with FXS, children with nsASD, and NT children through 8-10 years, as well as recruit a new large cross-sectional cohort of 8-to-10-year-olds. The specific aims are to (1) Determine change in anxiety symptoms and diagnoses from 3-10 years of age in FXS contrasted to children with nsASD and NT children; (2) Document the extent to which potential early risk factors predict change in anxiety symptoms and diagnoses in children with FXS contrasted to children with nsASD and NT children; and (3) Identify (a) rates of anxiety symptoms and diagnoses, (b) functional impairment associated with anxiety, and (c) sex differences in children with FXS contrasted to children with nsASD and NT children during middle childhood. This study is innovative in its inclusion of an IQ-matched nsASD contrast group, which will answer critical questions on syndrome specificity and amplify our impact by generating knowledge on the development, predictors, and consequences of anxiety in children with nsASD and intellectual disability. This work is significant in that it will greatly expand our understanding of anxiety in FXS by providing critical information about the developmental course, predictors, and consequences of childhood anxiety, which will inform the timing and targets of intervention that will improve quality of life for children with FXS and their families.