Background Cornelia de Lange syndrome (CdLS) and fragile X syndrome (FXS) are associated with co-occurring autism and anxiety. In autistic people, intolerance of uncertainty (IU) mediates the relationship between autistic characteristics and anxiety, but it is not known whether this relationship is evident in these genetic syndromes. Understanding the relationship between autism, anxiety and IU is essential to informing the theoretical frameworks of anxiety in rare genetic syndromes and improving clinical interventions.Method Sixty participants with CdLS or FXS participated in a questionnaire-based study to examine the association between autistic characteristics, anxiety and IU.Results IU mediated the association between autism and anxiety in participants with CdLS but not in participants with FXS.Conclusions These results suggest that other factors may contribute to the autism-anxiety relationship in FXS, and highlight the merit of syndrome-specific approaches to the study of anxiety. Recommendations are made for intervention-based research to ameliorate anxiety in CdLS.