In this study, DSM-5 and ASD-related anxiety symptomatology were examined in two genetic syndromes at high risk for anxiety. The CdLS and FXS groups were comparable for chronological age, level of adaptive functioning and ASD symptomatology. Associations between presence of anxiety symptomatology with chronological age, adaptive functioning, ASD characteristics and repetitive behaviour were assessed.

DSM-5 anxiety symptomatology was highly prevalent in both groups with most individuals reported to show behaviour consistent with at least one anxiety type. This is greater than previous estimates in individuals with ID, autistic individuals and CdLS and FXS specifically [1, 2, 4, 5, 8, 31] but expected as subthreshold symptomatology was assessed as opposed to symptomatology meeting threshold for diagnosis. However, consideration of subthreshold conditions is necessary as many individuals may fall into this category if they show presentations of anxiety that do not meet criteria that are based on ‘typical’ presentations or difficulties self-reporting internal states due to low cognitive and expressive language skills [19]. Prevalence of ASD-related anxiety types were also explored in verbal individuals only and found to be prevalent in both groups (CdLS = 43.8% and FXS = 35.5% meeting ASC-ASD cut-off scores).

Visual inspection of subscales revealed greater endorsement for the uncertainty subscale in comparison to other subscales for both individuals with CdLS and FXS. This indicates that, in individuals at high risk for anxiety, difficulties with Intolerance to Uncertainty may underlie presentations of symptomatology. Both presence of subthreshold DSM-5 and ASD-related anxiety is associated with decreased wellbeing and reduced quality of life [18]. However, due to poor recognition of ASD-related anxiety in clinical guidelines and without a diagnosis of a DSM-5 anxiety disorder, individuals are unlikely to have access support and so these high rates of anxiety here have critical implications for these groups.

Low endorsement of separation anxiety and performance anxiety on the ASC-ASD in comparison to the uncertainty subscale was surprising as theoretically it may have been expected that these would broadly map onto DSM-5 separation anxiety and social anxiety, which were highly reported in both groups. However, individuals reported to show separation anxiety symptomatology formed a comparatively small subgroup which may have been masked when scores were pooled and assessed at group level. Additionally, previous literature has described atypical presentations of social anxiety type behaviour in both CdLS and FXS groups, which may have confounded measurement of these when assessments developed for autistic individuals or the general population are used [4, 32]. It should also be noted that, whilst the ASC-ASD and KSADS may be described as assessing the same construct at a broad level (i.e. anxiety for social situations or separation from others), the way these constructs are conceptualised and thus measured may differ. That is, autistic and neurotypical individuals may evidence different profiles and presentations of symptoms for the same type of anxiety construct. Thus, the lack of agreement in measures may indicate that, whilst anxiety for social situations and separation from others are present in CdLS and FXS, this does not appear to be captured by an ASD-related presentation of such anxiety. A final consideration may be the inherent difficulties in assessing anxiety in individuals with severe to profound ID, as the ASC-ASD was not created for such individuals and is not appropriate for minimally verbal individuals [31]. The items of the questionnaire require informants to comment on individuals’ internal thoughts and feelings which is challenging for individuals with low cognitive and expressive language skills [19]. Comparatively, uncertainty subscale items focus on observable, behavioural indicators of anxiety. This may indicate why caregivers endorsed these items more, as they had more confidence in identifying these behavioural markers. These issues highlight a need for research to develop more robust assessments which are appropriate for individuals with ID and sensitive to atypical presentations of anxiety.

Cross-syndrome comparisons, controlling for adaptive behaviour and ASD phenomenology, revealed no significant group differences for ASD-related or DSM-5 anxiety except for social anxiety which was more prevalent in the FXS group. Difficulties in social situations are prominent in both CdLS and FXS behavioural phenotypes [15]. However, this finding suggests this is particularly significant for individuals with FXS, although it should be noted this was also highly reported in the CdLS group.

In general, comorbidity and co-occurrence within and between DSM-5 and ASD-related anxiety was high in both syndrome groups. This is consistent with high rates of comorbidity in the idiopathic ASD literature [3] and may indicate that presence of one anxiety type places individuals at greater risk of developing other types. Additionally, where high comorbidity and co-occurrence exists, a singular underlying construct (e.g. an ‘atypical’ presentation of anxiety), causal mechanism or common risk factors may be considered [38]. Analyses revealed uncertainty was associated with generalised anxiety (anxiety response) but not specific phobias (fear response) suggesting some DSM-5 anxiety symptomatology may emerge via an Intolerance to Uncertainty in individuals with CdLS and FXS. Further research is required to investigate whether uncertainty is associated with other DSM-5 anxiety types in these groups, that is, whether presentations of many separate DSM-5 anxiety types are underpinned by a singular anxiety construct of intolerance to uncertainty. This has significant implications for the assessment and intervention of anxiety in these groups in order to target underlying mechanisms. Specifically, assessment of anxiety symptomatology should carefully consider whether this appears indicative of an intolerance to uncertainty, with interventions such as coping with uncertainty in everyday situations [39] considered where this is the case.

Interestingly, co-occurrences between specific DSM-5 anxiety types appeared to differ across syndrome groups which may be indicative of separate underlying mechanisms. For example, a significant association was identified between occurrence of social anxiety symptomatology and selective mutism in the CdLS group only. As discussed previously, social anxiety had significantly greater prevalence in FXS; however, cross-syndrome comparisons of selective mutism indicated a greater prevalence in CdLS, approaching significance. The disproportionate rates of selective mutism in CdLS, apparent dissociation between social anxiety and selective mutism relative to FXS, alongside significant co-occurrence of these anxiety types in CdLS may be indicative of a syndrome-specific presentation. Individuals with CdLS are reported to show executive dysfunction and anecdotal evidence of difficulties initiating movement and speech [40]. Thus, in CdLS, rather than appearing downstream of social anxiety, selective mutism may contribute to the emergence of anxiety due to difficulties following and keeping the pace of conversations [7, 41]. This also has implications for how anxiety related to social situations may emerge in individuals with ID and ASD more broadly.

Finally, associations with participant characteristics including chronological age, adaptive functioning, ASD characteristics and repetitive behaviour were investigated in these high-risk groups. No significant associations between adaptive functioning and any DSM-5 or ASD-related anxiety type was identified except for specific phobias in CdLS which were reported significantly more in individuals with lower adaptive functioning. This is consistent with previous studies identifying ID as a putative risk marker for anxiety [1]. However, the lack of other associations between adaptive functioning and anxiety is interesting. Few studies report presence of anxiety symptomatology in individuals with level of ability as low as that described here (indicated by VABS-II standard scores). This suggests that whilst anxiety is prevalent in individuals with severe to profound ID, within this population, there are other person characteristics which are more predicative of risk.

No significant associations between chronological age and any DSM-5 anxiety were identified except for specific phobias in FXS which were significantly lower in the older group. No change with age in the CdLS group is somewhat inconsistent with previous evidence where age-related changes are described [5, 8, 33]; however, some studies also show evidence of anxiety emerging in childhood and persisting over time [15]. These findings support these and suggest that anxiety is prevalent across children and adults in CdLS and FXS. The lack of trajectory for separation anxiety in the CdLS and FXS groups and specific phobias in individuals with CdLS is interesting as these are reported to be more common in children than adults in the typical population and so a downward trajectory would be expected [18, 23]. Specific phobias were less prevalent in the older FXS group, broadly following typical developing trajectories [18, 23]. Thus, the relatively heightened presence of specific phobias in adults with CdLS may be of interest.

Associations between anxiety and ASD phenomenology were not significant, except for the uncertainty subscale, such that greater anxiety was associated with greater severity of ASD characteristics. This is consistent with Intolerance for uncertainty being conceptualised as an ASD-related anxiety trait [19, 42]. Notably, the lack of significant associations between ASD characteristics and social anxiety is important as it suggests, in CdLS and FXS, anxiety symptomatology presents independently from ASD. Assessment and recognition of social anxiety in individuals with ID is often confounded by an ASD presentation and limited by diagnostic overshadowing. This therefore has critical implications for clinical practice and the delivery of appropriate interventions, that is, whether interventions for difficulties in social situations draw from those recommended for autistic individuals or for social anxiety.

Associations were observed between specific repetitive behaviours in the CdLS group and agoraphobia, separation anxiety, specific phobias and uncertainty. Taken together, these indicate that individuals with greater propensity to show repetitive behaviours are more likely to show anxiety. Importantly, this association may not be driven by presence of ASD symptomatology, as no significant associations between DSM-5 anxiety and ASD characteristics were identified, as discussed previously. This suggests repetitive behaviour may be a behavioural marker of anxiety in this group, consistent with theories of behavioural equivalents of mental health difficulties [42]. However, as repetitive behaviours do not occur only in the context of an anxiety response, these behaviours lack specificity to be used reliably in diagnoses of anxiety unless a specific change in baseline frequency or severity is identified and so may have utility as supplementary information. Finally, the breadth and variability of repetitive behaviours implicated (as shown in Table 7) could be indicative of distinct underlying mechanisms for anxiety types. Specifically, insistence on sameness has been highlighted as a possible coping mechanism for autistic individuals to reduce demand in anxiety provoking situations [23]. In the typically developing literature, preference for sameness and routine is observed in young children and is proposed to serve as an adaptive regulation strategy before being replaced by more sophisticated strategies as the child grows older [43]. Therefore, the association between uncertainty and insistence on sameness here indicates preference for routine may also serve as an anxiety regulation strategy for individuals with CdLS, specifically for anxiety emerging from an intolerance to uncertainty.