Background
Research has revealed a spectrum of profiles of sociability across genetic syndromes that appears unrelated to degree of intellectual disability. This spectrum includes a heightened level of sociability evident in Angelman, Williams and Down syndromes (DS), and social anxiety in Fragile X (FXS) and Turner syndromes [
1‐
4]. In this study, we aim to identify the nature of aspects of the social impairment of Cornelia de Lange syndrome (CdLS) and the association between social anxiety and executive function impairments.
CdLS affects approximately 1 in 40,000 live births [
5] and is associated with intellectual disability as well as specific physical characteristics, including distinctive facial features and limb abnormalities. CdLS is primarily caused by a deletion in the NIPBL gene located on chromosome 5 [
6‐
8] with fewer cases being caused by mutations on the SMC3 gene on chromosome 10 [
9], the SMC1A gene [
10], the RAD21 gene [
11], and the HDAC8 gene [
12]. CdLS is associated with mild to profound intellectual disability [
13] and a discrepancy between expressive and receptive language skills [
13‐
15].
To date, the social impairment in CdLS has been characterised by social communication difficulties, selective mutism, social anxiety and extreme shyness [
16‐
21]. Our recent research has indicated that individuals with CdLS display less sociability than those with Angelman syndrome, DS and Rubinstein-Taybi syndrome and similar sociability to those with FXS and autism spectrum disorder (ASD), two neurodevelopmental disorders similarly associated with social withdrawal and social anxiety [
20]. Children with CdLS have also demonstrated lower levels of social motivation and enjoyment than those with Angelman and Cri du Chat syndromes [
22].
Interestingly, both social anxiety and sociability reported in CdLS may be dependent on the demands of the social situation presented. Richards and colleagues [
19] investigated the behavioural presentation of social anxiety in children with CdLS compared to children with Cri du Chat syndrome. Although no overall differences emerged on the frequency or duration of behaviours indicative of social anxiety, individuals with CdLS were significantly more likely to display social anxiety-related behaviors immediately before and after eye contact and speech. This suggests that the nature and\or level of social demand may play a role in the presentation of social anxiety in individuals with CdLS. In addition, fine-grained analysis conducted by Moss and colleagues [
20] revealed that individuals with CdLS were reported to be more sociable than individuals with FXS and ASD during three out of four social situations with an unfamiliar adult. This research also indicated that individuals with CdLS and other genetic syndromes are significantly more sociable when interacting with a familiar versus unfamiliar adult [
20]. The current study aims to further understanding of the social impairment in CdLS by investigating the effect of the familiarity of an interacting adult, and the nature of social demand, on social anxiety-related behaviour.
There is still no ‘gold-standard’ experimental measure of sociability. However, there has been a move towards the experimental assessment of social impairments in the intellectual disability research literature. This has been most notable in the FXS literature (e.g. [
23,
24‐
26]). Several studies on FXS have employed experimental conditions to provide a more detailed picture of social anxiety and the behavioural responses to specific social situations. It has also allowed researchers to determine if there are specific social situations (antecedents) that evoke social anxiety-related behaviours. Some of this research has also investigated differences in social behaviour as a function of both the familiarity of the interacting adult [
27] and the examiner’s behaviour [
28]. On the basis of this published research, it is clear that experimental methodology involving manipulations of social demand is an effective way to gain a detailed picture of social impairments in individuals who have an intellectual disability. However, careful consideration of the nature of the social tasks is important. One important consideration is the examination of the behaviour of the other person in the interaction which has not been evaluated in the FXS literature on social anxiety. Research in other genetic syndromes, such as DS and Angelman syndromes, has considered the importance of the inter-play between participant and adult behaviour [
29‐
32]. For example, in a study of 13 children with Angelman syndrome, Horsler and colleagues [
29] demonstrated that smiling, touch, eye contact and speech from adults were important factors in eliciting smiling and laughing in participants. The present study aims to explore this through behavioural observation of the interacting adult, as well as the participant.
In addition to documenting the phenomenology of social impairment in CdLS, it is also important to consider the cognitive processes that may be associated with the social impairments in this group. Existing literature on a number of neurodevelopmental disorders suggests that specific social impairments are associated with specific executive function processes. The literature on ASD, for example, has generated a wealth of information implicating ‘theory of mind’ deficits in underpinning socio-behavioural impairments characteristic of the disorder [
33]. Interestingly, research has demonstrated that theory of mind deficits in FXS are likely to be accounted for by impairments in working memory [
34]. More recent research has also identified that specific executive processes may be related to the social impairments reported in ASD. For example, a study examining the association between executive functioning and joint attention impairments in children with ASD found that ventromedial test performance was strongly associated with joint attention skills [
35]. These studies demonstrate that social impairments may be subserved by impairments in executive functioning.
In the current study, the relationship between executive functioning and social impairments were examined in order to identify whether impairments in social interactions in CdLS may be associated with specific cognitive impairments. As no gold-standard assessment of social anxiety exists for this population, the study employed novel experimental conditions which manipulate systematically both the
nature of social demand and the
familiarity of the other person in the interaction, so these effects on participants’ behaviour, including expressive language, can be examined. The behaviour of the other person in the interaction was also examined. A similar approach has been employed in younger children with CdLS before, highlighting the success of this methodological approach in this population [
22]. As DS is associated with a well-delineated phenotype [
4,
36,
37], the current study employed a contrast group of individuals with DS to control for the effect of degree of disability and expressive language difficulties. Importantly, chronological age is likely to be an important factor in social impairment. Existing literature indicates an increase in social anxiety and a reduction in sociability with chronological age, with these social impairments being particularly prominent in late adolescence and early adulthood. Therefore, the current study assessed social impairment in adolescents and adults [
17,
20].
To summarise, the aims of the current study were to:
1.
Investigate whether the familiarity of the interacting adult (hereinafter referred to as examiner) and the nature of social demand impacts differentially on behaviour indicative of social anxiety in adolescents and adults with CdLS and a matched group of participants with DS. It was hypothesised that the CdLS participant group would show more behaviours indicative of social anxiety than the DS group, and that these behaviours would be more prominent in conditions involving an unfamiliar examiner and in conditions with communication demands.
2.
Investigate the association between social anxiety and executive function in participants with CdLS, compared to participants with DS. It was hypothesised that compromised executive function would be correlated with social anxiety. Whether or not this would be syndrome-specific was not possible to predict due to limited literature.
Discussion
This novel experimental study assessed the phenomenology of the social impairment in verbal adolescents and adults with CdLS in contrast to a group of adolescents and adults with DS. This is the first study on social anxiety in CdLS to employ a robust factorial, experimental design, placing different social demands on participants whilst varying familiarity, in order to examine which factors evoked behaviours indicative of social anxiety. The study examined the relationship between any social impairments identified in the CdLS group and cognitive functioning in order to identify whether there was preliminary evidence for specific cognitive impairments underpinning specific social impairments in this group.
The most striking difference identified between the two groups was in the duration of participant verbalisation. The CdLS group showed significantly less verbalisation than the DS group in the familiar and unfamiliar Voluntary Social Interaction and Performance conditions, whilst no significant group difference was observed in the Required Social Interaction condition where there was an explicit expectation to verbalise. It appears that there are specific social demands in the Voluntary Social Interaction and Performance conditions which reduce verbalisation in the CdLS group. The two conditions which showed group differences in verbalisation rely more heavily on participants being able to initiate speech, so it may be that this is a particular difficulty for the CdLS group. For example, verbalisation in the Voluntary Social Interaction condition relies on participants being able to initiate speech to comment (offering information) on photographs or respond to a comment made by the examiner on a photograph (response), and there is no explicit expectation for the participant to do this. Taken together, these findings suggest that individuals with CdLS have a specific difficulty with the initiation of speech, particularly when the expectation to do so is implicit, which results in a marked reduction in verbalisation when social demands involving the initiation of speech are placed upon individuals with CdLS. Interestingly, participants with CdLS also looked at the examiner for longer than the DS group, indicating that participants with CdLS are not demonstrating complete social withdrawal, but rather the lack of social motivation is specific to verbalisation. It is unlikely that these differences in verbalisation were a product of expressive language deficits in the CdLS as the two participant groups did not differ on the Expressive Language Subdomain of the VABS. Although not a direct measure of expressive language, this measure, completed by parents, is more likely to reflect the abilities of participants with CdLS due to the elevated rates of selective mutism in this population. However, future research should examine this further to disentangle the effects of expressive language abilities on verbalisation in social situations which differ in terms of expectation of verbalisation.
This is the first empirical evidence showing a reduction in speech, in adolescents and adults with CdLS that may be due to a specific difficulty in the initiation of speech. These findings contribute to the sparse literature on social impairments in CdLS. To date, only one study has been published on the phenomenology of social anxiety in CdLS and this study found no significant difference in communication, which included both verbal and non-verbal communication, between children with CdLS and children in a comparable contrast group [
19]. Although these findings do appear to contrast with results reported in the current study, where we report significantly less verbalisation in individuals with CdLS compared to those with DS, these differences were particularly prominent in the Voluntary Social Interaction and Performance conditions. Interestingly, Richards and colleagues [
19] reported that individuals with CdLS were significantly more likely to display social-anxiety related behaviours immediately before and after eye contact and speech, suggesting that social anxiety is heightened in CdLS, particularly at the point of speech initiation. The consistency of findings indicating that social anxiety in CdLS is mediated by the type of social situation is particularly interesting given the different ages of participants across samples. Specifically, the mean age of participants in the current study was 22 years, whereas the mean age of participants in Richards et al. [
19] was 11 years. Socio-behavioural characteristics have been reported to change with age in CdLS, such that social anxiety increases and sociability decreases during early adulthood [
17,
20].
The findings in the current study therefore indicate that specific social demands reduce verbalisation in individuals with CdLS, with the familiarity of the other person being relatively unimportant. However, more in-depth analysis regarding the type of verbalisation revealed some empirical evidence for the effect of familiarity in the Voluntary Social Interaction condition. Specifically, the CdLS group responded significantly less to comments made by the unfamiliar examiner than the DS group, yet no significant difference was found between the groups in responding to the familiar examiner in this condition. This suggests that the presence of an unfamiliar examiner caused a significant reduction in responses by the CdLS group, providing support for the effect of familiarity on social interactions in CdLS. These results support previous literature indicating that the familiarity of the other person in the interaction does affect sociability in adolescents and adults with CdLS [
17,
20,
54].
Interestingly, no significant differences were found between the groups on some additional indicators of social anxiety such as fidgeting and non-verbal behaviour. In addition, the CdLS group actually showed significantly more positive facial expression with the familiar and unfamiliar examiners in the Performance condition and looked significantly longer at the familiar examiner in the Performance condition than the DS group. These are unexpected findings given that a longer duration of positive facial expression and a longer duration of looking in the direction of the examiner would not be expected if social anxiety was evident in the CdLS group. This supports the notion that the lack of social motivation or engagement in individuals with CdLS is specific to verbalisation and is not reflective of more global social withdrawal. It is likely that a specific communication problem affecting the initiation of speech makes it appear that individuals with CdLS show anxiety in social situations. Although this is possible, the reported effect of the presence of unfamiliar people on levels of sociability in the literature for individuals with CdLS would suggest that there is some anxiety-related difficulty in this group. Therefore, it may be that there is a communication problem which is enhanced by anxiety caused by the presence of unfamiliar people. A positive facial expression and looking in the direction of the examiner may then serve to compensate for the lack of verbalisation in demanding conditions or act as a coping strategy, prompting the examiner to speak on their behalf. This is supported by the fact that these behaviours were shown in the Performance condition where the most difficulties in verbalisation were evident.
Group differences were found in the duration of examiner verbalisation in the Voluntary Social Interaction and Performance conditions. Familiar and unfamiliar examiners showed significantly more verbalisation in the Performance condition with significantly more prompts and responses being used for the CdLS participants compared to the DS participants. It appears that the examiners tried to help the CdLS participants, although, this increase in verbalisation by examiners may have further increased the demands on the CdLS participants. The familiar examiners in the Voluntary Social Interaction condition also demonstrated this pattern of behaviour as familiar examiners used significantly more comments and prompts with the CdLS group. Interestingly, the Voluntary Social Interaction condition does not involve examiners prompting participants because there is no explicit expectation for participants to verbalise. Perhaps this indicates that the familiar examiners will try to prompt individuals with CdLS to verbalise whenever they can to encourage individuals to verbalise. This research indicates that further exploration of the extent to which participant social behaviour is governed by examiner behaviour is warranted.
There is currently no study of CdLS that examines how participant and examiner behaviour affect one another in social interactions. Therefore, this is the first study to contribute to the literature in this way. Further research examining the inter-play between participant and examiner behaviours would be useful to determine how these may affect one another. Research in other genetic syndromes has already demonstrated the inter-play between participant and adult behaviour. For example, increased laughing and smiling by individuals with Angelman syndrome is evoked by increased social interactions with adults and increased social contact from adults [
1]. This type of research is important in CdLS because it may also help when devising intervention strategies, e.g. asking adults not to prompt the person if it increases further demands on them.
In addition to describing the social impairment in CdLS, the current study also examined whether social impairments observed in the CdLS group were related to specific cognitive impairments. The results indicated that reduction of verbalisations in the CdLS group was associated with impairments in both planning and working memory. This was further supported by the fact that this relationship was not evident in the DS group and the fact that verbalisation was not related to adaptive behaviour in the CdLS group. It cannot be assumed that the relationship between verbalisation and cognitive impairments is causal from the correlational analysis and the use of an informant-based measure of executive functioning. However, the fact that a significant association between these domains was present in the CdLS group, but not in the DS group, suggests that further investigations examining the relationship between planning, working memory and verbalisation in CdLS are needed to understand whether deficits in working memory and planning underpin the difficulties observed in verbalisation in this group. Interestingly, whilst the relationship between inhibition and verbalisation approached significance, verbalisation was not related to the inhibition and attention switching in the same way. One interpretation of these findings concerns the reliance on working memory and planning resources in a social exchange with regard to holding conversational information in mind, and planning a response. Inhibition may similarly be required to restrict prepotent verbal responses; however, attention shifting and emotional control may not be relied upon to the same extent for the verbalisation aspect of a social exchange.
There were several limitations to the current study that may affect the interpretation of the findings. Only behavioural indicators of social anxiety were employed in the current study which meant that it was difficult to fully determine whether a reduction in verbalisation in the CdLS group was due to or affected by anxiety caused by the presence of unfamiliar people. Physiological measures have been used in combination with behavioural indicators of social anxiety in the FXS literature [
24,
25] to provide a more accurate picture about whether the behaviours shown in this group are anxiety-related. Any future research on social anxiety in CdLS should try to incorporate physiological measures as well as behavioural indicators. Furthermore, although preliminary analyses indicate differences in social behaviour between the control condition and experimental conditions, which points to the integrity of the Social Tasks, validation of the measure in a typically developing population would further demonstrate that the conditions differed in social pressure. An additional limitation to the present study is the lack of information available about any anti-anxiety medication that participants may have been taking at the time of data collection. Another drawback is that the levels of social anxiety in adolescents and adults with CdLS may be under-reported. Two individuals with CdLS were recruited for the current study but withdrew before the research visits because parents reported that both individuals were experiencing significant anxiety about being visited by an unfamiliar person. The fact that these and other individuals with CdLS may not have taken part in the current study due to anxiety about being visited by an unfamiliar person indicates that the effect of unfamiliar people on levels of anxiety may be under-reported in this study.