Neurobehavioral phenotype of Kabuki syndrome: Anxiety is a common feature

Abstract

Kabuki syndrome (KS) is a Mendelian Disorder of the Epigenetic Machinery (MDEM) caused by loss of function variants in either of two genes involved in the regulation of histone methylation, KMT2D (34–76%) or KDM6A (9–13%). Previously, representative neurobehavioral deficits of KS were recapitulated in a mouse model, emphasizing the role of KMT2D in brain development, specifically in ongoing hippocampal neurogenesis in the granule cell layer of the dentate gyrus. Interestingly, anxiety, a phenotype that has a known association with decreased hippocampal neurogenesis, has been anecdotally reported in individuals with KS. In this study, anxiety and behavior were assessed in a cohort of 60 individuals with molecularly confirmed KS and 25 unaffected biological siblings, via questionnaires (SCARED/GAS-ID and CBCL/ABCL). Participant age ranged from 4 to 43 years old, with 88.3% of participants having a pathogenic variant in KMT2D, and the rest having variants in KDM6A. In addition, data was collected on adaptive function and positive affect/quality of life in participants with KS using appropriate online surveys including ABAS-III and PROMIS Positive Affect. Survey scores were compared within the KS participants across age groups and between KS participants and their unaffected siblings. We found that children with KS have significantly higher anxiety scores and total behavior problem scores than their unaffected siblings (p = 0.0225, p < 0.0001). Moreover, a large proportion of affected individuals (22.2% of children and 60.0% of adults) surpassed the established threshold for anxiety; this may even be an underestimate given many patients are already treated for anxiety. In this sample, anxiety levels did not correlate with level of cognitive or adaptive function in any KS participants, but negatively correlated with positive affect in children with KS (p = 0.0005). These findings indicate that anxiety is a common neurobehavioral feature of KS. Providers should therefore carefully screen individuals with KS for anxiety as well as other behavioral issues in order to allow for prompt intervention. Neurobehavioral anxiety measures may also prove to be important outcome measures for clinical trials in KS.

Sleep disturbance is a common feature of Kabuki syndrome

“…There was also no significant difference between participants with KS1 (average of 64.7) and participants with KS2 (average of 75.5). It has been previously reported that anxiety is specific neurobehavioral feature of individuals with KS (Kalinousky et al, 2022). When comparing the 56 participant's SCARED/GAS-ID anxiety scores with their sleep scores, we found that sleep issues and anxiety were positively correlated (r = 0.40, p = 0.002).…”

Anxiety in Wiedemann–Steiner syndrome

“…KS1 is a neurodevelopmental disorder caused by mutations in the gene encoding KMT2D , a member of the same family of histone lysine methyltransferases as KMT2A , which is disrupted in WSS. The KMT2 family of proteins methylates H3K4, and pathogenic variants in KMT2D have already been shown to cause elevated risks of anxiety compared to sibling controls in KS (Kalinousky et al, 2022). Cross‐MDEM comparisons will elucidate shared mechanisms for developmental trajectories of select psychopathology.…”

The social phenotype associated with Wiedemann‐Steiner syndrome: Autistic traits juxtaposed with high social drive and prosociality

“…Likewise, pathogenic variants in KDM5B , a H3K4 demethylase, has been similarly linked to intellectual impairment and high risk of ASD (Tseng et al, 2022), with animal models of the disorder showing ASD‐like behaviors (repetitive behaviors, reduced socialization and vocalization, and learning deficits) (El Hayek et al, 2020). However, those with Kabuki syndrome (KS), a genetic disorder most commonly caused by loss of function variants in KMT2D —another related member of the KMT2 methyltransferases involved in methylation of H3K4—present with a relative strength in interpersonal and social communication skills despite higher risk for anxiety (Kalinousky et al, 2022; Mervis et al, 2005; Schrander‐Stumpel et al, 2005). At present, the specific mechanism by which chromatin regulatory systems impact neurogenesis of specific neural substrates involved in social cognition, communication skills and behavior regulation remains unknown.…”