Wiedemann-Steiner syndrome (WSS) is a rare Mendelian disorder of epigenetic machinery caused by a mutation in KMT2A, with hallmark features that include intellectual disability and developmental delay. Animal models have helped identify the critical roles KMT2A plays in prefrontal neuron maturation and executive function (i.e. working memory) development. However, the neurobehavioral phenotype of individuals with WSS, including executive functioning, remains poorly characterized. Accordingly, this study aimed to 1.) examine the neurobehavioral profile (adaptive, psychosocial, and executive functioning) associated with WSS and 2.) the correlations between executive functioning and these domains.

A total of 25 mothers of individuals with WSS (13 females, Mean age=12.78 years, SD=7.88) completed a combination of parent-informant questionnaires. The caregivers completed the Adaptive Behavior Assessment System 3rd Edition (ABAS-3), the Strengths and Difficulties Questionnaire (SDQ), and a version of the Behavior Rating Inventory of Executive Function (BRIEF). Descriptive analyses were conducted to examine proportion of the sample with clinically significant concerns on the BRIEF and SDQ, and low to very low adaptive skills based on ratings on the ABAS-3. Partial correlations were computed to examine the relationships between overall executive functioning (BRIEF General Executive Composite, GEC) with adaptive domains (ABAS-3 Conceptual, Practical, Social), and psychosocial functioning (SDQ Emotional Problems, Conduct Problems, Hyperactivity, Peer Relations, Prosocial Behaviors) while accounting for age. Associations that survived Benjamin Hochberg correction are reported.

Of our sample, 64% were rated in the very elevated range for executive functioning problems (BRIEF GEC), with a greater proportion endorsing clinically significant concerns with behavior regulation (68%) relative to cognitive regulation (48%). Majority of participants was rated in the low or very low range for ABAS-3 General Adaptive Composite (72%), with a greater proportion showing problems in Practical (64%) and Conceptual Domains (64%) relative to Social Domain (44%). Among those who completed the SDQ, caregiver ratings implicate elevated Total Problems (90%) with greater concerns observed in Emotional Problems (62%), Hyperactivity (81%) and Peer Relationship difficulties (95%). After controlling for age, executive functioning difficulties were associated with weaker skills in the Conceptual (r=-0.56, p=0.003), Social (r=-0.44, p=0.028) and Practical domains (r=-0.51, p=0.009); as well as more Hyperactivity (r=0.49, p=0.025) and Conduct problems (r=0.58, p=0.007). Specifically, day-to-day challenges with executive functions were related to weaker adaptive skills in Self-Care (r=-0.54, p=0.006), Self-Direction (r=-0.53, p=0.007), and Communication (r=-0.49, p=0.01).

Individuals with WSS are at risk for executive functioning deficits, which in turn may impact the development of and/or day-today application of adaptive skills and behavior regulation. Future clinical research should further explore the development and neurophysiology of executive functions among those with WSS with multidisciplinary methods, including behavioral, cognitive and neurobiological metrics. Those working with individuals with WSS may consider executive functioning interventions, which may yield indirect benefits to self-regulation and daily use of life skills.