The behavioural phenotype of Coffin-Siris syndrome beyond diagnostic categories: recognizing behavioural heterogeneity

Background Children with Mendelian neurodevelopmental disorders (NDDs) carry genetic variations that increase the risk for a variety of behavioural problems. Behavioural heterogeneity in these conditions often crosses traditional behavioural syndrome classification categories, highlighting the limitations of the use of these categorical classifications for outlining genetic risk. Instead, specific domains of behavioural functioning that are important for daily activities may be of relevance to understand the risk of developmental impact. Coffin-Siris syndrome (CSS), caused by pathogenic variants in chromatin remodeling genes including ARID1B, is increasingly well-characterized genetically, but the impact on behavioural dimensions contributing to its phenotype so far remain unclear. Methods Behavioural functioning was assessed using a multi-instrument approach to capture both broad patterns of emotional and behavioural problems and more specific symptom dimensions related to ADHD and ASD. For general screening of behavioral problems the CBCL (Child Behaviour Checklist) was used. In addition symptoms of ADHD were measured with the SWAN (Strengths and Weaknesses of ADHD Symptoms), and symptoms of ASD with the SRS-2 (Social Responsiveness Scale). Analyses focused on symptom severity relative to normative expectations, the proportion of children exceeding clinical thresholds, age-related variability and associations with severity of intellectual disability. Results CBCL analyses indicated that children with CSS showed elevated difficulties across multiple domains, with prominent attention problems, atypical or preoccupying thoughts, and social behavioural challenges. Dimensional analyses revealed that, although both inattention and hyperactive-impulsive behaviours were elevated, attentional deficits were more pronounced. Similarly, all ASD-related dimensions were elevated, but social cognition and repetitive behaviours were most prominent, whereas social motivation was relatively preserved. Symptom severity showed no association with age or intellectual disability. Conclusions These findings suggest that behavioural difficulties in CSS reflect selective elevations across specific behavioural dimensions rather than a behavioural syndrome that is defined by a specific combination of symptoms. A dimensional perspective highlights variability in attention regulation, cognitive processing, and social behaviour, providing a framework to link genetic variation in risk to individual developmental outcomes. Conceptualizing the impact of CSS in behavioral dimensions that may be at risk may provide directions towards targeted and personalized interventions and guide assessment strategies for genetically defined NDDs. Clinical trial number Not applicable.