Association Between Motor Function and Higher-Order Repetitive Behaviors in Monogenic Autism Spectrum Disorder

ImportanceMotor skill impairments affect up to 87% of children with autism spectrum disorder (ASD) and are associated with greater severity of repetitive behaviors. Yet, most research examining this relationship has treated ASD as a unitary condition. Understanding whether motor-behavior relationships differ by genetic etiology could inform stratified approaches to ASD research and clinical care. ObjectiveTo determine whether the relationship between motor function and restricted and repetitive behaviors (RRBs) differs between children with monogenic forms of ASD (SHANK3, DYRK1A, or SCN2A variants) and children with idiopathic ASD. Design, Setting, and ParticipantsMatched cohort cross-sectional study using data from the Simons Foundation Powering Autism Research for Knowledge (SPARK) database. Children with loss-of-function variants in SHANK3, DYRK1A, or SCN2A were matched to children with idiopathic autism and intellectual disability. Main Outcomes and MeasuresMotor function was assessed using the Developmental Coordination Disorder Questionnaire (DCDQ). Repetitive behaviors were assessed using the Repetitive Behavior Scale-Revised (RBS-R), with subscales categorized as lower-order (stereotyped, self-injurious) or higher-order (compulsive, ritualistic, sameness, restricted interests). The primary analysis compared motor-RRB correlations between groups. ResultsThe sample included 93 children with monogenic autism (SHANK3, n=34; DYRK1A, n=46; SCN2A, n=13) and 787 matched children with idiopathic ASD. In idiopathic ASD, motor function was negatively correlated with RRBs (r = -0.156); in monogenic ASD, this reversed to a positive correlation (r = +0.185; {Delta}r = 0.341, P = 0.002). This reversal was specific to higher-order RRBs (idiopathic r=-0.106; monogenic r=+0.234; {Delta}r=0.339, 95% CI 0.124-0.535, P=0.002) and was not observed for lower-order RRBs ({Delta}r=0.212, P=0.05). All three genes showed positive correlations (SHANK3 r=+0.033; DYRK1A r=+0.262; SCN2A r=+0.623) with no significant heterogeneity (P=0.153). Conclusions and RelevanceThe relationship between motor function and repetitive behaviors differs by genetic etiology, with children with monogenic ASD showing a positive motor-RRB correlation specific to higher-order behaviors, opposite to the negative correlation observed in idiopathic ASD. This reversal was consistent across three molecularly distinct genes. These findings support stratifying autism research and clinical care by genetic etiology. KEY POINTSO_ST_ABSQuestionC_ST_ABSDoes the relationship between motor function and restricted and repetitive behaviors (RRBs) differ between children with autism spectrum disorder (ASD) attributable to SHANK3, DYRK1A, or SCN2A variants and children with idiopathic ASD? FindingsWe conducted a matched cohort cross-sectional study comparing correlations between motor function and RRBs in children with monogenic ASD versus children with idiopathic ASD and intellectual disability. Motor function was negatively correlated with RRBs in children with idiopathic ASD but positively correlated in children with monogenic ASD. MeaningGenetic variants may alter behavioral organization, supporting the value of stratifying populations of individuals with ASD by genetic etiology in both research and clinical care.