The role of genetics on behavioral outcomes in nonsyndromic sagittal synostosis

Abstract

OBJECTIVE Previous work identified an association between genetics and neurodevelopmental delays in patients with nonsyndromic craniosynostosis. The authors investigated the role of genetic mutations on behavioral outcomes of patients with treated sagittal synostosis. METHODS Parents of children aged 6-18 years with surgically corrected sagittal synostosis were recruited to complete the Child Behavioral Checklist (overall behavioral problems), Conners 3rd Edition-Parent (attention-deficit/hyperactivity disorder), Social Responsiveness Scale 2nd Edition (autism spectrum disorder [ASD]), and Behavior Rating Inventory of Executive Function 2nd Edition (executive function). Genomic analysis was completed, and patients were identified if they had mutations in high probability of loss of function intolerant (pLI) genes (high pLI vs nonhigh pLI). Genetic burden was assessed relative to controls. Multivariate linear regression determined the association of mutations in high pLI genes with behavioral scores, while controlling for sociodemographic factors, age at surgery, surgery type, and IQ. RESULTS Sixteen of 45 patients were in the high pLI group. There were no differences between the groups in terms of sociodemographic factors. A greater proportion of children in the high pLI group scored at or above borderline clinical levels for aggression (18.8% vs 0.0%, p = 0.05) and externalizing problems (31.3% vs 3.7%, p = 0.02). Among children in the nonhigh pLI group, older age at surgery was associated with worse scores on the rule-breaking, aggression, and externalizing problems domains and four out of five ASD domains. CONCLUSIONS Children with treated nonsyndromic sagittal synostosis and mutations in high pLI genes had worse behavioral problems in externalizing behaviors and aggression, whereas older age at surgery was a significant predictor of worse behavioral outcomes in patients without mutations in high pLI genes.