Phenotypic characterization of five children with PACS1-NDD: Longitudinal insights into development, behavior and brain

PACS1 neurodevelopmental disorder (PACS1-NDD), also known as Schuurs-Hoeijmakers syndrome, is a rare genetic condition caused by a recurrent de novo mutation in the PACS1 gene. In addition to somatic and clinical features, autistic traits have been reported, although systematic and longitudinal assessments are lacking. We followed five children (3 females) with genetically confirmed PACS1-NDD, aged 1.4–6.2 years at study entry, over a 2–3.5-year period, yielding 29 repeated assessments. Assessments encompassed standardized measures of behavior and cognition, alongside eye-tracking and structural MRI. Data were compared to 357 autistic and 123 typically developing children from our large longitudinal cohort following autistic and typically developing children. Children with PACS1-NDD showed global developmental delays with heterogeneous individual trajectories. Adaptive and communication profiles overlapped with those of autistic children, while motor functioning was more severely affected. Vocabulary and grammar were delayed, but pragmatic skills were relatively preserved. All children exhibited some autistic traits with consistently elevated restricted and repetitive behaviors and milder social-communication difficulties. ADHD symptoms were subthreshold and predominantly inattentive. Eye-tracking revealed preserved social interest but reduced gaze typicality in more naturalistic contexts. Finally, MRI showed globally reduced gray and white matter volumes. In PACS1-NDD, the apparent dissociation between elevated restricted and repetitive behaviors and relatively preserved social communication may suggest opportunities to build on social strengths while addressing motor, adaptive, and executive functioning challenges. Together, these findings provide the first longitudinal, multimodal characterization of PACS1-NDD, inform clinical care and the development of targeted outcome measures for therapeutic trials, and highlight the need for future studies in larger samples to validate and extend these results.