Phenotypic Characterization of Five Children With PACS1 ‐ NDD : Longitudinal Insights Into Development, Behavior, and Brain

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Abstract
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. Autistic traits have been reported in PACS1‐NDD, but systematic longitudinal assessments are lacking. We followed five children (3 females) with genetically confirmed PACS1‐NDD, aged 1.4–6.2 years at entry, over 2–3.5 years (29 assessments). Measures included standardized behavioral and cognitive assessments, eye‐tracking, and structural MRI. Data were compared to 357 autistic and 123 typically developing children from a longitudinal cohort. Children with PACS1‐NDD showed global developmental delays with heterogeneous trajectories. Adaptive and communication profiles overlapped with autistic children, while motor impairments were more pronounced. Vocabulary and grammar were delayed, but pragmatic skills were relatively preserved. All children with PACS1‐NDD exhibited autistic traits with 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 naturalistic contexts. MRI showed globally reduced gray and white matter volumes. These findings provide the first longitudinal, multimodal characterization of PACS1‐NDD, informing clinical care and targeted outcome measures for therapeutic trials, and highlighting the need for larger studies to validate and extend these findings.
Funding Information
  • NCCR Catalysis (51NF40‐185897)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (163859)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (190084)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (202235)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (212653)
  • Fondation privée des Hôpitaux universitaires de Genève
  • Fondation Pôle Autisme

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